Type 1 diabetes: diagnosis and management of type 1 diabetes

Transcription

Type 1 diabetes: diagnosis and
management of type 1 diabetes
in children and young people
National Collaborating Centre for Women’s and Children’s Health
Commissioned by the National Institute for Clinical Excellence
Evidence Tables
September 2004
RCOG Press
Evidence tables must be read in conjunction with the main guideline.
References cited are listed in the main guideline.
Published by the RCOG Press at the Royal College of Obstetricians and Gynaecologists, 27 Sussex Place,
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www.rcog.org.uk
Registered charity no. 213280
First published 2004
© National Collaborating Centre for Women’s and Children’s Health
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ISBN 1-904752-05-5
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Evidence tables
Note: Chapter numbers for evidence tables relate to the equivalent chapter in the full guideline
Chapter 3
Chapter 4
Chapter 5
Chapter 6
Diagnosis and initial management
5
3.1
Diagnosis
5
3.2
Management from diagnosis
8
3.3
Natural history of type 1 diabetes
13
3.4
Essential education at diagnosis
25
Ongoing management
27
4.1
Education
27
4.2
Insulin regimens
29
4.3
Insulin preparations
47
4.4
Methods of delivering insulin
4.5
Non-insulin agents (oral antidiabetic drugs)
109
4.6
Monitoring glycaemic control
123
4.7
Diet
173
4.8
Exercise
180
4.9
Alcohol, smoking and drugs
183
89
4.10 Long-distance travel
189
4.11 Immunisation
190
Complications and associated conditions
192
5.1
Hypoglycaemia
192
5.2
Diabetic ketoacidosis
202
5.3
Surgery
221
5.4
Intercurrent illness
221
5.5
Screening for complications and associated conditions
221
Psychological and social issues
236
6.1
Emotional and behavioural problems
236
6.2
Anxiety and depression
238
6.3
Eating disorders
243
6.4
Cognitive disorders
246
6.5
Behavioural and conduct disorders
250
6.6
Non-adherence
253
3
Caesarean section
Chapter 7
4
6.7
Psychosocial support
255
6.8
Adolescence
264
Continuity of care
266
7.1
Communication between organisations
266
7.2
Transition from paediatric to adult care
268
Chapter 3 Diagnosis and initial management
3.1
Diagnosis
Study
Population
Intervention
Outcomes
Results
Neu et al,
200313
2121 children and
young people with type
1 diabetes who
presented between
1987 and 1997
None
% who presented with diabetic
ketoacidosis
All ages 0–15: 26.3% (558/2121)
Those aged 0–4: years 36.0%
Questionnaire sent to
paediatricians and physicians
who provide care for children
with diabetes
1) % of paediatricians who
provide care for children with
diabetes who expressed a
specialist interest in diabetes
1) 78% of the paediatricians
expressed a specialist interest in
diabetes
Comments
Design
EL
Observational III
study
Aged up to 15 years
Germany
Jefferson et al,
200318
1998 survey of 302
paediatricians identified
as providing care for
children with diabetes
aged under 16 years;
244 returned
questionnaire
UK
2) % of paediatricians who
provide care for children with
diabetes in a clinic dedicated to
their care
3) % of clinics that had a
specialist nurse
Children and young
people cared for
n = 17 192
Survey
III
2) 91% saw children in a designated
diabetic clinic
3) 93%
4) 66%
5) 47%
6) 65%
4) % of specialist nurses that were
7) 25%
trained in the care of children
5) % of clinics that had a nurse to
patient ratio of more than 1 to
100
6) % of clinics that had a
paediatric dietitian
7) % of clinics that had some
form of specialist psychology or
counselling available
Evidence tables
5
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Smith et al,
199820
82 randomly selected
patients with diabetes
from a diabetes clinic
Records kept through an
electronic management system
(n = 39)
1) Number of foot examinations
per year
1) 2.9 ± 1.1 vs. 1.8 ± 1.4, p < 0.001
Only 7 in each group
with type 1 diabetes
Cohort
IIb
Mean age 62.4 ± 12
years for the group who
had electronic
management system,
60.0 ± 17 years for the
group who had
traditional paper
medical records
versus
traditional paper medical records
(n = 43)
3) 76.9 vs. 51.2, p = 0.016
3) Number of patients having four 4) 9.7 ± 1.7% vs. 10.2 ± 1.9%
glycated haemoglobin tests in the 5) No difference
last year
4) Most recent glycated
haemoglobin level
5) Dilated eye examinations in
the previous year, documentation
of self-monitoring of blood
glucose, measurement of urinary
microalbumin lipid profile in the
previous year, tobacco status and
advice to quit, diet
documentation, diet education,
diabetes self-management
education
USA
Stroebel et al,
200219
2) Number of blood pressure
readings per year
2) 3.6 ± 1.6 vs. 2.7 ± 1.6, p < 0.0035
1083 patients with
29 physicians and nurse teams
Number of patients that
diabetes (unknown type)
completed the glycated
Randomised to one of three
haemoglobin test
Mean age of groups: A
implementation strategies for
67 ± 12, B 65 ± 13, C
using a diabetes registry
65 ± 14 years
A: Hot lists only (list of patients
USA
not complying with glycated
haemoglobin or lip measurement
or who have not achieved desired
control of glycated haemoglobin
level, low-density lipoprotein or
blood pressure level)
B: Hot lists and team time (20
min block in appointments at start
of study and every 2 months to
review list with team)
C: Hot lists, team time and letter
form appointment secretary aimed
to re-engage the patients with the
practice
Trial length: 6 months
No significant difference among
groups for performance in
completing glycated haemoglobin
No significant change in the
percentage of patients whose
glycated haemoglobin values fell
below target of 9.3% for any group
between the start and end of the
study
Analysed as a before/after Cluster RCT
study
No description of
randomisation
Unsure if cluster analysis
performed correctly due
to lack of information
Ib
Type 1 diabetes
6
Record keeping and registers
Record keeping and registers (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Jefferson et al,
200318
1998 survey of 302
paediatricians identified
as providing care for
children with diabetes
aged under 16 years;
244 returned
questionnaire
Questionnaire
% who use a computerised
database
34% of consultants reported using a
computer database
Survey
III
Which databases
‘Twinkle’ was used in 19 centres,
‘Novonet’ was used in five centres
and ‘Diamond’ was used in four
centres. The majority of services
were using a locally developed
database
Children and young
people cared for
n = 17 192
UK
Evidence tables
7
Management from diagnosis
What is the optimum location (home versus hospital) for the management of children and young people with newly diagnosed type 1 diabetes?
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Clar et al,
200330
6 studies in reviewed
total of 237 children
Home-based care and/or
outpatient management
1) Metabolic control (at 2 or 3
years’ follow-up)
Studies included
Systematic
review
Ia
2 RCTs
versus
4 cohort studies, 3
retrospective and one
prospective
hospital-based care
2) Psychosocial and behavioural
variables
1) One trial showed improvement,
no other studies found an
improvement
No description of
RCT
randomisation, other than
Unblinded
that it was stratified by
age group and sex
Ib
3) Diabetes complications within
two years
2) Results inconclusive. No
differences found in some studies;
other studies did find differences,
with one study finding significant
results in some selected subscales,
and another study finding an
outpatient/home group had
significantly better treatment
adherence, familial relationship and
sociability, but with further analysis
this seemed to be only in some
selected socio-economic subgroups
RCTs:
Dougherty 199924,
Simell 199525
Cohort studies:
Chase 199226,
Galater198227,
Siminerio 199929,
Spaulding 197628
3) No differences found
Dougherty et al, 63 consecutive children
199924
presenting to emergency
department with newly
diagnosed type 1
diabetes
Children home-based
management (n = 32)
versus
children hospital-based
management (n = 31)
2 year recruitment
period (October 1989 to Trial length: 3 years’ follow-up
September 1991)
Inclusion criteria:
age > 2 years, no sibling
with type 1 diabetes,
living at home and
within 1 hour of
hospital
Cases: mean age 10.7
years, 13 males
Controls: mean age 9.8
years, 15 males
Canada
1) Glycated haemoglobin (HbA1c) 1) HbA1c values lower in homebased group:
2) Mean nursing service hours per
patient (total services)
At 2 years: 6.1% vs. 6.8%, p < 0.05
3) Diabetes knowledge (Diabetes
Knowledge Scale), adherence to
treatment (Diabetes Regimen
Adherence Questionnaire) and
family impact (Impact on Family
Scale)
At 3 years: 6.4% vs. 7.1%, p < 0.02
4) Stress (Perceived Stress Scale)
4) For child at 1 month: 22.1 ± 7.6
vs. 14.6 ± 9.6, p < 0.05
5) Satisfaction (Satisfaction Scale)
and child behaviour (Achenbach
Child Behaviour Checklist)
2) 58.9 vs. 17.3 hours (difference
41.6 hours), p < 0.001
3) Not significantly different at 1, 12
or 24 months for parent or child
For child at 12 and 24 months: not
statistically different
6) Social cost (assessed for 2
For parent: not significantly different
years) and severe diabetes-related at 1, 12 or 24 months
adverse events
5) Not significantly different at 1, 12
or 24 months for parent or child
6) Not significantly different
Type 1 diabetes
8
3.2
What is the optimum location (home versus hospital) for the management of children and young people with newly diagnosed type 1 diabetes? (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Simell, 199525
60 consecutive nonketoacidotic children
newly diagnosed with
type 1 diabetes.
Children home-based
management (n = 30)
HbA1c
No significant difference between
treatment modes
Unknown if outcome
RCT
assessors were blinded to
treatment allocation
Ages unspecified
children hospital-based
management hospitalised for
5.9 ± 1.0 days (mean ± SD)
(n = 30)
Finland
versus
Insulin dosage
C-peptide positivity
Design
EL
Ib
Method of randomisation
not reported
Abstract published only
Trial length: 2 years’ follow-up
Forsander et al, 36 newly diagnosed
children with type 1
200035
diabetes
Aged 3–15 years
April 1986 – January
1989
Early discharge to hospital family
apartment (n = 19)
1) Glycaemic control HbA1c
1) No significant difference
2) Hospital readmission
versus
Method of randomisation RCT
not reported
Ib
Unknown number of
days each group spent in
hospital
conventional hospital care
(n = 19)
Sweden
Kirk et al,
200332
36 newly diagnosed
diabetes
Retrospective survey initial
management over 8 years
1) Number able to be fully home- 1) 5/36 (14%)
managed from diagnosis
2) From April 1995 onwards mean
2) Mean number of days newly
of 2.0 days, a change from 1994
diagnosed patients were admitted when average was 6.3 days.
for
236 newly diagnosed
diabetes
Home-based care
versus
1) Proportion of children
managed without hospital
admission
Aged 10–14 years
1979–1988
hospital-based care
2) Duration of admission
Aged 0–19 years
1994 – April 2002
NonIII
experimental
descriptive
study
UK
Swift et al,
199374
3) Comparison of readmission
rates and glycated haemoglobin
UK
1) 138/236 supervised home
management
2) 1979–1980: 7 days, 1987– 1988:
3 days
Possible bias: children
admitted at diagnosis
different from ones not
admitted
NonIII
experimental
descriptive
study
3) 30 (22%) vs. 40 (41%), p = 0.004
4) Concentration of glycated
haemoglobin
1182 newly diagnosed
diabetes
Outpatient care
Aged < 18 years
inpatient care
1978–1988
Colorado, USA
versus
Proportion of patients receiving
outpatient-only care
Total (all children) 23% vs. 77%
1978: 6% vs. 94%
1988: 35% vs. 65%
NonIII
experimental
descriptive
study
9
Evidence tables
Kostraba et al,
199233
Study
Population
Intervention
Outcomes
Results
Comments
Design
Chase et al,
199226
121 newly diagnosed
diabetes
Home-based care (≤ 1 inpatients
night) (n = 41)
1) Average length of stay
1) 4.5 nights
2) Severe hypoglycaemia
admitted
NonIII
experimental
descriptive
study
admitted
NonIII
experimental
descriptive
study
Aged < 18 years
1980–1984
Colorado, USA
Siminerio et al, 32 newly diagnosed
199929
diabetes
versus
hospital-based care (≥ 2 inpatients
4) Diabetes-related complications 4) No significant difference
nights) (n = 80)
5) HbA1
Home-based education (n = 16)
versus
Aged 6–18 years
hospital-based education (n = 16)
1980–1984
Trial length: survey 1 month after
diagnosis
USA
3) Diabetic ketoacidosis
1) Readmission/emergency room
visits
2) Knowledge (The test of
diabetes knowledge, revision 5)
3) Responsibility of care (the
diabetes family responsibility
questionnaire)
4) No significant difference in
adherence measured by the self care
inventory, however:
4) Adherence (the self care
inventory):
Blood glucose regulation: 4.47 vs.
4.93, p = 0.008
Scale 1–5, higher number is
closer adherence to instructions
Emergency precautions: 4.71 vs.
4.44, p < 0.001
5) Family functioning (the family
assessment device):
5) Behaviour control: 1.58 vs. 1.68,
p = 0.004
Score 1–4, lower number is
healthier family functioning
Problem solving: 1.63 vs. 1.79,
p = 0.060
6) Coping (the coping health
inventory for parents)
Roles: 1.98 vs. 2.13, p = 0.040
7) Coping (the coping health
inventory for children)
8) Quality of life (modified from
the DCCT research group’s
diabetes quality of life measure)
6) Maintaining family integration: no
significant difference
Maintaining social support: no
Understanding medical situations
through communication: no
7) Mood, irritable, acts out: no
8) Satisfaction: no significant
difference
Diabetes impact: no significant
difference
Diabetes worry: no significant
difference
EL
Type 1 diabetes
10
Study
Population
Hamman et al, 305 newly diagnosed
198534
diabetes
Aged < 18 years
1978–1982
Colorado, USA
Intervention
Outcomes
Results
Comments
Design
Outpatient-only medical care at
diagnosis (n = 37, 70.5 person
years follow-up)
1) Hospitalisation episodes
1) Rate 7.1 vs. 26.3 vs. 23.2
Children admitted at
diagnosis had more
severe symptoms at
onset: this may cause
bias in the relationship
between the type of
medical care received
and clinical outcome
NonIII
experimental
descriptive
study
Alternative assigned
Controlled
IIa
study without
randomisation
Alternative assigned
Controlled
IIa
study without
randomisation
versus
outpatient and inpatient care at
diagnosis (n = 145, 277.8 person
years follow-up)
2) Ketoacidosis episodes
Inpatient and outpatient compared
with outpatient group: RR 3.7 (95%
3) Insulin reactions severe enough CI 1.5–9.0)
to result in loss of consciousness
(assumed to be severe
Inpatient relative to outpatient
hypoglycaemia)
group: RR 3.3 (95% CI 1.3–8.1)
2) Rate 11.3 vs. 35.3 vs. 24.3
versus
EL
CI 1.5–6.3)
inpatient-only care at diagnosis
(n = 123, 271.1 person years
follow-up)
group: RR 2.1 (95% CI 1.0–4.6)
3) Rate 11.3 vs. 10.8 vs. 11.4
CI 0.3–3.3)
group: RR 1.0 (95% CI 0.9–1.1)
Simell et al,
199136
Simell et al,
199531
61 newly diagnosed
diabetes
Short-term initial stay (mean 9
days, range 4–13 days) (n = 31)
versus
Aged 0–15
January 1986 –
March 1987
long-term initial stay (mean 23
days, range 16–35 days) (n = 31)
Finland
Trial length: 2 years’ follow-up
61 newly diagnosed
diabetes
Further analysis from study above
Finland
2) C-peptide positive
3) Insulin dosage
Psychosocial ability to function:
1) Ability to function
2) Achievement of own goals
3) Fears
4) Anxiety
5) Family confidence in coping
with diabetes
11
Evidence tables
Aged 0–15 years
January 1986 –
March 1987
1) Metabolic control
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Sundlin et al,
199673
36 newly diagnosed
diabetes
Early discharge to hospital family
apartment (n = 19) – received
family therapy from
psychotherapist (7 sessions over 6
months) as well as
multidisciplinary team support
1) HbA1c
1) In subgroup of children aged
8–15 years (n = 12), worse HbA1c
seen (p < 0.05) at two years was
attributed to three extreme scores
Further analysis from
Forsander et al, 200035
RCT
Ib
Aged 3–15 years
April 1986 –
January 1989
Sweden
versus
conventional hospital care
(n = 19) with multidisciplinary
team support
2) Intelligence tests, children’s
behaviour checklist, family
climate and family relations
Method of randomisation
not reported
Unknown number of days
each group spent in
hospital
Type 1 diabetes
12
3.3
Natural history of type 1 diabetes
Partial remission phase in children with type 1 diabetes?
Physiological characteristics of the partial remission phase in children with type 1 diabetes
Study
Population
Intervention
Outcomes
Results
Comments
Lombardo et
al, 200239
67 children with
newly diagnosed
type 1 diabetes
Follow-up of children at
diagnosis, 3, 6, 12 and 18
months
Analysis of factors that may affect
partial remission occurrence and
duration:
80.6% (54/67) experienced partial remission
for 3 or more months, 41.7% experienced
partial remission that lasted more than 12
months, 16.4% experienced partial
remission that lasted more than 24 months
Remission defined as
HbA1c < 7% and insulin
dosage < 0.5 units/kg/day
Prospective observational
study III
Aged 7.9 ± 4.0
(1.4–17.3) years
Italy
Sex
Ketoacidosis at diagnosis
Age under or over 5 at diagnosis
-cell residual function evaluated
after glucagons stimulation test
Duration of symptomatic period
preceding diagnosis
Admission length
Parental education level
Blood pH and base excess at
diagnosis
HbA1c at diagnosis
Design
EL
Mean duration of remission period was
11.7 ± 8.9 months
The lowest average insulin requirement was
recorded 3 months after initial diagnosis for
the children (0.4 ± 0.3 units/kg/day)
Children diagnosed before the age of 5 had
a significantly lower chance of having a
remission period than the children diagnosed
after the age of 5 (remission period at least 3
months: 50 vs. 90.1%, p < 0.0005). Children
diagnosed before the age of 5 had a
significantly shorter average remission period
than the children diagnosed after the age of
5 (7.3 ± 8.4 vs. 13.1 ± 8.6 months, p < 0.05)
-cell residual function evaluated after
glucagons stimulation test (basal and 6 min
C-peptide) was statistically different in the
partial remission patients compared with
those children who experienced no
remission (baseline: 0.6 ± 0.5 vs.
0.4 ± 0.2 nmol/l, p < 0.005; 6 min: 1.1 ± 0.8
vs. 0.7 ± 0.4 nmol/l, p < 0.01)
13
Evidence tables
No statistically relevant difference in
whether the child had a partial remission or
not with the variables of: duration of
symptomatic period preceding diagnosis,
admission length, parental education level,
blood pH and base excess at diagnosis, and
HbA1c at diagnosis. No statistically relevant
difference in partial remission duration
comparing sex of the children, or presence
of ketoacidosis at diagnosis
Study
Population
Bonfanti, et al, 215 children and
young people with
199840
newly diagnosed
type 1 diabetes
Age median 8.9
(0–22) years
Italy
Intervention
Outcomes
Results
Comments
Follow-up of children at
Analysis of factors that may affect 11% (22/192) experienced remission at the 3 Remission defined as
diagnosis, 3, 6 and 12 months remission occurrence and residual month follow-up clinic visit, 8% (15/190)
HbA1c < 6% and insulin
C-peptide excretion:
experienced remission at the 6 month
follow-up clinic visit, 5% (8/169)
Age
experienced remission at the 12 month
follow-up point clinic visit
Glutamic acid decarboxylase
(GAD) antibodies
Remission was less prevalent in the younger
Acidosis at diagnosis
Sex
Human leucocyte antigen (HLA)
antibodies
IA-2 antibodies (tyrosine
[phosphatase autoantibodies)
patients (0/42 ≤ 5 years vs. 10/63 (16%)
5.1–9 years, vs. 2/43 (5%) 9.1–12 years vs.
10/44 (23%) > 12 years, p = 0.01). Residual
C-peptide secretion throughout the first year
of disease was significantly reduced in
children with disease onset before the age of
5 years (p < 0.001)
Remission was less prevalent in patients will
GAD antibodies compared with ones
without (8/128 (6%) vs. 14/64 (22%),
p = 0.001). GAD antibodies had a significant
independent association with decreased Cpeptide secretion at 6 months of follow-up
(p = 0.02)
Acidosis at diagnosis was significantly
related to C-peptide secretion at onset
(p = 0.007) and after 3 months of follow-up
(p = 0.007) but not thereafter
Sex, HLA and IA-2 antibodies were not
independently associated with C-peptide
secretion, insulin requirement or remission
in the first year
Design
EL
Prospective
III
observational
study
Type 1 diabetes
14
Physiological characteristics of the partial remission phase in children with type 1 diabetes (continued)
Physiological characteristics of the partial remission phase in children with type 1 diabetes (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Design
Knip et al,
198241
173 children with
newly diagnosed
type 1 diabetes
Follow-up of children from
diagnosis every 1 to 3
months.
Analyses of factors that may affect
remission period:
Occurrence of remission 112/173 (65%),
remission period > 12.0 months: 10/173.
(For remission period < 12 months: 102/173,
duration range 35–1104 days, 256 ± 14 days)
Remission defined as
glucose urea absent or
minimal and insulin
Prospective
III
observational
study
Results
Comments
Design
EL
10/12 had stable insulin requirements to
maintain preprandial blood glucose at
4–7 mmol/l
Small study
Noncontrolled
intervention
study
III
Age mean ± SEM
12.0 ± 0.3
(0.7–19.2) years
Age
Sex
C-peptide
Finland
EL
Sex (male vs. female): occurrence of
remission 72/98 vs. 40/75, p < 0.01; duration
of remission 279 ± 22 vs. 210 ± 25 days,
p < 0.01
Age of onset: with remission vs. without
remission 7.6 ± 0.4 vs. 6.3 ± 0.5 years,
p < 0.05
C-peptide in children still in remission vs.
without remission: 0.34 ± 0.08 vs.
0.02 ± 0.01nmol/l, p < 0.001; C-peptide in
children > 12 months remission vs. without
remission: 0.07 ± 0.02 vs. 0.02 ± 0.01nmol/l,
p < 0.05
Calculating insulin requirements for patients in the partial remission phase
Population
Intervention
Hosker and
Turner, 198242
12 patients with
newly diagnosed
type 1 diabetes
Method for patients to reduce
basal and preprandial insulin
doses if the self-monitored
blood glucose concentration
was 4 mmol/l on two
consecutive days
Age mean 21
(12–34) years
15
UK
Outcomes
Insulin dosage reduced over 4 weeks from
62 to 33 units/day
Not controlled
Evidence tables
Study
Study
Population
Intervention
Outcomes
Mirouze et al,
198047
33 patients with
newly diagnosed
type 1 diabetes
between 1976 and
1978
Mean age 20 ± 3
years
Insulin administered for an
1) Remission
average of 5 ± 1 days using
external, closed-loop delivery 2) Blood glucose
system (artificial pancreas),
sessions lasted 24–48 hours
and were repeated two or
three times after rest intervals
of 1 or 2 days (n = 23)
France
versus
Results
Comments
1) Number 18/23 (78%) vs. 3/10 (30%)
Allocation to groups not Controlled
IIa
randomised, first 15 and study without
last 8 patients admitted
randomisation
were allocated to 5 ± 1
days using external,
closed-loop delivery
system, middle 10 treated
for 24–48 hours by the
external, closed-loop
delivery system
Average duration 8 ± 1 vs. 8 ± 1 months (no
significant difference)
2) Basal 6.1 ± 0.4 vs. 5.8 ± 0.5 mmol/l (no
Postprandial 7.8 ± 0.5 vs. 5.8 ± 0.5 mmol/l
(no significant difference)
patients treated for
24–48 hours only by the
external, closed-loop delivery
system, then used continuous
infusion pump (preprogrammed open-loop
insulin infusion) for next 3 to
5 days (n = 10)
Design
EL
Patients previously treated
with oral hypoglycaemic
drugs
Treatment has changed
significantly since 1976,
may affect relevance of
experiment
No power calculation
Perlman et al,
198446
14 young people
with newly
diagnosed type 1
diabetes
Intravenous (n = 7) central
venous catheter inserted into
external jugular vein,
attached to pump, patients
hospitalised for 3–4 weeks.
Intravenous insulin for
minimum 28 days
1) Fasting plasma glucose during
treatment
2) 24 hour urinary glucose
excretion during treatment
Mean age
3) HbA1c
intravenous group
13.9 ± 2.3 years,
subcutaneous group versus
11.6 ± 1.6 years
subcutaneous (n = 7) onceCanada
daily insulin zinc suspension,
with or without soluble
insulin, hospitalised for
approximately 2 weeks, blood
glucose levels were measured
2–3 times a week
1) 88 ± 9 vs. 253 ± 41 mg/dl, p < 0.001
2) 0.29 ± 0.15 vs. 59 ± 29 g/day, p < 0.001
3) 1 month: 10.9 ± 0.6% vs. 14.6 ± 0.7%,
p < 0.005
4 months: 10.8 ± 0.9% vs. 12.1 ± 0.9% (no
12 months: 11.2 ± 1.7% vs. 12.9 ± 1.1% (no
No details of
randomisation
RCT
Ib
Type 1 diabetes
16
Insulin delivery during the period after diagnosis
Insulin delivery during the period after diagnosis (continued)
Study
Population
Edelmann et al, 14 young people
198745
with newly
diagnosed type 1
diabetes
Intervention
Outcomes
Results
Subcutaneous insulin pump
treatment (n = 7)
1) HbA1
1) After 1 year: 7.5 ± 0.8% vs. 7.8 ± 1.3% (no No details of
randomisation
versus
2) Glycated serum proteins
3) Mean blood glucose
subcutaneous one or two
Mean age
daily insulin injections (n = 7) 4) C- peptide value
subcutaneous
5) Insulin dosage
insulin pump group
21 ± 5 years,
subcutaneous group
21 ± 6 years
Germany
Comments
Design
EL
RCT
Ib
RCT
Ib
RCT
Ib
3) First year average: 116 ± 7 vs.
118 ± 7 mg/dl (no significant difference)
4) 14 days, and 5, 7 and 8 months:
significantly higher in subcutaneous insulin
injection group compared with pump
treatment, p < 0.005 (no numbers given –
displayed as graph)
De Beaufort et
al, 198544
30 children with
type 1 diabetes
Subcutaneous insulin pump
treatment (n = 15)
Mean age
subcutaneous
insulin pump group
8.9 ± 1.1 years,
subcutaneous group
6.5 ± 0.9 years
versus
Insulin antibodies
0.118 ± 0.057 vs. 0.600 ± 0.482 units/l (no
No details of
randomisation
subcutaneous one or two
daily insulin injections
(n = 15)
Netherlands
De Beaufort et
al, 198943
As reported in study As above
above
1) HbA1
2) Urinary C-peptide excretion
1) HbA1 was significantly lower after 2
Second paper on study
months in pump group than injection group, above
p < 0.05
3) Stimulated and fasting C-peptide
values
Evidence tables
17
Methylprednisolone
Study
Population
Intervention
Outcomes
Results
Comments
Design
Satman et al,
199663
31 children with
type 1 diabetes who
had a remission
phase within 12
weeks of receiving
multiple
subcutaneous
insulin injection
Methylprednisolone pulse
therapy, 4 times a day on
alternate days, dose of
30 mg/kg (maximum
1000 mg/day) by intravenous
bolus in hospital (n = 20)
(unknown duration of
treatment)
1) Remission period
1) Complete remission: 4/16 vs. 1/11
2) Duration of remission
Partial remission: 9/16 vs. 1/11
Controlled
IIa
study without
randomisation
3) HbA1c
p < 0.01
Control group did not
accept
methylprednisolone
pulse, baseline
characteristics were the
same other than islet cell
antibody assay
2) 6.6 ± 4.6 vs. 3.1 ± 2.3 months, p < 0.01
3) 9.2 ± 3.6 vs. 10.5 ± 1.9%, p < 0.01
Unknown duration of
methylprednisolone pulse
therapy (? 2 days)
Mean age 11.7 ± 3.6 versus
in intervention
group, 11.8 ± 3.1 in control group (n = 11)
control group (range Trial length: unknown
6–19 years)
Outcomes looked at 12
Turkey
months after treatment
Yilmaz et al,
199364
25 patients with
type 1 diabetes
Oral methylprednisolone,
1) Clinical remission
dosage of 0.7–1.0 mg/kg/day
2) HbA1c at clinical remission
for 2 weeks, dosage was
Mean age 23.8 ± 6.2 tapered 5 mg/week, treated in
3)
Adverse effects
years in intervention hospital, overall continued for
group, 21.8 ± 8.9
17–12 weeks (n = 15)
years in control
group (range 7–31 versus
years)
control group (n = 10)
Turkey
Trial length: unknown
Outcomes looked at 12
months after treatment
EL
1) 15/15 vs. 10/10
Control group did not
accept oral
Duration of remission in oral
methylprednisolone,
methylprednisolone group: 10/15 patients in baseline characteristics
non-insulin-requiring remission for a period were the same
of 16–91 months, 5/15 relapse after 3–15
months of therapy, control group: 3.4 ± 0.6
Unknown how many
months, p < 0.001
times intervention drug
was used
2) 6.7 ± 1.3 vs. 6.9 ± 1.1% (no significant
difference)
3) Adverse effects: acne (6/15), stress (4/15),
fatigue (5/15), irritation of gastrointestinal
tract (4/15), infection (2/15), weight loss
(12/15), hyperglycaemia (12/15); weight loss
and hyperglycaemia were reversed with
administration of insulin
Controlled
IIa
study without
randomisation
Type 1 diabetes
18
Immunotherapy for prolonging the partial remission phase
Cyclosporin
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Dupre et al,
198848
188 patients with
type 1 diabetes
within 6 weeks of
initiation of insulin
therapy
Cyclosporin 110 mg/kg daily
Insulin-free remission
6 months: 38.7 vs. 19.1, p < 0.001
Loss to follow-up
numbers do not add up
RCT
Ib
Aged 9–35 years
versus
12 months: 24.2 vs. 9.8, p < 0.002
placebo
Trial length: 1 year
Europe and Canada
Martin et al,
199149
188 patients with
type 1 diabetes
within 6 weeks of
therapy
Follow-up from above trial
using statistical twin pairs
HbA1c
Cyclosporin or placebo
discontinued on average at
13.8 ±7.4 months
6 months after discontinuation of
intervention: p < 0.05
15 months after discontinuation of
intervention: no significant difference
Numbers not given – only Follow-up
presented as a graph
from RCT
reported
above 48
IIa
Short article
IIa
Aged 9–35 years
Europe and Canada
Levy-Marchal
et al, 198651
28 children with
diabetes
Aged 2–15 years
France
Cyclosporine A soon after
start of insulin therapy given
3 times a day for 6 months
1) HbA1c
2) Remission period
Target trough plasma levels of 3) Adverse effects
100 ng/ml, dosage
9.8 ± 3.4 mg/kg/day (n = 14)
versus
target trough plasma levels of
200 ng/ml, dosage
17 ± 4 mg/kg/day (n = 14)
versus
control group children
referred to unit in the year
before this study (n = ?)
1) No difference among treatment groups
and control.
2) At 6 months no remission: 3/14 vs. 0/14
vs. all controls n = ?
Nonrandomised
intervention
study
At 6 months partial remission: 11/14 vs. 3/6
vs. 0/?
At 6 months total remission: 5/14 vs. 3/6 vs.
0/?
3) Cyclosporine A: in low-dose group
alkaline phosphatases were evaluated. In
high-dose groups, evaluated blood pressure
in 6/14 cases and elevated plasma creatinine
in 2 cases; all adverse effects were reversible
after cyclosporine A was discontinued
Evidence tables
19
Study
Population
De Filippo et
al, 199652
130 children
diagnosed with
diabetes before
1988
Feutren et al,
198650
Intervention
Outcomes
Results
Comments
83 cyclosporin-treated
1) HbA1c
children (treatment given at
2) Average frequency of severe
initial dosage of
hypoglycaemia
7.2 ± 0.1 mg/kg/day,
decreased stepwise then
Cyclosporin-treated interrupted after 6–62 months
children with
depending on response to
diabetes mean age therapy)
10.0 ± 3.2 years,
control children
versus
with diabetes mean
age 11.1 ± 2.6 years 47 children with diabetes not
treated with cyclosporin
France
Follow-up 4 years
1) During first 4 years of follow-up HbA1c
Children from previous
level was lower by approximately 1–1.5% in study
cyclosporin-treated children compared with
controls (displayed in graph – numbers not
given)
122 patients aged
15–40 with type 1
diabetes
At 6 months complete remission: 25.4%
(16/57) vs. 18.6% (11/53) (not significantly
different)
Cyclosporin 7.5 mg/kg/day
versus
Mean age 25.7 ± 0.6 placebo
(SEM) years
Followed up weekly for first
month and then monthly
France
Remission
Design
EL
Cohort
IIa
RCT
Ib
2) 0.03 ± 0.03 per patient per year vs.
0.23 ± 0.09 per patient per year, p < 0.05
At 9 months complete remission: 24.1% vs.
5.8%, p < 0.01
At 6 months partial remission: 46% (13/57)
vs. 28.8% (6/53)
Adverse effects: Hypertrichosis, gingival
hyperplasia, parasthesias, hypertension,
abdominal discomfort, lymphadenopathy,
adenofibroma of the breast
Randomisation based on
sequence of entry to the
study
Type 1 diabetes
20
Cyclosporin (continued)
Nicotinamide
Study
Population
Intervention
Pozzilli et al,
199653
211 children, young Nicotinamide
people and adults
versus
with newly
diagnosed type 1
control
diabetes
Outcomes
Results
Comments
1) HbA1c
1) Standardised difference at 6 months
0.08% approximate 95% CI –0.67 to 0.83
Unknown which trials
Meta-analysis Ia
used in the HbA1c
of 10 RCTs
calculation or the number
7 trials used
of people
in HbA1c
Unknown exclusion
calculation
criteria or inclusion
(systematic
criteria
review does
not specify
which of the
10 RCTs were
included in
the metaanalysis)
2) Adverse effects in the 291
patients treated with nicotinamide
(additional patients from nonRCTs)
Studies had mean
ages ranging from
10.0 to 23 years
Taboga et al,
199460
21 recently
Insulin and nicotinamide,
1) Remission phase
diagnosed patients 3 g/day for 1 year (n = 11)
2) HbA1c
versus
Ages: nicotinamide
control – insulin alone
group 23.0 ± 5.9
years, control group (n = 10)
26.7 ± 5.5 years
Trial length: 1 year, with
follow-up: 1 year after end of
Italy
trial
2) n = 2 skin rashes, n = 2 recurrent
hypoglycaemia, n = 2 liver serum aspartate
aminotransferase and alanine
aminotransferase levels slightly elevated
1) At 6 months: 4/11 vs. 4/10 in partial
remission phase, 2/11 and 3/9 in total
remission
Design
1 drop-out due to
pregnancy in control
group
RCT
Short letter only
Controlled
study,
unknown if
randomised
EL
Ib
Included in
meta-analysis
At 12 months: 3/11 vs. 3/9 in partial
remission
At 2 years: 1/11 and 1/9 in partial remission
2) At 6 months: 5.7 ± 0.5% vs. 5.4 ± 0.9%
At 12 months: 6.0 ± 0.6% vs. 5.8 ± 0.9%
At 2 years: 6.6 ± 0.9% vs. 6.0 ± 0.4% No
description of randomisation
Vague, 198761
16 patients with
newly diagnosed
type 1 diabetes
Nicotinamide 3 g/day and
intensive insulin therapy
(n = 7)
Aged 10–35 years
versus
2) At 6 months: 7.0 ± 0.5% SE vs. 7.7 ± 0.7%
SE
France
placebo and intensive insulin
therapy (n = 9)
At 1 year: 6.4 ± 0.6 SE vs. 8.6 ± 0.5 % SE
2) HbA1c
1) At 6 months: 5/7 vs. 2/9
At 1 year: 3/7 vs. 0/9
IIa
21
Evidence tables
Trial length: if insulin was still
required after 6 months
nicotinamide was
discontinued, follow-up at 1
year
1) Remission phase (not requiring
any insulin)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Pozzilli et al,
199462
90 patients with
type 1 diabetes
during the first 5
years of diagnosis
Nicotinamide 25 mg/kg/day
and low-dose cyclosporin
5 mg/kg/day (n = 30)
1) Clinical remission
1) At 3 months: 6/30 vs. 1/30 vs. 0/30,
p = 0.05
RCT
Ib
versus
3) Drop-outs
Permuted-block design
was employed to assign
patients randomly in
equal numbers to the
three treatment groups
Results
Comments
Design
EL
No description of
randomisation
RCT
Ib
Ages: nicotinamide
and low-dose
cyclosporin
20.1 ± 9.4 years
(7–35),
nicotinamide
18.9 ± 7.8 years
(9–33), control
18.5 ± 8.8 years
(8–40)
2) Length of clinical remission
At 6 months: 4/29 vs. 3/27 vs. 1/29, NS
At 1 year: 4/27 vs. 2/25 vs. 0/28
(nicotinamide vs. control p = 0.05)
nicotinamide 25 mg/kg/day
(n = 30)
versus
Total who experienced remission 7/30 vs.
5/30 vs. 2/30, NS
control group (n = 30)
2) p < 0.02 (no numbers – just a graph)
3) Nicotinamide and low-dose cyclosporin:
5 drop-outs, 2 due to persistent increased
transaminase levels, one patient from
hyperbilirubinaemia, 2 patients suffered hair
loss
Italy
multicentre
Nicotinamide: only 3 drop-outs, 1 no
reason, 1 moved away, 1 could not perform
blood glucose monitoring and did not return
to follow-up appointments
Control: 2 drop-outs, 1 moved away and the
other did not follow recommendations
Other immunotherapies
Study
Population
Intervention
Secchi et al,
199065
25 patients with
type 1 diabetes
within 8 weeks of
diabetes onset
Prednisone 15 mg/day (n = 10) 1) Partial remission
1) 6/9 vs. 1/4 vs. 2/10
versus
2) Prednisone: facies lunaris and
epigastralgia
Aged 24 ± 6 years
indomethacin 100 mg/day)
(n = 5)
Italy
versus
placebo (n = 10)
Outcomes
2) Adverse effects
Indomethacin: headache
multicentre
Type 1 diabetes
22
Nicotinamide and cyclosporin
Other immunotherapies (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Secchi et al,
198666
10 patients with
type 1 diabetes
Theophylline 800 mg/day
(n = 5)
Partial remission
4/5 vs. 2/4
No description of
randomisation
RCT
Ib
Italy
versus
1) Remission
1) At 6 months: 7/16 vs. 3/30
Ib
2) HbA1c
At 1 year: 9/16 vs. 2/30
Method of randomisation RCT
through the unbalanced
zanolomization method
placebo (n = 5)
Trial length: 1 month
Giordano et al, 16 patients with
199067
type 1 diabetes
within two weeks of
therapy
Aged 12–31 years
Thymopentin 1 mg/kg for 7
days and twice per week for
up to 3 months (n = 16)
versus
p range ≤ 0.05–0.001
control (n = 32)
2) At 1 month: 8.8 ± 0.4% vs. 8.7 ± 0.3%
2 patients in control
group lost to follow-up
At 6 months: 6.2 ± 0.2% vs. 6.5 ± 0.1%
Italy
At 1 year: 6.4 ± 0.4% vs. 7.5 ± 0.5%
No statistical difference
Koivisto et al,
198468
43 patients with
type 1 diabetes
Aged 15–25 years
Mean age 20 ± 1
years for
intervention group
and 21 ± 1 years for
control group)
Buckingham
and Sandborg,
200069
Interferon 3 106 iu and
2.3mg protein in phosphatebuffered saline for 2 weeks
(n = 20)
1) At 1 month: 8.9 ± 0.3% vs. 9.1 ± 0.4%
At 6 months: 8.1 ± 0.5% vs. 7.9 ± 0.5%
Methotrexate 5 mg/m2/week
(n = 5)
Aged 7–12 years
control (n = 5)
versus
Ib
Randomisation through
RCT
random number table, by
administrative assistant
not involved in patient
care
Ib
2) At 1 year: 6/20 vs. 12/23
Remission
At 18 months: 1/5 vs. 3/5
Adverse events during methotrexate
treatment: mouth sores (n = 1), upper
respiratory infection (n = 1), gastroenteritis
(n = 1), vermicelli (n = 1), transient increase
in liver function (n = 1)
23
Evidence tables
10 children with
type 1 diabetes
within 11 days of
diagnosis
RCT
At 30–36 months (n = 9, n = 9): 9.8 ± 0.6%
vs. 9.5 ± 0.7%
2.3 mg human albumin in
0.5 ml phosphate-buffered
saline for 2 weeks (n = 23)
Trial length: intervention for 2
weeks, follow-up for 30
months
No description of
randomisation
At 12 months: 8.6 ± 0.6% vs. 9.7 ± 0.7%
versus
Finland
USA
1) HbA1c
2) Remission
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Cook et al,
198970
49 children with
type 1 diabetes
within 20 days of
diagnosis
Azathioprine 2 mg/kg/day
(n = 24)
1) Remission
1) At 6 months: 7/24 vs. 10/25
RCT
Ib
2) HbA1c
At 1 year: 4/24 vs. 4/25
Randomisation unknown
to participating doctors
and patients
Mean age 11.7 for
azathioprine, 9.9
years for placebo
placebo (n = 25)
Australia
versus
2) At 6 months: 7.2 ± 0.4% vs. 6.6 ± 0.2%
At 12 months: 7.7 ± 0.3% vs. 7.1 ± 0.3%
Adverse effects: skin lesions
Type 1 diabetes
24
Other immunotherapies (continued)
3.4
Essential education at diagnosis
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Mitchell,
199676
32 children and
young people newly
diagnosed with type
1 diabetes
Additional educational
support at diagnosis, in the
form of a booklet called
‘Improving compliance with
treatment for diabetes’
Glycated haemoglobin
General trend for lower glycated
haemoglobin in the group given the booklet
but a significantly lower glycated
haemoglobin level was only seen at 10 to 13
months after diagnosis (p < 0.01, no numbers
reported)
No description of
randomisation
RCT
Ib
1) 85.0% vs. 65.5% positive adjustment,
p < 0.001
Effects were specific to
higher socio-economic
groups
Nonrandomised
controlled
study
IIa
RCT
Ib
Ages: intervention
group 10.4 (12.4),
control group 11.0
(2.4) years
Canada
Galatzer et al,
198227
223 patients at
diagnosis
Aged 7–24, mean
15 years
Israel
versus
standard education at
diagnosis
Loss to follow-up due to
relocation, lack of
ongoing interest in the
study and incomplete
data on the
questionnaires
Follow-up for 3.5 years postdiagnosis
Intensive psychosocial
support for the first month
after diagnosis
1) Compliance
versus
3) Sociability
usual care
4) School/work
2) Family relations
Follow-up 3–15 years
p < 0.02
p < 0.025
Included in Hampson et
al72
4) 92.5% vs. 86.2% positive adjustment, no
statistical difference
Nordfeldt et al, 332 patients with
200377
type 1 diabetes
Mean age 12.6 (SD
4.1) years, duration
of diabetes 5.3 (SD
3.8) years
Sweden
Videotapes and brochure
designed to review skills for
self control and treatment,
aimed at preventing
hypoglycaemia (n = 111,
n = 82 at 1 year)
versus
videotape and brochure with
general diabetes information
(control) (n = 111, n = 89 at 1
year)
1) Incidence of severe
hypoglycaemia
2) HbA1c
1) Difference between intervention and
Followed up by postal
control unadjusted for baseline 10% 95% CI survey
–4 to 24%, p = NS
Study was not looking at
However, the incidence in the intervention
initial education
group reduced from 42% for year before
intervention to 27% for following year. Risk
difference 15% 95% CI 1–29%, p = 0.039.
No reduction seen in the control and
traditional groups
2) No difference (compared with control and
traditional groups and to baseline)
versus
25
Evidence tables
traditional treatment only
(n = 110, n = 90 at 1 year)
Essential education at diagnosis (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Nordfeldt and
Ludvigsson,
200278
139 children with
type 1 diabetes
received
intervention, 86
replied to the
questionnaire
Brochures mailed twice to
participant’s house and
videos.
1) Hypoglycaemia (yearly
incidence)
Study was not looking at
initial education
Case series
III
Included in Hampson et
al72
RCT
Ib
Postal questionnaire
2) Mean yearly HbA1c
3) Patient attitude
Aged 1–18, mean
12.2 (SD 4.3),
duration of diabetes
0.1–16.6 years
Two years after intervention 6.4% (SD 1.1)
vs. before intervention 6.8% (1.2), p = 0.006
3) 84% in 2000 indicated that receiving a
video for home was valuable
84% of respondents anticipated future use of
the videos
Sweden
Delamater et
al, 199075
2) Year after intervention 6.5% (SD 1.1) vs.
before intervention 6.8% (1.2), p = 0.042
36 newly diagnosed Intervention group: selfchildren with
management training, within
diabetes
first 4 months of diagnosis
seven sessions of selfAged 3–16 years
monitoring blood glucose
training given to adjust diet,
USA
exercise and insulin
versus
placebo control group:
supportive counselling
versus
usual care control group
Follow-up assessment over 2
years
HbA1
At 1 year: lower HbA1 for the intervention
group compared with usual care group
controlling for C-peptides (p < 0.01)
At 2 years: lower HbA1 for the intervention
group compared with usual care group
controlling for C-peptides (p < 0.05)
No difference compared with placebo
control
Fewer dietary deviations for intervention
group compared with usual care control
(p < 0.05)
Type 1 diabetes
26
3.4
Chapter 4 Ongoing management
4.1
Education
What are the effects of education in children with type 1 diabetes?
Study
Population
Intervention
Hampson et al, Children and young Education psychosocial
200172
people (9–21 years) interventions
with type 1
diabetes.
Outcomes
Results
Comments
Design
EL
Clinical and cost effectiveness of
different methods
Analysis of the 25 RCTs suggests that
interventions have a small to medium
beneficial effect on diabetes management
outcomes. Polled effect size for psychosocial
outcomes 0.37 and 0.33 for glycated
haemoglobin with outliers (0.08 without
outliers)
Health Technology
Assessment
Systematic
review
Ia
Survey
III
Narrative review of the 21 pre-post studies
with no control groups found all studies
reported a beneficial effect
62 studies in total
25 RCTs (16 with
sufficient detail to enable
effect sizes to be
calculated)
pre-post design with no
control group
Largest trial n = 181,
smallest n = 16, the rest
n < 40
16 non-controlled studies
Ford et al,
200080
161 insulin-treated
patients with
diabetes in a multiethnic population
21-question multiple-choice Diabetes knowledge (maximum
questionnaire translated to the 21)
appropriate language
(Bengali, Urdu, Punjabi)
Caucasian: mean 13.1, 95% CI 12.3–14.0
(n = 104)
Asian: 8.2, 95%CI 6.8–9.6 (n = 36)
Aged 16–84 years
Afro-Caribbean: 9.1, 95% CI 7.2–11.0
UK
Caucasian patients displayed significantly
higher levels of diabetes knowledge when
compared with Asian and Afro-Caribbean
patients (p < 0.001)
No significant difference
was seen in the age,
duration of diabetes or
male/female ratio among
ethnic groups of patients
Caucasian patients displayed significantly
higher levels of formal education, there was
a significant association between level of
education and diabetes knowledge scores
(p < 0.0001)
Evidence tables
27
Study
Population
Intervention
Outcomes
Karter et al,
200081
44 181 patients with Survey reporting level of self- Less than 3 times daily vs. 3 or
type 1 diabetes
more times daily
Aged > 19 years
Results
Comments
Ethnic minority:
Caucasian (reference group): 1.0
Design
EL
Crosssectional
study
III
African-American: 1.5 (0.8–1.2)
USA
Hispanics: 1.2 (0.8–1.7)
Asian/Pacific Islander: 1.8 (1.0–3.3), p < 0.05
American Indian: 0.8 (0.8–1.3)
English language difficulty:
Yes: 0.6 (0.3–1.4)
No (reference group): 1.0
Methods of education
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Iafusco et al,
200079
43 children young
people and young
adults with type 1
diabetes
Online communication
teaching tool
1) HbA1c
1) Decreased from baseline 8.9% to 7.8%,
no confidence intervals given, p < 0.0001
Published as a letter
Before/after
intervention
study
IIb
Aged 10.6–24.7
years
Italy
2) Percent of children and young
people who decided to change
their treatment in the previous
three months
2) Percent of positive answers increased from
baseline 32.5% to 83.7%
Type 1 diabetes
28
What are the effects of education in children with type 1 diabetes? (continued)
4.2
Insulin regimens
What insulin regimens are currently used in children with type 1 diabetes in the UK?
Study
Population
Smith, 20011
All 0- to 16-yearSurvey
olds in England with
type 1 diabetes.
Information on
2090 of the known
15 437 children
Intervention
Outcomes
Results
Comments
1) Number of injections per day
1) 0 injections/day 0.3%
1 injection/day 1.7%
2 injections/day 86.1%
National Paediatric
CrossDiabetes Audit, report on sectional
data for the year 2001
study
2) Mean number of injections per
day stratified by age
Design
EL
III
Additional information
provided by author
2) 1-year-olds (n = 3) 1.67 mean injections/day
2-year-olds (n = 14) 1.79 mean injections/day
Evidence tables
29
Intensive compared with standard
Study
Population
Wang et al,
199387
Intervention
Outcomes
Results
Comments
Design
EL
6 trials looking at
Intensive insulin treatment
retinopathy in
patients with type 1 versus
diabetes (n = 271)
standard treatment
1) Retinopathy progression (more
than 2 years after treatment)
1) Combined OR 0.49 (95% CI 0.28–0.85)
Trials included:
7 trials looking at
neuropathy in
patients with type 1
diabetes (n = 266)
3) Glycated haemoglobin
Eschwege 1979, Steno-I
1985, Olsen 1987,
Verrillo 1988, Oslo 1988,
SDIS 1991, Kroc 1984,
Steno-II 1986, BeckNielsen 1985,
Christensen 1987
Systematic
review
Ia
2) Combined OR 0.34 (95% CI 0.20–0.58)
Systematic
review
Ia
Systematic
review
Ia
2) Nephropathy progression
3) Reduction of 1.4% (95% CI –1.8 to
–1.1%)
All studies thought
mainly to involve
adults
Egger et al,
199798
14 trials involving
2067 patients
(mainly adults)
Trials identified
from 1975 to 1995
Lawson et al,
199986
6 trials involving
1732 patients
(mainly adults)
Trials identified
from 1966 to 1996
(n = 1028)
1) Hypoglycaemia (one or more
severe episodes)
versus
2) Ketoacidosis
standard treatment (n = 1039)
3) All-cause mortality
(n = 861)
1) Macrovascular events (from
1) Combined OR 0.55 (95% CI 0.35–0.88)
cardiovascular disease,
cerebrovascular disease, peripheral 2) Combined OR 0.72 (95% CI 0.44–1.17)
vascular disease and
3) Combined OR 0.91 (95% CI 0.31–2.65)
macrovascular death; counted
more than once if 2 or more
different events happened)
versus
2) Macrovascular disease (only
counting first event for each
patient)
3) Macrovascular mortality
1) Combined OR 2.99 (95% CI 2.45–3.64)
Trials included:
2) Combined OR 1.74 (95% CI 1.27–2.38)
Steno-l 1983, Holman
1983, Kroc 1984, BeckNielsen 1985, Oslo 1986,
Steno-ll 1986,
Christensen 1987,
Marshall 1987, Helve
1987, Verrillo 1987,
Bangstad 1992, SDIS
1993, DCCT-PP 1993,
DCCT-SP 1993, MCSG
1995
3) Combined OR 1.40 (95% CI 0.65–3.01)
Trials included:
Steno-l 1983, Steno-ll
1986, Oslo 1986, DCCTPP 1993, DCCT-SP 1993,
SDIS 1991
Type 1 diabetes
30
What is the optimum insulin regimen in children with type 1 diabetes?
Intensive compared with standard (continued)
Population
Intervention
Outcomes
Results
DCCT, 199383
1441 patients with
type 1 diabetes.
Primary prevention cohort:
(n = 348)
Retinopathy (≥ 3-step sustained
retinopathy)
Retinopathy: Primary prevention cohort: 1.2 Study included in Egger
RCT
rate/100 person years vs. 4.7 rate/100 person systematic review, for
years, Risk reduction 76% (95% CI 62–85)
complications 98 and
Lawson systematic review
Secondary intervention cohort: 3.7 rate/100 for macrovascular events86
person years vs. 7.8 rate/100 person years,
Risk reduction 54% (95% CI 39–66)
The primary prevention
cohort consisted of the
Neuropathy: Primary prevention cohort: 3.1 patients who at the start
rate/100 person years vs. 9.8 rate/100 person of the study had no
years, Risk reduction 69% (95% CI 24–87)
retinopathy or
Secondary intervention cohort: 7.0 rate/100 nephropathy. The
person years vs. 16.1 rate/100 person years, secondary intervention
cohort consisted of
patients with minimal
Urinary albumin excretion ≥ 40: Primary
background retinopathy
prevention Cohort: 2.2 rate/100 person years
vs. 3.4 rate/100 person years, Risk reduction Results from primary
prevention and secondary
34% (95% CI 2–56)
intervention cohorts were
Secondary intervention cohort: 3.6 rate/100 combined, for the
outcomes of weight gain
Results for secondary
Urinary albumin excretion ≥ 300: Primary
intervention cohort only
prevention cohort: 0.2 rate/100 person years for macular oedema,
vs. 0.3 rate/100 person years, Risk reduction severe non-proliferative
69% (95% CI –124–86)
or proliferative
Secondary intervention cohort: 0.6 rate/100 retinopathy and laser
treatments, as too few
events in primary
prevention group
Macular oedema: Secondary intervention
Intensive insulin
cohort: 2.0 rate/100 person years vs. 3.0
treatment (n = 711) vs.
rate/100 person years, Risk reduction 23%
standard treatment
(95% CI –13–48)
(n = 730)
Severe non-proliferative or proliferative
retinopathy: Secondary intervention cohort:
1.1 rate/100 person years vs. 2.4 rate/100
person years, Risk reduction 45% (95% CI
14–67)
Aged 13–39 years
versus
Secondary intervention
cohort: Intensive insulin
treatment (n = 363)
versus
Trial length: 5 years
Clinical Neuropathy (at 5 years)
Urinary albumin excretion (mg/24
hr) ≥ 40 and ≥ 300
Macular oedema:
Severe non-proliferative or
proliferative retinopathy
Laser treatments
Weight gain at 5 years (weight
more than 120% above ideal)
Laser treatments: Secondary intervention
cohort: 0.9 rate/100 person years vs. 2.3
rate/100 person years, Risk reduction 56%
(95% CI 26–74)
31
Weight gain: 12.7 cases/100 person years vs.
9.3 cases/100 person years (mean difference
4.6 kg)
Comments
Design
EL
Ib
Evidence tables
Study
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
DCCT, 199491
209 patients with
type 1 diabetes
(n = 95)
1) Diabetic ketoacidosis
1) RR 0.62 (95% CI 0.32–1.23)
Ib
2) RR 2.96 (95% CI 1.90–4.62)
Aged 13–17 years
versus
DCCT83 adolescent
subgroup only
RCT
(requiring assistance)
Trial length: mean
7.4 years
RCT
Ib
Trial length: mean 6.5 years’
follow-up for total 7.4 years
3) Hypoglycaemia (resulting in
coma or seizures)
4) Overweight
3) RR 2.93 (95% CI 1.75–4.90)
Results from primary
5) HbA1c (% ± SE): 8.06 ± 0.13 vs. 9.76 ± 0.12 combined
(reduction of 1.7% ± SE 0.18)
4) RR 2.11 (95% CI 1.31–3.40)
5) HbA1c
DCCT, 1996102
1441 patients with
type 1 diabetes
(n = 711)
Aged 13–39 years
versus
Neuropsychological impairment,
derived from the Wechsler Adult
Intelligence Scale in over-16-yearolds, and Wechsler Intelligence
Scale for Children under 16, at
baseline, 2, 5 and 7 years
At 2 years:
Slightly improved: OR 1.4, 95% CI 0.7–2.9
(17/263 vs. 13/254)
No change: OR 1.0, 95% CI 0.6–1.5
(208/263 vs. 202/254)
Slightly worse: OR 1.0, 95% CI 0.6–1.6
(30/263 vs. 30/254)
Significantly worse: OR 0.9, 95% CI 0.3–2.2
(8/263 vs. 9/254)
At 5 years:
Slightly improved: OR 1.1, 95% CI 0.3–4.0
(4/119 vs. 4/126)
No change: OR 1.0, 95% CI 0.6–1.8 (91/119
vs. 96/126)
Slightly worse: OR 1.1, 95% CI 0.6–2.2
(21/119 vs. 20/126)
Significantly worse: OR 0.5, 95% CI 0.1–1.9
(6/119 vs. 3/126)
DCCT83
combined
Type 1 diabetes
32
Study
Population
Intervention
Outcomes
DCCT, 1996105
1441 patients with
type 1 diabetes
(n = 711)
Aged 13–39 years
versus
1) Quality of life after mean 6.5
No significant difference in any of the
years (Total score, impact,
quality of life measures or SCL-90R
satisfaction, diabetes-related worry,
social–vocational worry, global
health perception)
Trial length: mean 6.5 years
Results
2) SCL-90R (90 item test used to
measure psychiatric symptoms)
Comments
Design
EL
DCCT83
RCT
Ib
DCCT83
Nested
case–control
IIb
Followed up for a further
7 years after the end of
the DCCT (that lasted
mean 6.5 years) 83
RCT
Ib
RCT
Ib
combined
3) Hypoglycaemia and quality of
life relationship
DCCT, 1996105
1441 patients with
type 1 diabetes
Number of prior episodes of
hypoglycaemia in the study
Aged 13–39 years
DCCT/EDICRG, 1441 patients with
200299
type 1 diabetes
Aged 13–39 years
Intensively treated group: RR 1.21 (95% CI
1.05–1.40)
Proportional hazard regression
model for SCL-90R (90 item test
used to measure psychiatric
symptoms)
(n = 711)
1) 3-step progression from no
retinopathy
4 years after end of trial analysis:
versus
2) Severe non-proliferative
retinopathy
3) Severe proliferative retinopathy
Trial length: mean 6.5 years,
follow-up for a further 7 years 4) Clinically significant macular
oedema
Conventionally treated group: RR 0.81 (95%
CI 0.50–1.32)
1) RR 0.39 (95% CI 0.19–0.79), NNT 9.9
2) RR 0.20 (95% CI 0.10–0.37), NNT 13.0
3) RR 0.20 (95% CI 0.10–0.39), NNT 14.7
4) RR 0.19 (95% CI 0.10–0.39), NNT 5.2
5) RR 0.16 (95% CI 0.07–0.38), NNT 18.6
5) Laser therapy
6) RR 0.47 (95% CI 0.07–0.38), NNT 17.1
6) Microalbuminuria (excretion
≥ 40 mg/24 hours)
7) RR 0.12 (95% CI 0.04–0.34), NNT 22.0
combined
7) Albuminuria ( excretion
≥ 300 mg/24 hours)
Reichard et al,
1991100
96 adults with type
1 diabetes
(n = 44)
versus
Weight gain: 5.8% (22.5 ± 0.3 to
23.8 ± 0.3 kg/m2) vs. 0% (22.8 ± 0.3 to
22.8 ± 0.3 kg/m2)
Study included in Egger
systematic review, for
complications,98 Lawson
systematic review for
macrovascular events86
and Wang systematic
review for retinopathy
and nephropathy
33
Evidence tables
Weight gain –body mass index%
increase (at start of treatment to
after 5 years)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Reichard et al,
1991103
97 adults with type
1 diabetes
(n = 44)
Neuropsychological tests (at
baseline ± SEM to after 3
years ± SEM):
1) 216 ± 9 to 212 ± 5 ms vs. 216 ± 5 to
206 ± 4 ms (NS)
Further results from the
SDIS trial100
RCT
Ib
Power to measure longterm complications may
not be adequate
RCT
Ib
complications98
RCT
Ib
RCT
Ib
versus
1) Auditory reaction time
2) Visual reaction time
3) Digit span test
4) Perceptual maze test
Linn et al,
199693
49 patients with
newly diagnosed
type 1 diabetes
Aged: intensive
27 ± 8, standard
29 ± 9 years
(n = 23)
versus
2) 254 ± 8 to 234 ± 5 ms vs. 256 ± 8 to
230 ± 5 ms (NS)
3) 6.9 ± 0.2 to 7.1 ± 0.2 digits vs. 6.4 ± 0.1 to
6.7 ± 0.2 digits (NS)
4) 5.5 ± 0.3 to 4.7 ± 0.4 nodes/s vs. 5.4 ± 0.2
to 5.1 ± 0.4 nodes/s (NS)
5) Necker cube test
5) 16.6 ± 1.1 to 13.7 ± 1.4 reversals vs.
16.8 ± 1.9 to 15.5 ± 2.0 reversals (NS)
After 5 years of study:
1) HbA1c (after 2 weeks): not significantly
different (this became statistically significant
after 3 years of treatment, p < 0.01 but
figures not given)
1) HbA1c
2) Mean blood glucose levels
3) Retinopathy
4) Peripheral neuropathy
5) Urinary albumin excretion
6) Creatinine clearance
7) Weight gain
2) mean blood glucose levels 6.4 ± 4.5 vs.
6.9 ± 4.2 mmol/l, p < 0.001
3) 0/23 vs. 2/19
4) 1/23 vs. 6/19 (p < 0.05)
5) 19.4 ± 10 vs. 11.2 ± 10 mg/24 hours,
p < 0.05
6) 128 ± 51 vs. 124 ± 45 ml/min (NS)
7) no statistical difference between the
groups, numbers not given
Holman et al,
198392
MCSGUK,
199594
65 patients with
type 1 diabetes
(n = 33)
1) HbA1c (year 0–2)
1) 10.5 ± 1.4% vs. 11.4 ± 1.5% (p = 0.011)
2) 0.05 ± 0.51 vs. 0.13 ± 0.49 (no units)
versus
2) Progression to retinopathy
(index year 0–2)
Aged 21–60 years
3) Creatinine clearance (year 0–2)
4) Plasma creatinine (year 0–2)
4) 2.7 ± 26.4 vs. 17.4 ± 16.4 mol/l
(p = 0.009)
70 patients with
type 1 diabetes
(n = 36)
1) Glycated haemoglobin after 6
months
Aged 17–59 years
versus
1) mean 8.9% (SEM 1.5) vs. 9.8% (95% CI
9.2–10.3%) (p < 0.05) (stated that glycated
haemoglobin remained significant for up to
36 months but figures not given).
2) Progression to clinical
albuminuria (> 200 g/min on two
consecutive occasions)
2) 6/36 vs. 6/34 (NS)
Trial length: 2–8 years
3) 1.7 ± 30.1 vs. –17.3 ± 33.5 ml/min
(p = 0.022)
Power to measure longterm complications may
not be adequate
complications98
Type 1 diabetes
34
Study
Population
Intervention
Outcomes
Results
Comments
Design
Houtzagers et
al, 198988 106
16 patients with
type 1 diabetes
(n = 16)
1) HbA1 (24 weeks)
1) 8.1 ± 0.4% vs. 7.6 ± 0.4% (NS)
RCT crossover Ib
Aged 18–63 years
versus
Intensive treatment given
by pen and standard
treatment given by
syringe (possible bias)
DAFNE is an adult
education in flexible,
intensive insulin
management (unsure if
this is really comparing
intensive vs. standard
control, it may be
comparing education
with no education)
RCT
Trial length: two 6-month
periods
DAFNE, 200295 169 adults with type Training in intensive insulin
1 diabetes
treatment (DAFNE) from start
of study (n = 69)
Aged 18+ years
(mean 40 (SD 9)
versus
years)
no DAFNE education for first
UK
6 months and then training in
intensive treatment (n = 72)
2) Hypoglycaemia (frequency over 2) Hypoglycaemia Grade I: 0.88 ± 0.75 vs.
2 weeks mean ± SE)
1.19 ± 0.60 (NS), Grade II: 4.19 ± 1.14 vs.
2.88 ± 0.82 (NS), Grade III: 0.25 ± 0.19 vs.
3) State anxiety (measured by
0.13 ± 0.09 (NS)
existing and validated version of
S.T.A.I no units mentioned)
3) 36.0 ± 2.5 vs. 39.5 ± 2.7 (p < 0.05)
1) HbA1c (after 6 months)
1) HbA1c (mean ± SD): 8.4 ± 1.2% vs.
9.4 ± 1.3% (p < 0.0001)
2) Severe Hypoglycaemia (in last 6
months)
2) 12/67 vs. 11/72 (p = 0.68)
3) Weight
3) 81.5 ± 16.9 vs. 77.3 ± 13.4 kg (p = 0.11)
4) Quality of life:impact of
diabetes on freedom to eat as I
wish, impact of diabetes on quality
of life, present quality of life, total
wellbeing, total satisfaction,
perceived frequency of
hyperglycaemia, perceived
frequency of hypoglycaemia
4) Quality of life:
Impact of diabetes on freedom to eat as I
wish (+ increased positive effect): –1.8 ± 2.3
vs. –4.0 ± 2.8 (p < 0.0001)
EL
Ib
Impact of diabetes on quality of life (+
increased positive effect): –1.6 ± 1.6 vs.
–1.9 ± 1.4 (p < 0.01)
Present quality of life (+ increased positive
effect): 1.3 ± 0.9 vs. 1.0 ± 1.1 (p = 0.095)
Total wellbeing (+ increased positive effect):
24.3v5.7 vs. 21.37 ± 5.5 (p < 0.01)
Total satisfaction (+ increased positive effect):
31.58 ± 3.9 vs. 22.82 ± 6.0 (p < 0.0001)
Perceived frequency of hyperglycaemia (+
greater perceived frequency): 2.90 ± 1.4 vs.
4.03 ± 1.3 (p < 0.0001)
Perceived frequency of hypoglycaemia (+
2.40 ± 1.3 (p = 0.31)
Evidence tables
35
Study
Population
Intervention
Outcomes
Results
Comments
Shah et al,
198996
26 young people
with newly
diagnosed type 1
diabetes
through external artificial
pancreas (n = 12)
1) GHb (after 1 year)
1) 7.2 ± 0.7% vs. 10.8 ± 1.2% (p < 0.01)
Ib
2) Hypoglycaemia and diabetic
ketoacidosis
2) No cases that needed medical attention
For the first 2 weeks the
RCT
intensive treatment group
were hospitalised
whereas the standard
treatment group were
treated as outpatients,
possible bias
23 adults with type
1 diabetes
(n = 12)
1) HbA1 (8 months)
1) HbA1 (mean ± SD): 8.6 ± 1.6% vs.
8.1 ± 1.4% (NS)
Aged 25.6 ± 6.6
years
versus
3) Weight
The intensive treatment
RCT
group used a pen delivery
system whereas the
standard treatment group
used syringes, possible
bias
Ib
2) Hypoglycaemia (frequency per
month)
The intensive treatment
RCT
group used a pen delivery
system whereas the
2) Severe hypoglycaemia: 3/18 vs. 4/19 (NS) standard treatment group
Diabetic ketoacidosis: No cases observed in used syringes, possible
bias
the study period
Ib
versus
Aged: Intensive
therapy mean age
13.2 ± 0.7, standard Trial length: 2 weeks, followtherapy mean age
up for 1 year
13.8 ± 1.4 years
Ollenschläger
et al, 198989
2) Hypoglycaemia (slight): 10.8 ± 4.9 vs.
9.5 ± 5.3 (NS)
Severe hypoglycaemia: 1/11 vs. 1/12 (NS)
Design
EL
Diabetic ketoacidosis: No cases observed in
the study period
3) Not correlated to type of treatment, but no
numbers given
Small et al,
198890
36 adults with type
1 diabetes
(n = 18)
1) HbA1 (8 months)
Aged 25.6 ± 6.6
years
versus
2) Hypoglycaemia and diabetic
ketoacidosis
3) Weight
4) Patient preference for regimen
1) HbA1 (mean ± SD): 9.4 ± 2.1% vs.
10.3 ± 2.7% (NS)
3) 71.8 ± 11.3 vs. 64.7 ± 7.4 kg (NS)
4) Patient preference for regimen (number
preferred regimen): 15/19 vs. 3/19
Hershey et al,
1999104
25 children with
type 1 diabetes
(n = 13)
Aged 9–18 years
versus
Trial length: around 2–2.5
years
1) Memory
2) Reaction time
3) Task accuracy, word
recognition, paragraph recall
1) Significant increased error in intensive
treatment group (p= 0.05), numbers not
presented
2) Significant increase in response time in
intensive treatment group (p ≤ 0.01), numbers
not presented
3) No significant differences seen between
the treatment groups.
RCT
Ib
Type 1 diabetes
36
Study
Population
Intervention
Bougnères et
al, 199397
186 children with
type 1 diabetes
Intensive insulin treatment (3 1) GHb after 1 year
daily insulin injections, shortacting insulin before breakfast 2) Hypoglycaemia and diabetic
ketoacidosis
and lunch and mixture of
short-acting and long-acting
insulin before the evening
meal) (n = 91)
Aged 10–18 years
Outcomes
Results
Comments
1) 9.3 ± 0.2% vs. 9.8 ± 0.3% (p < 0.05 for
difference, in change from baseline, between
the two groups)
Design
EL
RCT
Ib
EL
2) Informed of no change in hypoglycaemia
or diabetic ketoacidosis in either group, but
no figures given
versus
standard treatment (2 daily
insulin injections, mixed
short-acting and long-acting
insulin before breakfast and
dinner) (n = 95)
Further comparisons of insulin regimens (not intensive versus standard)
Study
Population
Intervention
Outcomes
Results
Comments
Design
Langdon et al,
1981111
10 children with
type 1 diabetes
2 daily insulin injections of
mixture of short-acting and
intermediate-acting insulin
before breakfast and evening
meal (n = 10)
1) HbA1 (after 6 weeks)
1) HbA1 (mean ± SD): 9.7 ± 0.4% vs.
10.4 ± 0.5% (p = 0.003)
No record of when the
one dose was given and
whether a mixture of
intermediate-acting and
short-acting insulin was
used
RCT crossover Ib
2) Urine log
Aged 12–17 years
USA
versus
1 daily insulin injection
(n = 10)
5) Cholesterol
6) Triglycerides
2) Urine log (mean ± SD): 0.88 ± 0.14% vs.
0.74 ± 0.16% (p = 0.05)
3) Optimal dosage of insulin (mean ± SD):
0.9 ± 0.14 vs. 0.9 ± 0.10 units/kg/day (NS)
4) Mean blood glucose (mean ± SD):
211 ± 24 vs. 188 ± 23 mg/dl (p = 0.04)
(11.7 ± 1.3 vs. 110.4 ± 1.3 mmol/l converted
from mg/dl)
5) Cholesterol (mean ± SD): 197 ± 9 vs.
194 ± 18 mg/dl (NS) (10.9 ± 0.5 vs.
10.7 ± 1 mmol/l)
37
6) Triglycerides (mean ± SD): 136 ± 25 vs.
183 ± 49 mg/dl (p = 0.01) (7.6 ± 1.4 vs.
10.2 ± 2.7 mmol/l)
Evidence tables
Trial length: two 6-week
periods
3) Optimal dosage of insulin
Study
Population
Intervention
Outcomes
Results
Comments
Design
Hinde and
Johnston,
1986112
18 children with
type 1 diabetes
3 daily insulin injections,
intermediate-acting and shortacting before breakfast, shortacting before evening meal,
and intermediate-acting
before bedtime (n = 18)
1) HbA1c (mean ± SEM): 11.67 ± 0.46 vs.
11.76 ± 0.40% (NS)
Supported by Novo
RCT crossover Ib
Supported by Novo
RCT crossover Ib
Aged 10–16 years
versus
EL
2) Hypoglycaemia (frequency over
4 months, mean ± SEM)
2) Hypoglycaemia Grade I: 3.9 ± 0.91 vs.
4.1 ± 1.2 (NS), Grade II: 0.2 ± 0.2 vs.
3) Weight gain
0.4 ± 0.1 (NS), Grade III: 0 vs. 0.1 ± 0.1 (NS)
4) Convenience of regimen
3) 1.90 ± 0.42 vs. 1.02 ± 0.52 kg/4 months
intermediate-acting and shortacting before breakfast and
before main evening meal
(n = 18)
(NS)
4) Convenience of regimen (number who
find it more convenient): 13/18 vs. 2/18
periods
Smith et al,
1988109
10 young people
4 daily injections, short-acting 1) Glycated haemoglobin
with type 1 diabetes insulin before the three meals
2) Insulin doses
and intermediate-acting at
Aged 13–19 years
bedtime (n = 10)
3) Perception of hypoglycaemia
UK
versus
4) Blood glucose concentration at
08:00 and 10:00
intermediate-acting and shortacting insulin in the morning
and short-acting insulin
before lunch and evening
meal (n = 10)
periods
1) Glycated haemoglobin (mean ± SD):
12.7 ± 1.0 vs. 13.1 ± 0.8% (NS)
Insulin doses: 1.14 ± 0.08 vs.
1.14 ± 0.08 units/kg (NS)
3) No difference
4) At 08:00: 17.9 ± 1.9 vs. 13.1 ± 2.3 mmol/l,
p < 0.02
At 10:00: 18.6 ± 0.7 vs. 14.5 ± 1.4 mmol/l,
p < 0.03
(but no significant difference at any other
time of day)
Type 1 diabetes
38
Further comparisons of insulin regimens (not intensive versus standard) (continued)
Study
Population
Intervention
Outcomes
Results
Fanelli et al,
2002110
22 adults with type
1 diabetes
short-acting insulin before the
three main meals and longacting insulin at bedtime
(split) (n = 22)
1) Insulin dosages
1) Insulin dosages: 35 ± 2 vs.
35 ± 2.5 units/day (NS)
versus
3) Hypoglycaemic episodes
Aged 29 ± 3 years
Italy
2) Blood glucose concentration at
fasting, 03:00, before lunch and
before dinner
short-acting insulin before
breakfast and lunch, and longacting and short-acting insulin
at dinner time (mixed) (n = 22)
periods
Comments
Design
EL
RCT crossover Ib
2) At fasting: 7.6 ± 0.2 vs. 8.9 ± 0.5 mmol/l,
p < 0.030
At 03:00: 7.2 ± 0.2 vs. 6.2 ± 0.2 mmol/l,
p < 0.001
Before lunch: 8.1 ± 0.2 vs. 9.2 ± 0.4 mmol/l,
p = 0.050
Before dinner: 7.81 ± 0.3 vs.
8.7 ± 0.4 mmol/l, NS
3) 28 (9.3%) vs. 90 (29%), OR 3.1 (95% CI
2–5), p < 0.001
No difference in perception of
hypoglycaemia
Tallroth et al,
1989113
18 adults with type
1 diabetes
Aged 31.0 ± 7.4
years
Sweden
HbA1c
short-acting insulin before the
three meals and intermediateacting at bedtime (n = 18)
versus
intermediate-acting and shortacting before breakfast, shortacting before supper,
intermediate-acting or longacting at bedtime (n = 18)
During the first time period the group who
received 4 injections daily experienced a
decrease in HbA1c to 90.4% of the pre-study
level (p < 0.02). No significant change
experienced in the group who received 3
injections daily:e HbA1c decreased to 94.7%
of the pre-study level (NS). No significant
differences were experienced in the second
period (full values not given)
For patients on the 4
injections daily regimen,
the insulin was given
through an insulin pen.
However, during the 3
injection daily regimen
the insulin was given
through conventional
syringes
Insulin dosage: 48.2 ± 11.6 vs.
48.2 ± 11.6 units/day
Full information not given
in the paper
RCT crossover Ib
periods
Evidence tables
39
Study
Population
Intervention
Outcomes
Results
Comments
Design
Stades et al,
2002107
104 patients with
type 1 diabetes
5 daily insulin injections: 2
injections of isophane insulin
each day, one at bedtime and
one at lunch time, and short/rapid-acting insulin before
meals (n = 60)
1) HbA1c (mean difference ± SE):
0.061 ± 0.068% (NS)
Supported by Eli Lilly
RCT crossover Ib
1) Glycated haemoglobin (mean ± SD):
6.5 ± 0.9% vs. 6.6 ± 1.1% (NS)
Supported by Novo
Nordisk
RCT crossover Ib
2) Fasting blood glucose (mean ± SD):
9.0 ± 4.4 vs. 9.6 ± 4.2 mmol/l (NS)
Total units of insulin
given were the same in
each regimen but for 5
daily injections regimen
28 units given by shortacting insulin, and
28 units given by
intermediate-acting
insulin. However, for 4
daily injections regimen
33 units given by shortacting insulin, and
23 units given by
intermediate-acting
insulin
Aged 16–65 years
Netherlands
2) Mild hypoglycaemia (events/30
days)
(events/patient years)
versus
4) Asymptomatic hypoglycaemia
4 daily insulin injections with (events/30 days)
one injection of intermediateacting insulin at bedtime, and
short-/rapid-acting insulin
before meals (n = 61)
periods
EL
2) Mild hypoglycaemia (mean difference
(range)):
Average over 24 hours: –0.93 (–13.7 to 15.4)
(p = 0.002)
Split by time: 00:00–05:59: –0.48 (–3.4 to
1.5) (p = 0.053), 06:00–11:59: –0.25 (–5.1 to
7.11) (NS), 12:00–17:59: –0.40 (–6.2 to 3.8)
(NS),: –0.56 (–5.5 to 3.4) (p = 0.001)
3) Severe hypoglycaemia (mean difference
(range)):
Average over 24 hours: –5.8 (–95.6 to 21.5)
(p = 0.083)
Split by time: 00:00–05:.59: –5.8 (–9.1 to
17.4) (NS), 06:00–11:59: –5.8 (–43.4 to 6.6)
(NS), 12:00–17:59: –5.5 (–17.4 to 7.3) (NS),
18:00–23:59: –6.9 (–26.0 to 5.8) (p = 0.007)
4) Asymptomatic hypoglycaemia (mean
difference (range)): 0.06 (–12.8 to 5.2) (NS)
Wolffenbuttel
et al, 1990108
43 patients with
type 1 diabetes
Aged 37 ± 11 years
Netherlands
before breakfast and at
bedtime, and short-acting
insulin before the three main
meals (n = 43)
versus
5) Patient preference
intermediate-acting insulin at
bedtime and short-acting
insulin before the three main
meals (n = 43)
periods
2) Fasting blood glucose
3) Mean daily blood glucose
4) Serum fructosamine
3) Mean daily blood glucose (mean ± SD):
7.9 ± 2.0 vs. 8.1 ± 2.2 mmol/l (NS)
4) Serum fructosamine (mean ± SD):
2.97 ± 0.43 vs. 2.99 ± 0.39 mmol/l (NS)
5) Patient preference: 13/43 vs. 21/43
Type 1 diabetes
40
Study
Population
Intervention
Outcomes
Results
Comments
Design
Schrezenmeir
et al, 1985114
12 patients with
type 1 diabetes
Computer-assisted mealrelated insulin therapy (3–4
injections per day)
1) HbA1c
1) 10.2 ± 1.5% to 8.6 ± 0.8% vs. 9.8 ± 1.3%
to 9.1 ± 1.0% (p < 0.05)
The number of insulin
injections was flexible
RCT crossover Ib
2) 9.10 ± 2.96 to 6.22 ± 0.65 mmol/l vs.
8.86 ± 1.83 to 6.91 ± 0.90 mmol/l (p < 0.05)
Unknown age of patients
1) GHb (mean (SEM)): 9.88% (0.23%) vs.
9.61% (0.23%) (NS)
Supported by Novo
Germany
2) Glucose level
versus
EL
conventional therapy (2–3
injections per day)
periods
Hinde and
Johnston,
1985115
16 children with
type 1 diabetes
Aged 3–12 years
intermediate-acting and shortacting in the morning and
only before bedtime (n = 18)
versus
1) GHb (mean from last 2 months
of 4 of treatment)
RCT crossover Ib
2) Hypoglycaemia (frequency over 2) Hypoglycaemia Grade I: 7.25 ± 2.9 vs.
4 months, mean ± SEM)
5.25 ± 2.4 (p < 0.04), Grade II: 0.81 ± 0.38 vs.
0.38 ± 0.16 (NS), Grade III: 0.23 ± 0.11 vs.
0.13 ± 0.09 (NS)
intermediate-acting and shortacting in the morning and
intermediate-acting with or
without short-acting before
the evening meal (n = 19)
periods
Evidence tables
41
Study
Population
Golden et al,
1985116
19 children with
type 1 diabetes
Intervention
Group A: (n = 11) children
treated with an ‘intensive’
programme from diagnosis
Aged under 5 years (mean duration of observation
13.6 months)
versus
Group B: (n = 8) children
treated from diagnosis with
less-intensive treatment (for
mean duration of observation
of 14.9 months)
versus
Group B: (n = 8) after lessintensive treatment referred to
‘intensive’ programme (for
mean duration of observation
of 14.6 months)
Intensive programme
involved: frequent home
blood glucose monitoring
used as the basis of an
educational programme
emphasising parental
adjustment of insulin in
response to current glucose
levels and anticipated diet
and exercise
Outcomes
Results
Comments
Design
EL
1) Hospitalisations for
hypoglycaemia
1) Hospitalisations: Group B had 11 before
referral and 2 during intensive programme;
group A had 1 during intensive programme
(p < 0.01 for each comparison)
Not robust methodology.
Confusion in analysis as
duration of diabetes was
different between the
groups group B compared
before and after intensive
programme, and group A
just used as a reference
level
Nonrandomised
intervention
study
IIb–III
2) Episodes of severe
hypoglycaemia
2) Episodes of severe hypoglycaemia per
child: Group B had 3.3 episodes per child
per 18 months before referral and 1.7
episodes per child per 18 months during
intensive programme; group A had 0.4
episodes per child per 18 months during
intensive programme
3) Overall mean HbA1 levels were higher in
Group B than Group A (p < 0.10); at
equivalent durations of illness Group B had
higher levels than Group A (p < 0.05)
Type 1 diabetes
42
Continuous subcutaneous insulin infusion
Study
Population
Intervention
Schiffrin et al,
1984122
24 young people
CSII and short-acting insulin
and young adults
(n = 20)
versus
(20 analysed)
multiple daily injections with
Aged 13–20 years
short-acting insulin (n = 20)
Canada
versus
Outcomes
Results
Comments
1) HbA1 (after 4 months)
1) 8.8% vs. 9.6% vs. 9.3% (numbers from
NICE TA,121 no confidence intervals given)
4 patients dropped out of Crossover
study
RCT
2) Frequency of severe
hypoglycaemia
4) ‘Would you recommend
regimen to a friend?’
CSII and multiple daily
5) Insulin dosage
injections, CSII overnight with
preprandial injections of
short-acting insulin during the
day, pumps used for prebreakfast bolus (n = 20)
Design
EL
Ib
CSII treatment HbA1c level significantly lower Discussed in NICE TA121
than other treatment arm, p < 0.05
Patients ‘failed’ to
2) 1 vs. 1 vs. 0 episodes
respond to a twice-daily
injections with home
3) 11 vs. 4 vs. 3 episodes
blood glucose monitoring
regimen, had not
4) 100% vs. 66% vs. 70%
previously been on
5) 44 (SD 12) vs. 60 (SD 16) vs. 48 units/day intensive therapy, were
(SD 16), p < 0.001
not significantly obese
Trial length: three 4-months
periods
Schiffrin et al,
1983124
Cohen et al,
2003126
20 young people
CSII and short-acting insulin
and young adults
(n = 19)
versus
(19 analysed)
Aged 13–18 years, intensive therapy with 3 or 4
mean age 15 years daily injections of insulin
(n = 19)
Canada
periods
HbA1 (after 4 months)
16 young people
CSII (n = 12)
versus
(12 patients
analysed)
multiple daily insulin
injections with three or 4
Aged 14.5–17.9
daily injections (n = 12)
years, median age
1) HbA1c
1) 8.15 ± 1.3% vs. 8.57 ± 0.44% (NS)
2) Fructosamine
2) 384 ± 77 vs. 399 ± 55 nmol/l (NS)
3) Frequency of symptomatic
hypoglycaemia
3) 0.13 vs. 0.61 rate per patient year (NS)
14.2 years
Israel
periods
Not significant (numbers not given)
1 patient dropped out of
study
Crossover
RCT
Ib
4 patients dropped out of Crossover
study
RCT
Ib
Patients ‘failed’ to
respond to a twice-daily
injections regimen
4) Frequency of hyperglycaemic
events
6) Body mass index standard
deviation score
7) Treatment satisfaction (can
range from 6 to 36, the higher the
more satisfied)
43
8) Quality of life
5) 1 vs. 0 episodes
6) 0.23 ± 0.45 vs. 0.25 ± 0.44 (NS)
7) 32 ± 6.5 vs. 21.8 ± 3.7, p < 0.05
8) Satisfaction scale: 82.7 ± 13 vs.
76.4 ± 14.3, p < 0.05
Evidence tables
5) Frequency of diabetic
ketoacidosis
4) 0.58 ± 1.7 vs. 0.2 ± 0.4 mean per patient
per study period (NS)
Study
Population
Intervention
Pozzilli et al,
2003127
23 young people
CSII and nicotinamide (n = 19)
and adults with type
versus
1 diabetes
intensive subcutaneous
Aged 12–35 years
therapy and nicotinamide
Italy
(n = 19)
Outcomes
Results
Comments
Design
EL
1) HbA1c at 2 years
1) 6.3 ± 0.5% vs. 6.2 ± 0.3% (NS)
Ib
2) Frequency of severe
hypoglycaemia events
2) No differences observed (numbers not
given)
4 patients dropped out of RCT
study
3) Body weight
3) No differences observed (numbers not
given)
1) Mean glycated haemoglobin
over the whole treatment period
1) Mean 9.1% SD 0.9% vs. 10.4% SD 0.2%, 5 patients dropped out of RCT
p < 0.001
study
Ib
2) Moderate or severe
hypoglycaemia
2) 7 vs. 4 episodes (NS)
Davies et al,
1984125
13 children and
young people with
type 1 diabetes
CSII (n = 13)
Aged 8–16 years
intensified conventional
treatment (n = 13)
UK
Kaufman et al,
2000132
10 children with
type 1 diabetes
Aged 7–10 years
USA
versus
Night time only CSII
combined with pre-breakfast
injection of intermediateacting insulin and rapidacting insulin (n = 10)
versus
3 injections per day of insulin
(n = 10)
Trial length: two periods of 4
weeks with 2 weeks in
between optimisation/washout
3) 6 vs. 0 episodes
3) Episodes of diabetic
ketoacidosis
1) Fructosamine
1) 345 ± 36.6 vs. 390 ± 36.6 mol/l, p = 0.03
2) % of blood glucose levels in
target
2) 44 ± 6.7% vs. 37 ± 6.7%, p = 0.04
Crossover
RCT
Ib
Type 1 diabetes
44
Continuous subcutaneous insulin infusion (continued)
Continuous subcutaneous insulin infusion (continued)
Study
Population
Intervention
Outcomes
Results
CSII (n = 23)
1) HbA1c
1) 8.0 ± 0.7% vs. 8.1 ± 0.8%, p = 0.03
versus
2) Fructosamine
2) 362 ± 43 vs. 354 ± 56 nmol/l (NS)
Aged 9.4–13.9
years
multiple daily injections
(n = 23)
3) Frequency of symptomatic
hypoglycaemia
3) 0.13 (95% CI 0.0–0.4) vs. 0.36 rate per
patient year (95% CI 0.0–0.84) (NS)
Israel
Trial length: two periods of
3.5 months
4) Frequency of hyperglycaemic
events
4) 7.9 ± 7 vs. 6.7 ± 7.3 (NS)
Weintrob et al, 23 children and
2003129
young people with
type 1 diabetes
5) Frequency of diabetic
ketoacidosis
6) Body mass index standard
deviation score
7) Treatment satisfaction (can
range from 6 to 36, the higher the
more satisfied)
8) Quality of life
Willi et al,
2003130
51 children and
young people with
type 1 diabetes
Followed 12 months before
and after introducing CSII
Comments
Design
EL
Crossover
RCT
Ib
5) 0 vs. 0 episodes
6) 0.35 ± 0.83 vs. 0.37 ± 0.85, p = 0.012
7) 30.6 ± 3.7 vs. 21.9 ± 3.8, p < 0.001
8) Satisfaction scale: 74.8 ± 13.5 vs.
73.5 ± 14.0 (NS)
Impact scale: 73.2 ± 9.6 vs. 73.5 ± 9.7 (NS)
Worry scale: 81.6 ± 12.4 vs. 79.8 ± 12.8 (NS)
HbA1c
12 months before CSII 8.4 ± 0.2% vs. 12
months after transfer to CSII 7.9 ± 0.1%,
p < 0.01
1) HbA1c
1) Before CSII treatment mean 9.5 ± 0.4% vs.
after initiation of pump therapy 7.9 ± 0.3%
No strict selection criteria Case series
for study
III
Case series
III
Aged 1.2–15.5
years, mean age
10.7 ± 3.1 years
USA
Litton et al,
2002131
9 infants with type
1 diabetes
Aged 20–58
months, mean age
34.1 ± 4.5 months
USA
Children were transferred to
CSII after a mean of 13.7
months on multiple daily
injections
Children followed for a mean
of 12.7 months (range 7–19
months)
2) Episodes of hypoglycaemia
2) Before CSII treatment mean 0.52 episodes
per month vs. after initiation of pump
therapy 0.09 episodes per month
Evidence tables
45
Study
Population
Intervention
Outcomes
Results
Mortensen et
al, 1998117
1443 males and
1430 females with
type 1 diabetes
Cross-sectional survey
investigating HbA1c, insulin
dosage, number of daily
insulin injections, type of
insulin, height, weight,
duration of diabetes, year of
birth, sex
1) Average HbA1c
1) In children under 11: 8.3 ± 1.3%
2) Insulin dosage
In children aged 12 to 18: 8.9 ± 1.8%
3) Number of injections
2) Children aged 2 to 9: mean insulin dosage
was 0.654 units/kg/24 hours
Aged 1–18, mean
13 years
22 paediatric
departments in 18
countries in Europe,
Japan and North
America
Comments
Design
EL
Crosssectional
survey
III
Highest mean dosage was
0.98 ± 0.03 units/kg/per 24 hours, which was
recorded at 14 years for females and at 17
years for males
Prepubertal females: 95% CI
0.5–1.2 units/kg/24 hours
Prepubertal males: 95% CI
0.4–1.0 units/kg/24 hours
Pubertal females: 95% CI 0.7–1.7 units/kg/24
hours
Pubertal males: 95% CI 0.6–1.5 units/kg/24
hours
3) 60% of children used two or three daily
injections
37% used pre-mixed insulins either alone or
in combination with short- and intermediateacting insulin
Mann and
Johnston,
1984119
10 young people
with poor blood
glucose control
during the previous
year
Increased dosage of insulin:
1.4 units/kg/day
Mean age 14.1
years
periods
UK
versus
Limited dosage of insulin:
1.0 units/kg/day
1) HbA1
1) 13.5% (SE 0.7%) vs. 15.9% (SE 0.7%),
p < 0.001
10.6 (SE 1.1) vs. 12.5 mmol/l (SE 1.0),
p < 0.01
RCT crossover Ib
Type 1 diabetes
46
Insulin dosage
4.3
Insulin preparations
The treatment of children with type 1 diabetes with human compared with animal insulin
Study
Population
Intervention
Richter and
2156 participants in Human insulin
Neises, 2002135 45 RCTs
versus
Patients with
animal insulin
diabetes, all ages
Duration of trials at least 1
month
Outcomes
HbA1c
HbA1
Fasting plasma glucose
Insulin dosage
Insulin antibodies
Results
Comments
No significant differences in metabolic
control or hypoglycaemic episodes between
various insulin species could be elucidated
A comparison of the
effects of human and
animal insulin as well of
the adverse reaction
Insulin dosage and insulin antibodies did not profile did not show
show relevant dissimilarities
clinically relevant
differences
Design
EL
Systematic
review of
RCTs
Ia
RCT
Ib
Many patient-oriented
outcomes such as healthrelated quality of life,
diabetes complications or
mortality have never been
investigated in highquality RCTs
Greene et al,
1983136
14 children with
type 1 diabetes
Mean ages:
13.2 ± 1.8 and
13.7 ± 2.5 years
Setting: UK single
centre
Human monocomponent
insulin zinc suspension
(Monotard) and soluble
insulin (Actrapid insulin)
1) HbA1
1) 11.9 ± 2.5% vs. 11.5 ± 3.8%
2) Fasting plasma glucose
2) 7.8 ± 4.9 vs. 8.3 ± 4.6 mmol/l
3) Insulin dosage
3) 48 ± 18 vs. 45 ± 18 units/day
versus
4) Adverse effects
4) 3 drop-outs
between the two groups
was seen overall
Insulin antibodies
78% vs. 100%
Randomisation
procedure: data missing
porcine monocomponent
(Monotard) and soluble
insulin (Actrapid insulin)
Randomisation
Allocation concealment:
unclear
Double blind
crossover
study
Duration of trial 3 months
Heding et al,
1984137
21 children with
type 1 diabetes
Semisynthetic human insulin
1) HbA1
1) 14.4 ± 1.8% vs. 13.8 ± 1.7%
versus
2) 12.0 ± 2.1 vs. 11.0 ± 2.4 mmol/l
purified porcine insulin
3) Insulin dosage
3) 37 ± 10 vs. 37 ± 13 units/day
4) Adverse effects
4) 3 drop-outs vs. 1 drop-out
47
Setting: UK single
centre
Ib
Parallel
unclear
multicentre
Mean age 12/11
years
(human/animal
insulin)
RCT
Randomisation
unclear
RCT
Double blind
crossover
study
Ib
Evidence tables
Mann et al,
1983138
135 newly
diagnosed children
with type 1 diabetes versus
purified porcine insulin
Setting: Denmark
Study
Population
Marshall et al,
1988139
100 newly
diagnosed children
with type 1 diabetes versus
Mean age 9/9 years purified porcine insulin
(human/animal
insulin)
Setting: Denmark
multicentre
Intervention
Outcomes
Results
Comments
Design
EL
Adverse effects
12 vs. 13 drop-outs
Randomisation
procedure: adequate
RCT Parallel
Ib
unclear
Type 1 diabetes
48
The treatment of children with type 1 diabetes with human compared with animal insulin (continued)
What is the ideal type of insulin therapy in the treatment of children with type 1 diabetes: analogue or conventional?
Rapid-acting insulin analogues versus soluble insulin
Systemic reviews
Study
Population
Intervention
Davey et al,
1997143
8 RCTs (n = 2834) of Rapid-acting insulin analogue
people with type 1 (insulin lispro)
or type 2 diabetes
versus
Studies of at least 6
human soluble insulin
months duration
and more than 30
people, all studies
were open label
Outcomes
Results
1) Decrease in postprandial blood
glucose level to ≤ 8 mmol/l
For studies in patients with type 1 diabetes
only:
Comments
Data is from the New
Drug Application
package, from Eli Lilly,
2) A 2-hour postprandial blood
1) Significantly more patients had a decrease the studies have been
glucose level within 20% of the
in postprandial blood glucose level to
presented either
pre-meal level
≤ 8 mmol/l with insulin lispro (OR 1.52, 95% individually or in various
CI 1.27–1.83, p < 0.00001)
combinations at
3) At least a 50% decrease from
international meetings,
baseline in 2-hour postprandial
2) No significant difference (OR 1.05, 95%
but it is unknown if they
blood glucose excursion
CI 0.89–1.25, p = 0.55)
have been published and
3) No significant difference (OR 1.14, 95%
peer reviewed
CI 0.95–1.37, p = 0.15)
5) Fasting blood glucose level
A literature search was
4) No difference seen (WMD 0.028, 95% CI also performed on
6) 1- and 2-hour postprandial
–0.196 to 0.253, p > 0.5)
MEDLINE and EMBASE,
blood glucose level
up to 1996 three papers
5) No difference seen (WMD 0.2, 95% CI
7) 1- and 2-hour blood glucose
were found but excluded
–0.828 to 1.399, p = 0.10–0.20)
excursion
from the study due to
6) Insulin lispro showed significant
8) Hypoglycaemic rate per 30 days advantages in the 2-hour postprandial blood small sample times and
short durations
glucose level (WMD –1.546, 95% CI –2.708
Unknown if any children
to –0.383, p < 0.05), and the 1-hour
postprandial blood glucose level approached were involved in the
studies
significant levels (WMD –0.794, 95% CI
–1.924 to –0.336, p = 0.05–0.10)
Sponsored by Eli Lilly
Design
EL
Systematic
Ia
review
resulting in a
meta-analysis
of 8
unpublished
clinical trials
7) Insulin lispro showed significant
advantages in the 1-hour blood glucose
excursion (WMD –1.183, 95% CI –1.975 to
–0.391, p < 0.02) and the 2-hour blood
glucose excursion (WMD –1.915, 95% CI
–2.933 to –0.897. p < 0.01)
8) No difference seen (WMD –0.489, 95%
CI –1.774 to 0.796, p = 0.3–0.2)
Evidence tables
49
Study
Population
Intervention
Outcomes
Brunelle et al,
1998144
8 RCTs (n = 2576) of Rapid-acting insulin analogue Severe hypoglycaemia
people with type 1 (insulin lispro)
diabetes
versus
Studies of at least 4
months duration
and more than 90
people
Results
Comments
Severe hypoglycaemia was significantly
reduced with treatment with insulin lispro
(RR 0.703, 95% CI 0.518–0.956, p = 0.024)
One study included in the Meta-analysis Ia
meta-analysis is
of 8 large
unpublished
multicentre
clinical trials.
The trials were identified
from the database of Eli
3 parallel and
Lilly; a full systematic
5 crossover
review was not performed design studies
5 of the studies included
in this systematic review
were also included in the
Heinemann141 study and
three were included in
the Shukla142 study
were involved in the
studies
Design
EL
Type 1 diabetes
50
Systemic reviews (continued)
Study
Population
Intervention
Heinemann,
1999141
24 clinical trials
including 20 studies
in patients with type
1 diabetes and 2
studies in patients
with type 2
diabetes, and 2
studies in patients
with both type 1
and type 2 diabetes
Rapid-acting insulin analogue Incidence of hypoglycaemic
events
versus
Change in perception of
soluble insulin
hypoglycaemic events
22 studies of insulin lispro
and 2 studies of insulin aspart
1 study investigated
pubertal children
and 1 study
investigated
paediatric patients
Outcomes
Results
Comments
Design
A significant reduction in the incidence of
mild hypoglycaemic events with insulin
lispro compared with soluble insulin was
reported in 5 out of 21 studies (not including
the aspart studies). 1 study only saw an
improvement in nocturnal hypoglycaemia.
No summary statistics were given
Unknown how the papers
were found, the only
details are that published
up to May 1998
Review of 24 Ia
controlled
clinical trials
(2 studies are
of insulin
aspart)
1 of 21 studies reported a significant
increase in the incidence of mild
hypoglycaemic events in the insulin lispro
compared with soluble insulin group. No
summary statistics were given
The incidence of severe hypoglycaemia was
reported in 9 studies (studies in patients with
type 1 diabetes and excluding the aspart
studies). No change was observed in 7
studies. 2 studies found a significant
reduction in the incidence of severe
hypoglycaemic events in the insulin lispro
compared with soluble insulin (values
0.07 ± 0.3 vs. 0.53 ± 1.5 (lispro vs. soluble)
and 36/2249 vs. 58/2344)
The incidence of nocturnal hypoglycaemic
events was reported in 5 studies. They all
showed a reduction in nocturnal
hypoglycaemia in the insulin lispro groups,
one did not give values, all the rest showed
that there were statistically significantly
fewer cases of nocturnal hypoglycaemia in
insulin lispro compared with soluble insulin
(values 176 vs. 312 (lispro vs. soluble),
1.0 ± 1.9 vs. 1.7 ± 2.6, 52 vs. 181, 1.2 ± 2.2
vs. 1.7 ± 2.4)
13 of the studies were
only published in abstract
form
EL
It is unknown if some
patients may appear in
more than one study
19 of the studies were
open, unblended study
design, 10 studies were
multicentre and 20 were
crossover in design
Measure of severity of
hypoglycaemia is
subjective
5 of the studies included
in this systematic review
were also included in
Brunelle144 and 5 studies
were also included in the
Shukla142 study
Studies including patients
with type 1 and type 2
diabetes were included in
the systematic review
were involved in the
studies
Evidence tables
51
Study
Population
Intervention
Shukla and
Otten, 1999142
7 published studies,
4 studying patients
with type 1
diabetes, 2 papers
studying patients
with type 1 and 2
diabetes, and 1
paper studying type
2 diabetes
Rapid-acting insulin analogue 1) Postprandial rise in serum
(insulin lispro)
glucose
6 unpublished
studies, including 4
studying patients
with type 1
diabetes, 1 studying
and 2 diabetes, and
one with unknown
type of diabetes
versus
Outcomes
Postprandial glucose excursions
2) HbA1c
3) Hypoglycaemia
4) Quality of life evaluation
Results
Comments
1) Lispro significantly decreases the
postprandial rise in serum glucose and
postprandial glucose excursions compared
with soluble insulin therapy (6 published and
5 unpublished studies reported difference in
2-hour postprandial increase in glucose, all 6
of the published studies and 4 of the
unpublished studies gave p values and
showed significant values
Studies include a
mixture of designs
such as unblinded
or blinded,
multicentre or
single centre,
parallel or crossover
or sequential trials
EL
6 unpublished studies
Systematic
Ia
included in the systematic review for a
review
technology
report, critical
5 of the studies included evaluation of
in this systematic review the 13
were also included in
controlled
Heinemann141, and 3 of
clinical trials
the studies were also
(2 studies are
144
included in Brunelle
of insulin
2) The studies showed insulin lispro had a
aspart)
mixed impact on long-term glycaemic control Measures of severity of
hypoglycaemia and
(just 2 out of 6 (of the studies including
quality of life are
patients with type 1 diabetes) published
subjective, and varied
studies and 3 out of 5 unpublished studies
between studies
showed a significant difference in HbA1c
Lispro use in insulin pump therapy was
considered by 2 additional short-term studies. were involved in the
studies
In 1 of the studies HbA levels were shown
1c
The study durations
were 2 to 12
months
Design
to be significantly lower in the lispro group
(lispro 7.66% vs. human insulin 8.00%), in
the second study lispro decreased HbA1c
levels significantly more (–0.62%) than the
continuous infusion of soluble human insulin
(–0.09%, p = 0.01)
Studies including patients
with type 1 and type 2
diabetes were included in
the systematic review
No statistical analysis to
summarise data from
3) Differences in frequency of hypoglycaemic different studies
episodes were measured in all of the studies.
In 3 out of 6 of the published studies with
patients with type 1 diabetes but none of the
unpublished studies there were a significantly
lower number of hypoglycaemic episodes in
the patients treated with lispro
4) Quality of life evaluation of the impact of
lispro was studied in 2 published studies and
3 abstracts. One of the published studies
looking at patients with type 1 and 2 diabetes
concluded that the lispro had a measurable
impact on lifestyle benefits in patients with
type 1 diabetes. In a second study no
difference in quality of life was found. In the
3 abstracts it was concluded that the patients
perceived an improvement in their wellbeing
and quality of life due to the freedom and
flexibility of injections and improvement in
number and severity of hypoglycaemic
reactions
Type 1 diabetes
52
RCTs included in the meta-analysis presented in the Guideline
Study
Population
Anderson et al, 1008 adults with
1997146
type 1 diabetes
Intervention
Outcomes
Results
Comments
Design
EL
RCT
multicentre
crossover
Ib
RCT
multicentre
parallel
Ib
Rapid-acting insulin analogue 1) HbA1c
(insulin lispro) (n = 1008)
2) Hypoglycaemic episodes per
versus
patient per 30 days
1) 8.20 ± 3.17% vs. 8.20 ± 3.17%, WMD
0.00, 95% CI –0.28 to 0.28
Anderson et al, 336 adults with type Rapid-acting insulin analogue 1) HbA1c
1997145
1 diabetes
Australia, Belgium, versus
patient per 30 days
Canada, Finland,
soluble insulin (n = 174)
France, Germany,
Israel, Italy,
Netherlands, New
Zealand, Norway,
South Africa, Spain,
Sweden, UK, USA
1) 8.10 ± 1.27% vs. 8.30 ± 1.32%, WMD
–0.20, 95% CI –0.48 to 0.08
Annuzzi et al,
2001147
8.27 ± 0.79% vs. 8.12 ± 0.85%, WMD 0.15,
95% CI –0.10 to 0.40
RCT
multicentre
crossover
Ib
7.06 ± 1.30% vs. 6.82 ± 0.80%, WMD 0.24,
95% CI –0.71 to 1.19
RCT single
centre
crossover
Ib
1) 6.96 ± 0.57% vs. 6.84 ± 0.57%, WMD
0.12, 95% CI –0.44 to 0.68
RCT single
Ib
centre parallel
Australia, Austria,
Belgium Finland,
France, Germany,
Israel, Netherlands, Trial length: two 3-month
South Africa, Spain, periods
USA
85 adults with type
1 diabetes
Rapid-acting insulin analogue HbA1c
Italy
versus
2) 6.40 ± 6.35 vs. 7.20 ± 9.52, WMD –0.80,
95% CI –1.51 to –0.09
2) 4.40 ± 6.36 vs. 4.50 ± 5.28, WMD –0.10,
95% CI –1.35 to 1.15
periods
Caixas et al,
1998148
118 adults with type Rapid-acting insulin analogue HbA1c
1 diabetes
13 withdrew
versus
Spain
periods
16 adults with type
1 diabetes
Italy
versus
patient per 30 days
2) 8.10 ± 2.26 vs. 4.00 ± 1.14, WMD 4.10,
95% CI 2.25 to 5.95
53
Evidence tables
Ciofetta et al,
1999149
Study
Population
Colombel et al, 25 adults with type
1999150
1 diabetes
Aged 37.2 ± 12.6
years
France
Intervention
Outcomes
Rapid-acting insulin analogue 1) Patient preference
(insulin lispro) (n = 25) (5 min
2) HbA1c reduction
before meals)
3)
Mean of the daily blood glucose
versus
level (from self-monitored capillary
soluble insulin (n = 25) (20–30 blood glucose levels)
min before meals)
4) Variability of blood glucose
profiles
periods
5) Hypoglycaemia
Results
Comments
1) 21/25 vs. 4/25, RR 5.25, 95% CI 2.10 to
13.10
No description of how
RCT single
randomisation took place centre
crossover
Ib
RCT
multicentre
crossover
Ib
2) –0.40 ± 0.86% vs. –0.08 ± 0.71%, NS
Design
EL
Decreases in HbA1c were seen in 72% of
patients with lispro and 48% patients with
soluble insulin (p = 0.019). The decrease in
HbA1c from baseline was significant for both
lispro treatment groups (p < 0.05) but not for
the soluble insulin groups
3) 1.53 ± 0.48 vs. 1.82 ± 0.57 g/l, p < 0.05
4) Within-day blood glucose variability index
0.73 ± 0.36 vs. 0.99 ± 0.50 g/l, p < 0.01
Between-day blood glucose variability index
0.64 ± 0.26 vs. 0.80 ± 0.40 g/l, p < 0.05
5) Mild hypoglycaemic episodes (2.2 < blood
glucose < 3.3 mmol/l) 19.9 ± 13.5 vs.
19.4 ± 11.0
Moderate hypoglycaemic episodes (blood
glucose < 2.2 mmol/l) 4.4 ± 6.4 vs. 3.1 ± 3.2
Severe hypoglycaemic episodes (external
help needed) lispro 3 in 3 patients and
soluble insulin 8 in 3 patients
Deeb et al,
2001151
61 children with
type 1 diabetes
Aged 2.9–11.4,
mean 7.6 years
Canada, USA
versus
patient per 30 days
Trial length: three 3-month
periods
1) 8.40 ± 1.10% vs. 8.43 ± 1.00%, WMD
–0.03, 95% CI –0.41 to 0.35
2) 13.60 ± 9.30 vs. 13.80 ± 9.80, WMD
–0.20, 95% CI –3.65 to 3.25
Type 1 diabetes
54
RCTs included in the meta-analysis presented in the Guideline (continued)
Study
Population
Intervention
Del Sindaco
and Ciofetta,
1998152
15 adults with type
1 diabetes
Italy
Outcomes
Results
Comments
Rapid-acting insulin analogue 1) Hypoglycaemic episodes per
patient per 30 days
1) 5.30 ± 4.80 vs. 4.00 ± 3.40, WMD 1.30,
95% CI –1.68 to 4.28
versus
2) Mean daily blood glucose concentrations
8.8 ± 1.2 vs. 8.6 ± 0.8 mmol/l, p > 0.05
After 1-month run-in
RCT single
period patients were
centre
randomly assigned to 4
crossover
different studies. (1
reported here and 1
below). No description of
how this randomisation
took place
2) Blood glucose profiles
Fasting, pre-meal and nocturnal blood
glucose levels 8.9 ± 1.1 vs. 8.3 ± 1.2 mmol/l,
p < 0.05
periods
Design
EL
Ib
90 min postprandial glucose 8.9 ± 0.7 vs.
9.2 ± 1.4 mmol/l, p < 0.05
Del Sindaco
and Ciofetta,
1998152
12 adults with type
1 diabetes
Rapid-acting insulin analogue 1) Hypoglycaemic episodes per
patient per 30 days
1) 4.40 ± 3.80 vs. 11.00 ± 4.80, WMD –6.60, Reported in same paper
95% CI –10.06 to –3.14
as above
Italy
versus
2) Mean daily blood glucose levels 8.1 ± 0.8
vs. 8.5 ± 1.1 mmol/l, p < 0.001
RCT single
centre
crossover
Ib
9.10 ± 0.83% vs. 9.30 ± 1.00%, WMD –0.20,
95% CI –0.64 to 0.24
RCT single
centre
crossover
Ib
1) 8.50 ± 0.96% vs. 8.80 ± 1.44%, WMD
–0.30, 95% CI –1.01 to 0.41
RCT single
centre
crossover
Ib
periods
Ferguson et al,
2001153
33 adults with type
1 diabetes
UK
versus
weeks (5.5 months)
Ford-Adams et
al, 2003154
23 children with
type 1 diabetes
Mean age 9.4,
range 7–11 years
UK
versus
patient per 30 days
2) 6.40 ± 5.75 vs. 6.80 ± 5.75, WMD –0.40,
95% CI –3.72 to 2.92
periods
Evidence tables
55
Study
Population
Gale, 2000155
93 adults with type
1 diabetes
Intervention
Outcomes
Mean age 35, range versus
patient per 30 days
18–63 years
UK
Trial length: after 6-week run- 4) Mean blood glucose
in period, two periods of 12
5) Quality of life
weeks (3 months)
Results
Comments
Design
EL
1) 7.50 ± 1.10% vs. 7.40 ± 1.10%, WMD
0.10, 95% CI –0.23 to 0.43
RCT crossover Ib
randomisation took place multicentre
2) 3.10 ± 4.40 vs. 2.60 ± 3.00, WMD 0.50,
95% CI –0.62 to 1.62
Nocturnal hypoglycaemia (00:00–06.00)
0.7 ± 1.6 vs. 1.8 ± 3.1, p < 0.001
Morning hypoglycaemia (06.00–12.00)
2.8 ± 3.7 vs. 2.2 ± 3.0, p < 0.029
3) 35/84 vs. 24/84, RR 1.46, 95% CI 0.96 to
2.22
4) Fasting: pre-breakfast 9.1 ± 3.5 vs.
8.4 ± 3.1 mmol/l, p = 0.02; pre-lunch
7.6 ± 2.3 vs. 7.2 ± 2.5 mmol/l, p = 0.03; preevening meal 9.1 ± 3.0 vs. 7.9 ± 2.8 mmol/l,
p = 0.002
Mean 2 hours post-meal: post-breakfast
8.3 ± 2.9 vs. 9.3 ± 3.0 mmol/l, p = 0.006;
post-lunch 7.4 ± 2.5 vs. 8.8 ± 2.8 mmol/l,
p < 0.001; post-evening meal 9.1 ± 2.6 vs.
9.4 ± 2.6 mmol/l, p = 0.433
Postprandial glucose excursions: morning
–0.9 ± 3.0 vs. 9.0 ± 3.3 mmol/l, p < 0.001;
afternoon –0.1 ± 2.5 vs. 1.6 ± 2.4 mmol/l,
p < 0.001; after evening meal 0.2 ± 2.6 vs.
1.4 ± 2.6 mmol/l, p = 0.002; bedtime
10.1 ± 2.8 vs. 9.4 ± 3.1 mmol/l, p = 0.079
5) No difference in the quality of life scores
between the two treatment groups
Garg et al,
1996156
39 adults with type
1 diabetes
USA
versus
patient per 30 days
1) 9.00 ± 1.90% vs. 8.80 ± 1.40%, WMD
0.20, 95% CI –0.91 to 1.31
2) 2.22 ± 2.87 vs. 2.95 ± 2.98, WMD –0.73,
95% CI –2.65 to 1.19
RCT parallel
single centre
Ib
Type 1 diabetes
56
Study
Population
Intervention
Outcomes
Heller et al,
1999157
135 adults with type Rapid-acting insulin analogue 1) HbA1c
1 diabetes
Mean age 39 ± 11
versus
patient per 30 days
years
3) Capillary glucose profiles
UK
Trial length: 4 months (after 2
month run-in)
Results
Comments
1) 6.00 ± 0.90% vs. 6.20 ± 0.80%, WMD
–0.20, 95% CI –0.49 to 0.09
30 patients were removed RCT parallel
before randomisation, 21 multicentre
chose not to enter the
study, 6 failed to meet
entry requirements and 3
were withdrawn from the
study at the physician’s
discretion
2) 3.30 ± 2.60 vs. 4.30 ± 3.20, WMD –1.00,
95% CI –1.99 to –0.01
3) after breakfast 7.4 ± 0.55 vs.
8.5 ± 0.4 mmol/l, p = 0.048
after lunch; 6.6 ± 0.3 vs. 7.2 ± 0.3 mmol/l,
p = 0.043
at bedtime 8.1 ± 5 vs. 7.5 ± 0.4 mmol/l,
p = 0.03
Holcombe et
al, 2002158
463 children with
type 1 diabetes
Mean age
14.9 ± 2.0, range
9–18 years
Australia, Belgium,
Canada, Denmark,
France, Germany,
Hungary, Italy,
Netherlands, New
Zealand, South
Africa, Spain,
Sweden, UK, USA
versus
patient per 30 days
1) 8.69 ± 1.52% vs. 8.70 ± 1.65%, WMD
–0.01, 95% CI –0.21, 0.19
Design
EL
Ib
randomisation took place
Sponsored by Lilly
RCT crossover Ib
multicentre
2) 4.02 ± 4.50 vs. 4.37 ± 4.50, WMD –0.35,
95% CI –0.93 to 0.23
periods
Evidence tables
57
Study
Population
Intervention
Outcomes
Holleman et al, 199 adults with type Rapid-acting insulin analogue 1)
1997159
1 diabetes
2)
Aged 5.4 ± 9.6 years versus
3)
Belgium,
4)
Netherlands, UK
periods after 4-week run-in
period
HbA1c
Patient preference
Quality of life data
Blood glucose
Results
1) 7.60 ± 1.30% vs. 7.50 ± 1.20%, WMD
0.10, 95% CI –0.15 to 0.35
2) 144/199 vs. 55/199, RR 2.26, 95% CI
2.06 to 3.33
3) 94% of patients indicated that whilst using
insulin lispro they had more flexibility in
their lifestyle in general (86% easier vs. 2%
as more difficult, p < 0.0001), timing of
meals (70% vs. 3%, p < 0.0001), planning of
physical (51% vs. 9%, p < 0.0001) and social
activities (60% vs. 8%, p < 0.0001)
4) Home blood glucose measurements
showed the mean glucose excursion
–0.8 ± 1.7 vs. 1.1 ± 1.6 mmol/l, p < 0.001
2-hour postprandial blood glucose: breakfast
7.7 ± 2.6 vs. 9.7 ± 3.2 mmol/l, p < 0.001;
lunch 7.5 ± 2.3 vs. 8.6 ± 2.5 mmol/l,
p < 0.001; dinner 7.7 ± 2.6 vs.
8.9 ± 3.1 mmol/l, p < 0.001
Mean preprandial 8.4 ± 1.9 vs.
7.9 ± 2 mmol/l, p = 0.001
Pre-dinner 8.7 ± 2.8 vs. 7.5 ± 2.6 mmol/l,
p < 0.001
No significant difference in the fasting, prelunch or bedtime glucose between the two
treatment groups (all p > 0.05)
Comments
Design
EL
RCT crossover Ib
multicentre
Type 1 diabetes
58
Study
Population
Intervention
Home and
Lindholm,
2000160
1070 adults with
type 1 diabetes
(insulin aspart) immediately
2) Hypoglycaemia incidence
before main meals (n = 698)
3) Blood glucose level
versus
Mean age 38 ± 12
years
Austria, Denmark,
Finland Germany,
Norway, Sweden,
Switzerland, UK
Outcomes
soluble insulin 30 min before 4) Quality of life assessment from
questionnaire, completed by just
meals (n = 349)
UK patients (n = 419)
Trial length: 6 months, 45) Adverse events
week run-in period
Results
Comments
1) 7.88 ± 0.79% vs. 8.00 ± 0.75%, WMD
–0.12, 95% CI –0.22 to –0.02
RCT parallel
randomisation took place. multicentre
Asymmetrically
open label
randomised in 2:1 ratio to
receive insulin aspart or
soluble insulin
2) Major hypoglycaemic episodes RR 0.83,
95% CI 0.59 to 1.18; minor hypoglycaemia
RR 1.01, 95% CI 0.89 to 1.16;
hypoglycaemic events at night 0.03 vs. 0.05
per patient year, p < 0.05
3) Average prandial blood glucose increment
0.54 ± 0.09 vs. 1.69 ± 0.12 mmol/l,
p < 0.0001
Design
EL
Ib
Supported by Novo
Nordisk
8 point self measured blood glucose level
post-breakfast 8.9 ± 0.15 vs. 10.1 ± 0.21,
difference 1.20 mmol/l
post-lunch 8.0 ± 0.12 vs. 8.5 ± 0.17,
difference 0.55 mmol/l
post-dinner 8.4 ± 0.14 vs. 9.0 ± 0.19,
difference 0.63 mmol/l, p < 0.01
before breakfast and dinner difference 0.79
and 0.69 mmol/l, p < 0.01
4) Quality of life assessment showed overall
improvement in treatment satisfaction with
insulin aspart
5) Adverse events were equally distributed
between the two treatments
Janssen et al,
2000161
35 adults with type
1 diabetes
Mean age insulin
lispro 33.0 ± 8.5,
soluble insulin
29.4 ± 8.7 years
Netherlands
(insulin lispro) (immediately
before meal) (n = 17)
patient per 30 days
versus
3) Self-monitored blood glucose
soluble insulin (30 min before
meal) (n = 18)
RCT parallel
randomisation took place single centre
2) 4.87 ± 3.53 vs. 6.60 ± 4.06, WMD –1.73,
95% CI –4.25 to 0.79
Sponsored by Lilly
Ib
3) Fasting, 2-hour post-breakfast and dinner
and pre-breakfast, lunch and dinner were
not significantly different
2-hour post-lunch blood glucose 8.0 ± 1.8
vs. 9.4 ± 1.6 mmol/l, p = 0.046
59
Evidence tables
Trial length: 12–14 weeks
(3–3.5 months) after 8–10
week run-in period
1) 7.20 ± 0.70% vs. 6.70 ± 0.60%, WMD
0.50, 95% CI 0.07 to 0.93
Study
Population
Intervention
Lalli et al,
1999162
56 adults with type
1 diabetes
(insulin lispro) (0–5 min
patient per 30 days
versus
soluble insulin (10–40 min
4) Variation in daily blood glucose
Mean age 34 ± 1.3
years
Italy
Outcomes
Trial length: 12 months after
1-month run-in period
Results
Comments
Design
1) 6.34 ± 0.53% vs. 6.71 ± 0.58%, WMD
–0.37, 95% CI –0.66 to –0.08
RCT parallel
randomisation took place single centre
EL
Ib
2) 7.40 ± 2.65 vs. 11.50 ± 3.70, WMD –4.10,
95% CI –5.79 to –2.41
3) 8.0 ± 0.1 vs. 8.8 ± 0.1 mmol/l, p < 0.05
post-meal 8.1 ± 0.2 vs. 9.7 ± 0.2 mmol/l,
p < 0.05
fasting, pre-meal, bedtime and 03:00 blood
glucose levels (8.1 ± 0.2 vs. 8.3 ± 0.2 mmol/l,
p < 0.07)
4) 52 ± 9% vs. 67 ± 11%, p = 0.05
Pfutzner et al,
1996163
1 diabetes
Germany
versus
patient per 30 days
1) 7.34 ± 0.98% vs. 7.33 ± 1.08%, WMD
0.01, 95% CI –0.28 to 0.30
RCT crossover Ib
multicentre
2) 8.57 ± 6.89 vs. 9.61 ± 7.09, WMD –1.04,
95% CI –3.01 to 0.93
periods
Provenzano et
al, 2001164
12 adults with type
1 diabetes
Italy
versus
periods (3 months)
7.62 ± 0.49% vs. 7.84 ± 0.49%, WMD –0.22,
95% CI –0.61 to 0.17
RCT crossover Ib
single centre
Type 1 diabetes
60
Study
Population
Intervention
Outcomes
Results
Raskin et al,
2000165
1) 7.78 ± 0.70% vs. 7.93 ± 0.81%, WMD
1 diabetes
(insulin aspart) (n = 552)
–0.15, 95% CI –0.26 to –0.04
2) 8 point blood glucose profile at
Aged 18–75 years
versus
3-month intervals
The difference in HbA1c was shown to
continue in the patients who completed the
Study in 59 sites in soluble insulin (n = 263)
extension to the trial (7.78 ± 0.04% vs.
Canada, USA
7.91 ± 0.06%, p = 0.046)
Trial length: 6 months after a 4) Adverse events
4–5 week run-in period
2) Significantly lower in the insulin aspart
Comments
Design
EL
Randomised in a 2:1 ratio RCT
Ib
multicentre
714 completed a 6-month parallel open
extension to the trial
label
Supported by Novo
treatment compared with the soluble insulin Nordisk
treatment group
3) Occurrence of minor and major
hypoglycaemic episodes 43.44 vs. 45.48 per
patient year. The number decreased steadily
during the extension to the study: aspart
36.12 vs. soluble 36.60, p < 0.05
Major hypoglycaemic events 0.91 vs. 1.13.
The number decreased steadily during the
extension to the study: aspart 0.62 vs.
soluble 0.67, p < 0.05
4) Comparable between the two treatment
groups
Tamas et al,
2001166
Tupola et al,
2001167
423 adults with type Rapid-acting insulin analogue HbA1c
1 diabetes
(insulin aspart) (n = 209)
Belgium, Croatia,
Czech, Republic,
France, Hungary,
Israel, Macedonia,
Poland, Russian
Federation, Sovenia,
Spain
versus
24 Children with
type 1 diabetes
Rapid-acting insulin analogue Patient preference
Aged 3.9–9.9,
mean 6.2 years
versus
RCT
multicentre
parallel
Ib
18/22 vs. 4/22, RR 2.70, 95% CI 1.65 to
4.42
RCT single
centre
crossover
Ib
Trial length: 12 weeks (3
months)
periods
61
Evidence tables
Finland
8.02 ± 0.72% vs. 8.18 ± 0.72%, WMD –0.16,
95% CI –0.30 to –0.02
Study
Population
Intervention
Valle et al,
2001168
1184 adults with
type 1 diabetes
versus
patient per 30 days
Italy
Outcomes
Results
1) 8.10 ± 1.50% vs. 8.20 ± 1.50%, WMD
–0.10, 95% CI –0.27 to 0.07
2) 1.80 ± 1.80 vs. 1.80 ± 1.70, WMD 0.00,
95% CI –0.20 to 0.20
Comments
Design
EL
RCT
multicentre
parallel
Ib
RCT
multicentre
parallel
Ib
RCT
crossover
Sponsored by Lilly
Ib
Vignati et al,
1994170
1 diabetes
USA
versus
patient per 30 days
1) 8.14 ± 1.30% vs. 8.38 ± 1.37%, WMD
–0.24, 95% CI –0.64 to 0.16
2) 5.41 ± 6.74 vs. 5.40 ± 6.36, WMD 0.01,
95% CI –1.98 to 2.00
Vignati et al,
1997169
1 diabetes
Mean age 39.1,
versus
patient per 30 days
range 18–70 years
Australia, Austria,
Trial
length:
two
2-month
Belgium, Canada,
periods after 4-week run-in
Finland, France,
period
Germany, Italy,
Netherlands, New
Zealand, South
Africa, Spain,
Sweden,
Switzerland, UK,
USA
1) 7.80 ± 1.40% vs. 7.90 ± 1.50%, WMD
–0.10, 95% CI –0.31 to 0.11
2) 4.60 ± 5.50 vs. 4.50 ± 5.00, WMD 0.10,
95% CI –0.66 to 0.86
3) Morning 2-hour postprandial serum
glucose levels 8.6 ± 3.1 vs. 9.8 ± 3.1 mmol/l,
p < 0.001
Evening 2-hour postprandial serum glucose
levels 8.6 ± 3.0 vs. 9.6 ± 3.1 mmol/l,
p = 0.005)
No significant difference in morning fasting
blood glucose, or the noon preprandial,
noon 2-hour postprandial and evening
preprandial serum glucose levels
Type 1 diabetes
62
RCT with different outcomes to those in meta-analysis
Study
Population
Intervention
Home and
Lindholm,
1998171
90 adult patients
4-week run-in period: patients
with type 1 diabetes were treated with human
unmodified insulin (soluble
Aged 18–60 years
insulin) just before meal
times, and bedtime isophane
11 sites in the UK
insulin. Patients were then
randomised to a treatment A
or B for 4 weeks and then
crossed over to the other
treatment for a final 4 weeks
A: rapid-acting insulin
analogue (insulin aspart)
B: soluble insulin
Outcomes
Results
Insulin dosage
No significant difference in the insulin
dosage. The post-breakfast serum insulin
Preprandial blood glucose profiles concentration was lower in the aspart group
24-hour plasma and serum insulin (aspart 44 ± 20 vs. unmodified
60 ± 37 munits/l, p < 0.05), it was also lower
profile were performed
in the early part of the night (aspart 26 ± 16
Serum fructosamine concentration vs. unmodified 32 ± 27 munits/l at 01:00
p < 0.05)
Hypoglycaemia (classified as
minor if self dealt with or major if Overall 24-hour glucose control defined by
required help from a third party)
plasma glucose leaving 4.0–7.0 mmol/l
range. Significantly improved in aspart
Adverse events
treatment (aspart 5260 ± 3361 vs.
unmodified 4713 ± 4310 mmol/l/min
p < 0.01). When split by > 7.0 and < 4.0, the
decrease in deviations from plasma glucose
level was significant in the > 7.0 for the
aspart treatment but not for the < 4.0 mmol/l
plasma glucose level
Comments
Design
EL
RCT crossover Ib
double blind
Supported by Novo
Nordisk
8-point self measured blood glucose level
showed no statistical change in glucose
concentrations apart from the lunch and
dinner postprandial concentrations, which
were lower in the aspart treatment, (after
lunch: aspart 6.4 ± 3.0 vs. unmodified
8.1 ± 3.7 mmol/l, p < 0.05; after dinner:
aspart 7.2 ± 3.1 vs. unmodified
8.8 ± 3.5 mmol/l, p < 0.05)
No difference in blood glucose control as
assessed by serum fructosamine (aspart
3.76 ± 0.53 vs. unmodified
3.82 ± 0.56 mmol/l, NS)
There were a higher number of other
treatment-emergent adverse events
(excluding hypoglycaemia) in the aspart
group (81 vs. 66, NS). 5 adverse events in
the aspart and 8 in the unmodified treatment
group were judged by the clinician as
possibly being related to the insulin aspart
63
Evidence tables
There was no significant difference in the
number of hypoglycaemic events (aspart 567
vs. unmodified 615). The were significantly
fewer major hypoglycaemic event in the
aspart treatment (20 events in 24 patients vs.
44 events in 24 patients, p < 0.002)
Study
Population
Intervention
Roach et al,
2001191
166 adults with type After 2–4 week run-in period
1 diabetes
patients were randomly
assigned for 12 months to
Mean age 47.0,
receive either:
range 18–75 years
Canada, Australia,
analogue (insulin lispro)
New Zealand,
combined with insulin lispro
Germany, Italy
protamine suspension (NPL),
an intermediate-acting
formation of lispro
B: soluble human insulin
combined with human
isophane insulin
Outcomes
Results
1) HbA1c
1) There was a significantly lower HbA1c
RCT
level in the group treated with insulin lispro randomisation took place multicentre
+ NPL compared with the group treated with
open label
soluble human insulin + isophane (7.54 vs.
7.92%, p = 0.019, difference of 0.38%)
3) Hypoglycaemia (< 3.5 mmol/l)
fasting, lunch 2-hour postprandial, lunch
excursion, evening meal preprandial and
03:00 blood glucose between the insulin
lispro + NPL and soluble human insulin +
isophane
There was a significantly lower morning 2hour postprandial, morning excursion, prelunch, evening 2-hour postprandial, evening
excursion and bedtime blood glucose for the
insulin lispro + NPL compared with soluble
human insulin + isophane (2-hour
postprandial 8.84 vs. 10.29 mmol/l,
p = 0.005; morning excursion 0.45 vs.
1.80 mmol/l, p = 0.007; pppre-lunch 6.21 vs.
7.10 mmol/l, p = 0.016; evening 2-hour
postprandial 7.86 vs. 10.18 mmol/l,
p < 0.001; evening excursion –0.77 vs.
0.96 mmol/l, p < 0.001; bedtime; 7.85 vs.
9.43 mmol/l, p = 0.001)
3) There was no significant difference in the
hypoglycaemia incidence between the two
treatment groups (1.11 vs. 1.12)
Comments
Design
EL
Ib
Type 1 diabetes
64
Biphasic rapid-acting insulin analogues
Biphasic rapid-acting insulin analogues (continued)
Study
Population
Intervention
Outcomes
Hermansen et
al, 2002192
50 adult patients
Patients studied on three trial 1) Postprandial serum glucose
with type 1 diabetes days, 5–21 days apart in
2) Fatty acids and triglycerides
random order
Aged 35.7 ± 9.4
3) Hypoglycaemia
years
A: biphasic rapid-acting
insulin analogue (insulin
Denmark
aspart 30) (30% insulin aspart
and 70% insulin aspart
protamine) injected
immediately before breakfast
B: biphasic isophane insulin
30 (30% soluble insulin and
70% isophane) injected 30
min before breakfast
Results
Comments
Design
EL
1) Postprandial serum glucose: reduced in
the aspart group by 23% and 9% compared
with the isophane insulin injected at 0 and
30 min before breakfast (p < 0.05)
Randomised through
Latin square design
RCT crossover Ib
open label
Supported by Novo
Nordisk
2) No significant differences seen in the free
fatty acids and triglycerides
3) No major hypoglycaemia events on trial
days. 16 events with aspart, 9 events with
isophane insulin injected at 0 min before
breakfast and 9 events with isophane insulin
injected at 30 min before breakfast (not
enough information in paper to see if these
differences are significantly different)
C: biphasic isophane insulin
30 injected immediately
before breakfast
Roach et al,
1999193
37 adults with type
1 diabetes
Mean age 39.4,
range 18–70 years
USA
After 4-week run-in period
assigned to receive either:
biphasic insulin containing
rapid-acting insulin analogue
(insulin lispro) and isophane
insulin
1) HbA1c
1) 7.69% vs. 7.40%, NS
2) Hypoglycaemia
2) 71% vs. 68%, NS
RCT crossover Ib
No confidence intervals
given
Sponsored by Lilly
versus
biphasic insulin containing
soluble human insulin and
isophane insulin
After 3 months the patients
were switched to the other
treatment
Evidence tables
65
Study
Population
Intervention
Outcomes
Colquitt et al,
2003172
6 RCTs
versus
Hypoglycaemic episodes
soluble insulin
Body weight
Trial length: at least 10 weeks Insulin dosage
Results
Comments
Design
5 crossover design RCTs investigated the use RCTs included Bode
Systematic
of insulin lispro compared with soluble
2002178, Melki 1998173,
review
insulin
Raskin 2001174, Renner
175
176
1999 , Schmauss 1998
1 parallel design RCT has 3 groups and
Zinman 1997 177
investigated the use of insulin lispro, insulin
aspart and soluble insulin
EL
Ia
HbA1c level was found to be significantly
improved with insulin lispro (WMD –0.26,
95% CI –0.47 to –0.06)
Some studies reported fewer hypoglycaemic
episodes with analogue insulin but this
varied with the definition of hypoglycaemia
used
No differences in body weight or insulin
dosage were seen
Bode et al,
2002178
146 adult patients
with type 1 diabetes using an external CSII,
Aged 18–71 years
USA
1) HbA1c change from baseline
1) 0.00 ± 0.51% vs. 0.15 ± 0.63% vs.
0.18 ± 0.84%
2) Hypoglycaemic episodes (p
value from wilcoxon rank-sum test 2) All: 6.7 ± 5.4 vs. 10 ± 8.9 (p = 0.034) vs.
relative to insulin aspart group)
10.5 ± 8.1 (p = 0.044)
analogue (insulin aspart)
(n = 59)
With blood glucose < 50 mg/dl: 3.7 ± 3.6 vs.
4.8 ± 4.2 (p = 0.175) vs. 4.4 ± 4.7 (p = 0.841)
(n = 59)
Nocturnal < 50 mg/dl: 0.5 ± 0.83 vs.
0.9 ± 0.97 (p = 0.004) vs. 0.6 ± 0.61
(p = 0.189)
In systematic review
multicentre
parallel RCT
Ib
Crossover
RCT
Ib
C: rapid-acting insulin
(n = 28)
Trial length:16 weeks
Raskin et al,
2001174
58 adult patients
After 2–4 week run-in period
Aged 13–60 years
USA
(n = 58)
(n = 58)
periods
1) HbA1c
1) 7.41 ± 0.97% vs. 7.65 ± 0.85%, p = 0.004
2) Hypoglycaemia
2) 7 patients reported 8 episodes vs. 7
patients reported 11 episodes
3) Hyperglycaemia
3) 12 patients reported 16 episodes due to
occlusion vs. 12 patients reported 23
episodes
Type 1 diabetes
66
CSII
CSII (continued)
Study
Population
Intervention
Schmass et al,
1998176
11 adult patients
Mean age 30 ± 2.5 assigned to receive either:
years
Germany
(n = 11)
Outcomes
Results
Comments
Design
EL
1) Blood glucose
1) Fasting: 6.5 ± 0.4 vs. 7.5 ± 0.4 mmol/l, NS
Ib
2) HbA1c in first period
2-hour postprandial: 6.8 ± 0.3 vs.
8.3 ± 0.3 mmol/l, p = 0.03
Crossover
RCT
3) Hypoglycaemia
4) Adverse effects
2) 5.7 ± 0.3% vs. 6.5 ± 0.3%
(n = 11)
periods
Zinman et al,
1997177
30 adult patients
After 1-month run-in period
Aged 35.1 ± 1.5
years
Canada
(n = 30)
Patients were all
treated using CSII
system
(n = 30)
treatment for a further 3
months
1) Blood glucose levels
2) HbA1c
1) Postprandial blood glucose levels were
significantly lower with insulin lispro
compared with soluble human insulin: (from
graph lispro vs. soluble human insulin) postbreakfast; 8.3 vs. 9.8 mmol/l, post-lunch 7.5
vs. 8.6 mmol/l, post-supper 7.7 vs.
8.8 mmol/)
RCT crossover Ib
randomisation took place double blind
2) The decrease in HbA1c after treatment was
greater in the insulin lispro treatment group
than the soluble human insulin group
(7.66 ± 0.13% vs. 7.00 ± 0.16%, p = 0.0041,
difference of 0.66%)
Evidence tables
67
Study
Population
Intervention
Melki et al,
1998173
39 adults with type
1 diabetes
1) HbA1c (measured only during
using an external CSII patients the first period of treatment, so no
were randomly assigned to
carry-over effect)
receive either:
2) Mean daily blood glucose levels
3) 2-hour postprandial blood
glucose level
(n = 39)
4) Preprandial blood glucose level
Aged 39.4 ± 1.5
years
France
(n = 39)
treatment
Outcomes
Results
Comments
Design
EL
1) The reduction in HbA1c level was
RCT crossover Ib
significantly more pronounced with insulin
lispro than soluble human insulin (lispro:
Sponsored by Lilly France
from 7.74 ± 0.20% to 7.11 ± 0.15%, a
difference of –0.62 ± 0.13% vs. soluble
human insulin: from 7.97 ± 0.13% to
7.88 ± 0.16%, a difference of –0.09 ± 0.15%,
p = 0.01, difference of 0.71%)
2) There was significantly lower mean daily
blood glucose levels in the lispro group
compared with the soluble human insulin
group (7.93 ± 0.15 vs. soluble human insulin
8.61 ± 0.18 mmol/l, p < 0.0001)
3) There was significantly lower 2-hour
postprandial blood glucose level in the lispro
group compared with the soluble human
insulin group (8.26 ± 0.19 vs.
9.90 ± 0.20 mmol/l, p < 0.0001)
preprandial blood glucose level between the
two groups (7.70 ± 0.17 vs.
7.75 ± 0.21 mmol/l, p > 0.05)
Type 1 diabetes
68
CSII (continued)
CSII (continued)
Study
Population
Intervention
Renner et al,
1999175
113 adults with type After 4-week run-in period
1 diabetes
assigned to receive treatment
Mean age 37 ± 12
through CSII either:
years
Germany
(n = 113)
Patients were all
treated with CSII for B: soluble human insulin
6 months or more
(n = 113)
prior to study
treatment for 4 months
Outcomes
Results
1) HbA1c
1) The mean HbA1c at the end of the period was
significantly lower after insulin lispro treatment than
2) Daily and postprandial after soluble human insulin treatment (6.77 ± 0.88%
blood glucose profiles
vs. 6.90 ± 0.97%, p < 0.02, difference of 0.13%)
3) Adverse events
2) Insulin lispro compared with the soluble human
Comments
Design
RCT open
randomisation took place label
crossover
Sponsored by Lilly
EL
Ib
4) Hypoglycaemic events insulin treatment significantly reduced the breakfast,
lunch and dinner postprandial blood glucose
(< 3.5 mmol/l)
excursions and the 22:00 blood glucose level
5) Treatment satisfaction (breakfast 7.0 ± 1.9 vs. 8.6 ± 2.6 mmol/l, p < 0.001;
lunch 7.6 ± 1.9 vs. 8.7 ± 2.4 mmol/l, p < 0.001; dinner
7.2 ± 1.9 vs. 8.3 ± 1.9 mmol/l, p < 0.001 22:00
7.6 ± 1.8 vs. 8.3 ± 2.0 mmol/l, p < 0.001)
There was no significant difference in the 02:00 or
breakfast, lunch or dinner preprandial blood glucose
results between the treatment groups (p > 0.05)
3) There were 6 serious adverse events during
treatment with soluble human insulin and 1 during
treatment with insulin lispro; these were not identified
to be related to the study drug.
The most frequently reported adverse events in both
groups were infections (lispro 19.4%, soluble 21.1%;
mainly common cold) and rhinitis (lispro 15.8%,
soluble 13.8%)
Among adverse events possibly related to study drug,
the most frequent was ketosis, reported by 5 (4.5%)
patients receiving lispro and 4 (3.7%) patients
receiving soluble human insulin
4 (3.7%) patients during insulin lispro treatment and 2
(1.8%) patients during soluble human insulin
treatment reported injection site reactions
No difference between insulin lispro and soluble
human insulin in the rate and number of catheter
occlusions
69
5) The questionnaire used to assess the satisfaction of
patients with each therapy (maximum score 48)
showed a statistically significant result in favour of
insulin lispro treatment (35.16 ± 4.25 vs. 32.36 ± 5.87,
p < 0.001)
Evidence tables
4) There were no significant differences between
groups in the average number of hypoglycaemic
episodes per patient (12.4 ± 13.9 vs. 11.0 ± 11.2,
p > 0.05)
Study
Population
Guerci et al,
1999179
10 adults with type
1 diabetes
Intervention
After 1-month run-in period
assigned to receive through
Mean age 41.1± 7.1 CSII either:
years
France
(n = 10)
Patients were all
treated using CSII
B: soluble insulin (n = 10)
system
After 1 month the patients
treatment for 1 month
Outcomes
Results
Comments
HbA1c
There was no significant difference in HbA1c,
mean blood glucose levels or mean standard
deviation of blood glucose between the two
treatment groups ((mean ± 1SD) HbA1c
7.07 ± 0.51% vs. 6.67 ± 0.67%, mean blood
glucose 9.04 ± 0.89 vs. 9.32 ± 1.17 mmol/l,
mean standard deviation of blood glucose
4.44 ± 0.49 vs. 4.82 ± 0.83 mmol/l)
RCT crossover Ib
Mean blood glucose levels
Mean standard deviation of blood
glucose levels
Postprandial blood glucose level
Hypoglycaemia
There was a significant decrease in the
postprandial blood glucose level and the
hypoglycaemia incidences in the lispro
compared with the soluble insulin treatment
group (postprandial blood glucose level
9.43 ± 1.39 vs. 10.49 ± 2.05 mmol/l, p < 0.05;
hypoglycaemia incidence 7.1 ± 4.6 vs.
12.6 ± 10.2, p < 0.05)
Small number of
participants
Patients used CSII – can
this be generalised to
general population?
Design
EL
Type 1 diabetes
70
CSII (continued)
CSII (continued)
Study
Population
Johansson et al, 41 adults with type
2000180
1 diabetes
Mean age
40.2 ± 10.0 years
Intervention
Outcomes
Results
Comments
After 2–4 week run-in period
assigned to receive (through
CSII or injection treatment)
either:
1) HbA1c
1) There was a significantly higher level of
HbA1c in the soluble insulin treatment group
than the insulin lispro treatment group: mean
HbA1c (lispro vs. soluble insulin) 7.4 vs.
7.6%, p = 0.047, difference of 0.2%
RCT crossover Ib
Sweden
Some patients were analogue (insulin lispro) (5
min before meal) (n = 40)
treated using CSII
system
B: soluble insulin (30 min
treatment for 2 months
2) Mean glycaemia and SD of all
blood glucose levels
3) Mean postprandial glycaemia
and SD of postprandial blood
glucose levels
4) Mean preprandial glycaemia
and SD of preprandial blood
glucose levels
5) Hypoglycaemic events
Design
EL
Sponsored by Lilly
Some patients used CSII –
can this be generalised to
2) There was a significantly higher mean
glycaemia and SD of all blood glucose levels general population?
in the soluble insulin treatment group than
the insulin lispro treatment group: (lispro vs.
soluble insulin) mean glycaemia 7.4 vs.
7.6 mmol/l, p < 0.001; SD of all blood
glucose levels 3.6 vs. 3.9 mmol/l, p = 0.012
3) There was a significantly higher mean
postprandial glycaemia and SD of
postprandial blood glucose levels in the
soluble insulin treatment group than the
insulin lispro treatment group: (lispro vs.
soluble insulin) mean postprandial
glycaemia 8.1 vs. 9.6 mmol/l, p < 0.001; SD
of postprandial blood glucose levels 3.6 vs.
4.0 mmol/l, p = 0.006
4) There was no significant difference in
mean preprandial glycaemia and SD of
preprandial blood glucose levels between
the soluble insulin treatment group and the
insulin lispro treatment group: (lispro vs.
soluble insulin) mean preprandial glycaemia
8.5 vs. 8.4 mmol/l, p = 0.86; SD of
preprandial blood glucose levels 3.4 vs.
3.6 mmol/l, p = 0.86
hypoglycaemic events between the soluble
insulin treatment group and the insulin lispro
treatment group: (lispro vs. soluble insulin)
9.7 vs. 8.0 per 30 days, p = 0.23
Evidence tables
71
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Del Sindaco
and Ciofetta,
1998152
69 adults with type
1 diabetes
Treatment groups. All the
studies were for 3 months
then swapped over to the
other treatment
HbA1c
There were no episodes of severe
hypoglycaemia during the studies
Patients were randomly
assigned to the 4 different
studies. However, it is not
known if randomisation
was used to assign the
patients to treatments
within the study groups
RCT open
label
crossover
study
Ia
Mean age
30–34 ± 5.2–8.8
years
Italy
Study group 2: (n = 18) The
conventional soluble insulin
at meals (n = 9) of group 1
was compared with a mixture
of rapid-acting insulin
analogue (insulin lispro) and
isophane (n = 9) at each meal.
Isophane was given to all
patients at bedtime
Study group 4: (n = 24) The
effect of a 10–40 min time
interval (n = 12) between
injection of conventional
soluble insulin and meal, as
compared with no interval
(n = 12) was assessed.
Isophane was given to all
patients at bedtime
Lispro injected 0–5 min
before meals, soluble insulin
injected 10–40 min before
meals except group 4
Hypoglycaemia (< 3.5 mmol/l)
Study group 2. Effects of substitution of
soluble with lispro insulin and increase in
number of daily isophane insulin injections:
The mean daily blood glucose levels and
postprandial blood glucose levels were
significantly lower with lispro + multiple
isophane insulin than soluble insulin (daily
blood glucose levels 8.1 ± 0.8 vs.
8.6 ± 0.8 mmol/l, p < 0.05; postprandial
blood glucose 8.3 ± 0.7 vs. 9.3 ± 0.8 mmol/l,
p < 0.05). There was no significant difference
in the pre-meal and nocturnal blood glucose
concentrations (8.2 ± 0.7 vs.
8.2 ± 0.7 mmol/l, p < 0.05)
HbA1c was significantly lower after lispro +
multiple isophane insulin compared with
soluble insulin (lower by 0.35% in the
insulin lispro group, p < 0.05)
The frequency of hypoglycaemia was similar
between the two groups (3.7 ± 2.9 vs.
3.4 ± 2.9, p > 0.05)
Study group 4. Effect of time interval
between injection of soluble insulin and
meal:
The mean blood glucose concentration was
not significantly lower when conventional
soluble insulin was given 10–40 min prior to
meals than given at meal ((10–40 min prior
vs. 5 min before meal) 8.5 ± 1.1 vs.
8.9 ± 1.2 mmol/l)
The HbA1c was significantly lower when
conventional soluble insulin was given
10–40 min prior to meals than given at meal
(lower by 0.18 ± 0.15%, p < 0.05)
Hypoglycaemia was more frequent when
conventional soluble insulin was given
10–40 min prior to meals than given at meal
(4.4 ± 1.4 vs. 6.8 ± 2.4 mmol/l, p < 0.05)
Type 1 diabetes
72
Other topics
Glargine
Study
Population
Intervention
NICE
Technology
Appraisal
Guidance No.
53, 2002194
4 fully published
Insulin glargine compared
open label
with isophane insulin
randomised
controlled trials in
diabetes. 7
published abstracts
and 1 unpublished
abstract made
available by
manufacturer, 3
observational
studies
Outcomes
Results
Comments
Design
EL
Fasting blood glucose,
fasting plasma glucose
or HbA1c
From the 4 fully published studies all 4 trials found that
the mean change in fasting plasma glucose was
significantly greater in those using insulin glargine (range
between 1.34 and 2.23 mmol/l). In 3 trials the insulin
glargine was significantly superior to isophane insulin in
terms of reducing fasting blood glucose (difference in
mean change 0.71–1.50 mmol/l). The fourth study
showed no difference between the insulin glargine and
isophane insulin
Guidance: insulin is
recommended as a
treatment option for
people with type 1
diabetes
NICE
guidance
Ia
Incidence and severity
of hypoglycaemic
episodes
3 of the 4 studies reported no change in HbA1c. 1 study
showed an overall statistically significant superiority of
insulin glargine over isophane insulin in teams of
reducing HbA1c although this study was of 4-week
duration and HbA1c reflects the average glycaemic
control over 6 to 8 weeks
Nocturnal hypoglycaemia was reduced in insulin
glargine group compared with isophane group in 2
studies (36% vs. 56% respectively, p < 0.05), 1 study
showed no difference in nocturnal hypoglycaemia and 1
study did not distinguish between nocturnal and other
hypoglycaemic episodes
1 study reported a smaller percentage of people
experiencing symptomatic hypoglycaemia in the group
using insulin glargine compared with the group using
isophane insulin, for the whole trial and the posttitration phase (40% vs. 49% respectively for posttitration phase). Two studies reported no difference in
terms of severe hypoglycaemia during either the entire
trial period or the post-titration phase
Observational studies: in 1 study after 8 weeks of insulin
glargine patients showed a 1.7% reduction in HbA1c
levels compared with baseline, 70.3% of people
reported fewer hypoglycaemic episodes when they were
receiving insulin glargine. A second study reported a
0.36% reduction in HbA1c levels compared with baseline
when treated with insulin glargine for 6 months
Guidance was peerreviewed and made
available for consultation
prior to publication of the
final report
73
Evidence tables
3 studies reported severe hypoglycaemia. 1 reported that
a significantly smaller percentage of people experienced
severe hypoglycaemia in the insulin glargine group
compared with the isophane insulin group, in the posttitration phase (1.9% vs. 5.6% of patients respectively,
p < 0.05). 2 studies reported no significant differences
between the entire trial period and the post-titration
phase
Implications for the NHS:
It is estimated that up to
137 000 individuals
would be eligible for
insulin glargine treatment
(type I and type 2
diabetes). The
incremental cost of
insulin glargine (based on
vial costs) is assumed to
be £101 per annum for
people with type I
diabetes (annual cost of
insulin glargine is £203
and annual cost of
isophane insulin is £102)
Study
Population
Intervention
Outcomes
Results
Comments
Design
Chase et al,
2003195
114 children and
young people with
type 1 diabetes
9 months treatment with
isophane then 9 months
treatment with insulin
glargine
1) HbA1c
1) 9.3 ± 0.13% vs. 9.6 ± 0.12%, p = 0.01
2) Incidence and severity of
hypoglycaemic episodes
2) Non-severe hypoglycaemia 2.0 ± 0.1 vs.
1.3 ± 0.1 per week, p = 0.001
No randomisation, all
patients received
isophane then insulin
glargine
Within-group IIb
comparison
Design
Aged 2–18, mean
12.2 ± 4.2 years
EL
Severe hypoglycaemia 9 vs. 22 over the 9month study period
USA
Timing of insulin
Study
Population
Intervention
Hamann et al,
2003196
378 adult patients
Insulin glargine administered
with type 1 diabetes before breakfast
Aged 18–65 years
versus
Germany
insulin glargine administered
before evening meal
versus
insulin glargine administered
at bedtime
Trial length: 24 weeks
Outcomes
Results
Comments
1) Mean HbA1c
1) 7.4% vs. 7.4% vs. 7.5%, no statistical
difference
RCT parallel
2) 24-hour blood glucose profiles
3) Incidence of total symptomatic
and severe hypoglycaemia
4) Nocturnal hypoglycaemia
2) 8.0 ± 0.2 vs. 8.3 ± 0.2 vs. 8.6 ± 0.2 mmol/l, Supported by Aventis
no statistical difference
Pharma
3) 92.6% vs. 93.8% vs. 96.9%, p = 0.28, no
4) 59.5% vs. 71.9% vs. 77.5%, p = 0.005
EL
Ib
Type 1 diabetes
74
Glargine (continued)
Determir
Study
Population
Intervention
Outcomes
Hermansen et
al, 2001198
59 adult patients
with type 1
diabetes. (56
patients completed
the trial)
2-week run-in period
8-point self-monitored blood
followed by randomisation in glucose profile
blocks of four to two 6-week
24-hour serum glucose profile.
treatment periods
Serum fasting blood glucose
A: insulin detemir
Aged 19–52 years
(100 units/ml)
7 sites in Denmark
B: isophane insulin
Results
Comments
Design
EL
The maximum glucose concentrations were
not statistically different between the two
treatment groups. The mean serum glucose
was different between the two treatment
groups; during the night serum glucose was
higher with detemir than with isophane
insulin.
RCT crossover Ib
Supported by Novo
Nordisk
Hypoglycaemia (classified as
minor if self dealt with or major if
required help from a third party or There was no significant difference between
the treatment groups in the area under the
Treatments were injected
intravenous glucose or glucagon
curve of the 24-hour serum glucose profile.
subcutaneously between
treatment was required)
No significant difference was seen between
21:00 and 23:00 and human
the two treatment groups in the 8-point selfshort-acting insulin was given Adverse events
monitored blood glucose profile for the last
30 min before each main
week of the treatment period
meal
mean fructosamine level between the two
treatment groups
There were significantly smaller numbers of
hypoglycaemia events in the last week of
detemir treatment compared with isophane
insulin treatment: detemir 74 (60%) vs.
isophane insulin 116 (77%), p < 0.05
There were similar adverse events between
the two treatment groups
Vague et al,
2003197
Detemir (1200 nmol/ml)
before breakfast and bedtime
(n = 284)
Aged 38.9 ± 13.3
years for detemir
group and
41.8 ± 14.2 years for
intermediate-acting
(isophane) insulin
group
(isophane) (600 nmol/ml)
before breakfast and bedtime
(n = 141)
Europe
Randomised via a 2:1 ratio
versus
Trial length: 6 months (first
month considered as a
titration phase)
1) Mean HbA1c (n = 419)
1) 7.60 ± 0.09% vs. 7.64 ± 0.10%, p = 0.61
2) Mean fasting plasma glucose
(n = 412)
2) 9.19 ± 0.44 vs. 9.94 ± 0.52 mmol/l,
p = 0.09
3) Major hypoglycaemic events
3) RR 0.65, 95% CI 0.28 to 1.50, p = 0.312
4) Minor hypoglycaemic events
4) RR 0.72, 95% CI 0.56 to 0.93, p = 0.011
5) Body weight
5) 70.9 ± 0.28 vs. 71.8 ± 0.33 kg, p = 0.001
Withdrew from study due multicentre
to:
RCT
Ib
detemir group: ineffective
therapy (n = 1), noncompliance (n = 1), ‘other
reasons’ (n = 1), adverse
events (n = 2)
intermediate-acting
insulin: ineffective
therapy (n = 2), ‘other
reasons’ (n = 3)
75
Evidence tables
448 patients with
type 1 diabetes.
(425 completed
trial, n ≤ 419
analysed)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Gibb et al,
1990199
52 children and
young people with
type 1 diabetes
Isophane insulin
1) Glycated haemoglobin level
1) 11.1 ± 2.2% vs. 12.0 ± 2.2%
versus
2) 8.3 ± 3.8 vs. 8.8 ± 4.6 mmol/l
RCT crossover Ib
Aged 5–18 years
3) Fructosamine concentration
3) 4.0 ± 0.7 vs. 4.0 ± 0.8 mmol/l
UK
periods
4) Number of episodes of
hypoglycaemia
4) Grade I: 75/17 vs. 110/23
Grade II: 141/36 vs. 177/42
Grade III: 18/8 vs. 14/9
Grade IV: 9/8 vs. 9/4
Turnbridge et
al, 1989200
82 adult patients
Isophane insulin
versus
Aged 17–61 years
UK
periods
1) Glycated haemoglobin level
2) Fructosamine level
5) Hypoglycaemic event rate
1) 9.2 ± 0.1% vs. 9.3 ± 0.1%, no statistical
difference
RCT crossover Ib
2) 1.55 ± 0.02 vs. 1.57 ± 0.02 mmol/l, no
3) 8.8 ± 0.5 vs. 9.0 ± 0.5 mmol/l, no statistical
difference
4) 8.2 ± .03 vs. 7.6 ± 0.3 mmol/l, no statistical
difference
5) No statistical difference
Buysschaert et
al, 1987201
18 adult patients
with type 1
diabetes.
Isophane insulin
Aged 42 ± 4 years
Belgium
periods
versus
HbA1 level
10.1 ± 0.4% vs. 9.9 ± 0.3%, no statistical
difference
RCT crossover Ib
Type 1 diabetes
76
Isophane insulin compared with insulin zinc suspension
Isophane insulin compared with crystalline insulin zinc suspension
Study
Population
Wolfsdorf et al, 20 children and
1991202
young people with
type 1 diabetes
Aged 7–18 years
USA
Intervention
Outcomes
Pre-breakfast and pre-evening 1) HbA1 level
meal mixture of isophane
2) Mean fasting blood glucose
insulin and soluble insulin
levels pre-breakfast
versus
3) Mean blood glucose before a
pre-breakfast mixture of
bedtime snack
isophane insulin and soluble
insulin and a pre-evening
meal mixture of crystalline
insulin zinc suspension and
soluble insulin
Results
Comments
Design
EL
difference
RCT crossover Ib
2) 10.3 ± 2.2 vs. 9.6 ± 1.9 mmol/l, p < 0.05
3) 8.4 ± 1.9 vs. 10.0 ± 2.1 mmol/l
At no other times were the blood glucose
levels different
periods
Zinman et al,
1999203
178 adult patients
Isophane insulin
versus
Aged 42 ± 4 years
crystalline insulin zinc
USA
suspension
1) HbA1c levels
2) Rates of severe hypoglycaemia
difference
RCT parallel
2) 0.05 ± 0.03 vs. 0.07 ± 0.04 per patient
every 30 days
Ib
Parillo et al,
1992204
Riccio et al,
1994205
10 adult patients
Isophane insulin
versus
Aged 28 ± 2 years
Italy
suspension
Fasting blood glucose levels At
06:00: 10.82 ± 4.27 vs.
6.26 ± 0.88 mmol/l
There were no differences in blood
glucose levels at any other time of
day
16 adult patients
with type 1
diabetes.
Isophane insulin
Aged 41 ± 4 years
suspension
Supported by Novo Farmacutici Italia SpA
8.2 ± 0.3% vs. 7.9 ± 0.4%
RCT crossover Ib
77
Evidence tables
Italy
RCT crossover Ib
At 08:00: 14.03 ± 1.08 vs.
9.26 ± 1.02 mmol/l
versus
No description of how randomisation took
place
Study
Population
Intervention
Outcomes
Results
Comments
Johnson et al,
1992206
77 children and
young people with
type 1 diabetes
Twice-daily use of crystalline
insulin zinc suspension with
soluble insulin
1) HbA1 level
difference
RCT parallel
Aged 5–18 years
versus
USA
twice-daily use of insulin zinc
suspension with soluble
insulin
66 adults with type
1 diabetes
Aged 18–62, mean
age 38 years
UK
1) Glycated haemoglobin levels
versus
3) Serious hypoglycaemic events
periods
Ib
pre-breakfast: 10.6 ± 0.6 vs.
12.6 ± 0.6 mmol/l, p < 0.02
Twice-daily use of crystalline
insulin zinc suspension with
soluble insulin
twice-daily use of insulin zinc
suspension with soluble
insulin
EL
2) Pre-lunch: no statistical difference, preSupported by Eli Lilly
dinner: no statistical difference, bedtime: no
statistical difference, mid-sleep: no statistical
difference
Turnbridge et
al, 1989 207
Design
2) Fasting blood glucose levels
1) The trial found no difference between the No description of how
RCT crossover Ib
two groups: 9.3 ± 0.2%
2) 6.6 ± 0.5 vs. 8.2 ± 0.5 mmol/l, p < 0.05
3) 0.38 ± 0.10 vs. 0.09 ± 0.04 events per
patient per month, p < 0.02
Supported by Novo
Laboratories
Type 1 diabetes
78
Insulin zinc suspension compared with crystalline insulin zinc suspension
B9AspB27GLu
Study
Population
Intervention
Kang et al,
1990181
6 adult patients with Patients were studied twice
type 1 diabetes
within an interval of about a
week. The patients were
Aged 26–47 years
randomised to:
Wales
A: insulin analogue
B9AspB27Glu (equivalent to
10 units human soluble
insulin)
B: human soluble insulin 10 u
Outcomes
Results
Comments
Design
EL
Plasma glucose level
Baseline comparison of plasma glucose level No description of how
RCT crossover Ib
was significantly different: analogue insulin randomisation took place
7.8 (SE 1.4) vs. human soluble insulin 9.4
Supported by Novo
(SE 1.6) mmol/l, p < 0.05)
Nordisk
The changes in the plasma glucose level
from baseline were significantly smaller in
the analogue insulin group compared with
the human soluble insulin treatment group,
between 15 and 210 min after
administration: analogue insulin 5.6 (SE 0.6)
vs. human soluble insulin 10.8 (SE 1.8)
mmol/l, p < 0.05
The cumulative areas under the incremental
plasma glucose curve were significantly
smaller for the analogue insulin than human
soluble insulin from time 0 to the end of the
study: for analogue insulin they were 55%
that of human soluble insulin, p < 0.01
For every member of the study the peak
change in plasma glucose and the total area
under the curve were significantly lower
under the analogue insulin than those after
Evidence tables
79
Study
Population
Intervention
Wiefels et al,
1995182
14 adult patients
Patients were randomised to
with type 1 diabetes treatment for 3 days then
crossed over to the other
Aged 27–60 years
treatment for 3 days:
Germany
A: insulin analogue B28Asp
Outcomes
Results
Comments
1) Blood glucose level
1) The areas under the curve of the blood
glucose were significantly lower for the
insulin analogue compared with the human
soluble insulin: 312.0 vs. 66.0 mmol.min/l
RCT crossover Ib
randomisation took place double blind
Design
EL
Supported by Novo
Nordisk
The maximum blood glucose concentrations
were lower after the administration of insulin
analogue compared with the human soluble
insulin, though no statistical test was
performed: 9.3 vs. 12.8 mmol/l
B: human soluble insulin
2) The same number of hypoglycaemic
events was seen in both groups
B10Asp
Study
Population
Intervention
Outcomes
Results
Nielsen et al,
1995183
21 adult patients
with type 1
diabetes. (Aged
18–40 years)
After a 4-week run-in period,
pre-meal insulin for treatment
for 8 weeks, the patients were
than crossed over to the other
insulin for 8 weeks:
HbA1c
7 capillary blood samples 2 days
before end of the study period. To
give mean blood glucose, fasting
blood glucose
No significant difference between the
RCT crossover Ib
treatment groups in the HbA1c, mean blood randomisation took place double blind
glucose, fasting blood glucose, but there was
a significantly lower blood glucose level
after breakfast in the insulin analogue
compared with the human soluble insulin
(p < 0.05)
Denmark
Insulin analogue B10Asp
versus
Human soluble insulin
Triglycerides, Total cholesterol,
HDL-cholesterol, LDL cholesterol,
Hypoglycaemic events (classified treatment groups in the triglycerides, total
as mild if self dealt with or severe cholesterol, HDL cholesterol, LDL
if required help from a third party) cholesterol and mild hypoglycaemic events.
Although there were 3 severe hypoglycaemic
events in the human soluble insulin group
compared with 0 in the insulin analogue
group
Comments
Design
EL
Type 1 diabetes
80
B28Asp
What is ideal: self-mixed or pre-mixed insulin therapy in the treatment of children with type 1 diabetes?
Study
Population
O’Hagan and 40 children with
Greene, 1993208 type 1 diabetes
Aged 7–16 years
UK
Arslanoglu et
al, 2000209
Intervention
Outcomes
Results
Comments
After a run-in period of 1
month patients were
randomised. After 3 months
the patients were swapped to
the other treatment
1) Glycated haemoglobin HbA1
1) No significant difference in the mean
HbA1 at the beginning and the end of the
treatment periods: start 13.1 ± 0.6%, selftitrating 11.8 ± 0.5%, pre-mixed 12.5 ± 0.4%
RCT crossover Ib
All children were
on a twice-daily
self-titrating regimen
of short- and
intermediate-acting
insulins. 14 children
were using insulin
ratios other than
30:70 (range 10:90
to 50:50)
A: self titrating regimen (selfmixed) by conventional
syringe
20 patients with
type 1 diabetes
Patients were divided
randomly into 2 groups. After
2 months the patients were
swapped to the other
treatment
Aged 8.2–19.6
years
Turkey
Duration of diabetes
greater than 6
months, and they
used conventional
insulin therapy
B: pre-mixed regimen,
disposable pen injector
A: self-mixed conventional
insulin therapy by
conventional syringe (12 mm
long, 29 gauge)
B: pre-mixed insulin therapy
(available insulin ratios were
10:90, 20:80, 30:70, 40:60
and 50:50) by pen injector
(8 mm long, 30 gauge)
2) 6-point blood glucose profile
Design
EL
Different delivery systems
used for each treatment
2) No statistically significant difference
group (syringes for selfbetween the self-mixed and pre-mixed
mixed and pens for pre4) Questionnaire discussing:
treatments group children in their blood
mixed) may lead to bias if
convenience of use, ease and
differences are due to
accuracy of dose settings, as well glucose profiles throughout the day
delivery system not preas in preference to conventional
3) No statistical difference in number of
mixed or self-mixed
syringes. Completed after the study hypoglycaemic or ketoacidotic episodes
insulin, (especially in the
had ended
reported during the self-titrating or pre-mixed patient preference
treatments
questionnaire)
4) The disposable pen was preferred by 95% Novo Nordisk provided
of the patients as regards convenience of
financial support, pen
use, ease and accuracy of dose setting as
injectors and all insulin
well as in preference to conventional
preparations
syringes
3) Hypoglycaemic and
ketoacidotic episodes
1) HbA1c
1) No significant difference in HbA1c values No description of how
RCT crossover Ib
between the two groups at the end of the
2) Hypoglycaemic and
treatment periods: self-mixed 11.1 ± 2.6% vs.
ketoacidotic episodes reported
pre-mixed 10.9 ± 2.7%
3) Blood glucose measurements to 2) No significant difference in total number group (syringes for selfgive mean glycaemia values
of hypoglycaemic episodes: 53 for selfmixed and pens for premixed and 88 for pre-mixed periods. When mixed) may lead to bias
4) Patient acceptance
divided by time, hypoglycaemic attacks were
Novo Nordisk provided
more common at 07:00 during pre-mixed
treatment (p < 0.05) and at 03:00 during self- pen injectors and
questionnaires
mixed treatment (p < 0.00001)
3) No significant difference in mean
glycaemia values between the two groups:
self-mixed 8.3 ± 1.7 vs. pre-mixed
8.1 ± 1.7 mmol/l
81
Evidence tables
4) 100% of patients preferred the pre-mixed
insulin delivered by pen to the self-mixed
insulin delivered by syringe
Study
Population
Intervention
Outcomes
Results
Dunbar et al,
1994212
27 adults with type
1 diabetes
After a 1-month run-in period
patients were randomised.
were swapped to the other
treatment
1) Total glycated haemoglobin
level
1) No significant difference in glycated
RCT crossover Ib
haemoglobin values between the two groups randomisation took place
2) Plasma glucose measurements
3) No systematic differences were noted in
the seven point blood glucose profiles
Aged 18–63 years
Comments
Ireland
3) Blood glucose measurements
group (syringes for self4) No significant difference in
A: continue previous
mixed and pens for prePatients had been
hypoglycaemic
episodes
between
the
two
treatment (self-mixed)
mixed) may lead to bias if
receiving stable
(classified in grades; I- mild, IIgroups. Total episodes: Grade I self-mixed 60 differences are due to
insulin regimens of B: pre-mixed insulin
severe symptoms not requiring
vs. pre-mixed 83; Grade II self-mixed 59 vs. delivery system not preshort-acting and
assistant from others and IIIpreparation that delivered
pre-mixed 32; Grade III self-mixed 17 vs.
intermediate-acting short- and intermediate-acting reduction in level of consciousness pre-mixed 7; Grade IV self-mixed 1 vs. pre- mixed or self-mixed
insulin for 2 months insulin in the preparation
so assistant from others is required mixed 0; total all grades self-mixed 137 vs. insulin, (especially in the
patient preference
IV- severe reduction in
closest fit to previous ratio
pre-mixed 122, p = 0.20
questionnaire)
consciousness
necessitating
from 10:90, 20:80, 30:70,
5) No significant difference in dose of insulin
40:60 and 50:50 preparations parenteral treatment or treatment
from a physician)
received: pre-mixed 46.6 ± 18.9 units vs. selfmixed 46.9 ± 19.3 u, p = 0.62
5) Dose of insulin received
6) Pre-mixed regimens delivered by pen
6) Questionnaire discussing
were preferred to self-mixed regimens
preference for treatment A or B
delivered by syringe in 82% of patients
after the study had ended
Originally 32 patients, 5 dropped
out due to a variety of reasons, 2
specially due to pen concerns
Design
EL
Type 1 diabetes
82
What is ideal: self-mixed or pre-mixed insulin therapy in the treatment of children with type 1 diabetes? (continued)
Study
Population
Davies et al,
1988213
10 male adults with After a 4-week run-in period
type 1 diabetes
patients were allocated in
random order to 3 regimens
Aged 21–40 years
for 1 day each
UK
A: usual twice-daily mixtures
Patients had been
receiving twicedaily mixtures of
short- and
intermediate-acting
insulin
Intervention
of short- and intermediateacting insulin
B: pre-mixed insulin
preparation 50:50 soluble
(human actrapid), isophane
(human protaphane).
Administered by penject
(Hypoguard). The total insulin
dose was divided to give 30%
at 07:30, 20% at 12:00, 30%
at 17:30 and 20% at 21:30h
C: pre-mixed insulin
preparation 30:50 soluble and
isophane (human
Actraphane). Administered by
NovoPen. The total insulin
dose was divided to give 30%
at 07:30, 20% at 12:00, 30%
at 17:30, and 20% at 21:30
D: prandial soluble and
isophane insulin by NovoPen
was divided to give 40%
before breakfast, 20% before
lunch and 40% before dinner.
Evening crystalline insulin
zinc human Ultratard) by
disposable plastic syringe
Outcomes
Results
Comments
1) Total glycated haemoglobin
level
1) Total glycated haemoglobin level did not
statistically significantly change during the
study period, from 8.8 ± 1.6% at the start of
the study to 8.3 ± 1.5% at the end of the
study, this was not analysed by treatment
group
RCT crossover Ib
2) There were significant differences in the
mean plasma glucose profiles of the basal
and prandial regimen (D) compared with the
other three regimens. Between 24:00 and
03:00, regimen D was significantly higher
(p < 0.05), between 08:30 and 11:00,
regimen D was significantly lower (p < 0.05)
differences are due to
delivery system not premixed or self-mixed
insulin
2) Plasma glucose measurements
Design
EL
group may lead to bias if
Novo Industries provided
financial support
Peak morning glucose levels were
significantly lower on the basal and prandial
regimen (D) than on the other three
regimens: D 9.5 ± 4.3 vs. A 13.8 ± 2.8 vs. B
13.6 ± 5.3 vs. C 13.5 ± 4.2 mmol/l, p < 0.01
The mean 24-hour plasma glucose
concentrations were similar for all 4
regimens but mean concentration between
07:30 and 12:00 was significantly lower on
the basal and prandial regimen (D) than on
the other three regimens: D 7.8 ± 3.6 vs. A
10.8 ± 3.3 vs. B 11.4 ± 5.1 vs. C
10.7 ± 3.6 mmol/l, p < 0.01
83
Evidence tables
There were significant differences in the
plasma free insulin profiles (as collected
from 8 of the patients). The mean
concentrations between 19:00 and 21:30
were significantly lower on the pre-mixed
30:70 regimen than the pre-mixed 50:50
regimen and the twice-daily regimen
(p < 0.05). The mean concentrations between
22:30 and 01:00 were significantly lower on
the basal and prandial regimen (D) than on
the other three regimens (p < 0.05). Insulin
concentrations were similar in the remainder
of the 24-hour study period
Study
Population
Intervention
Pizzey et al,
1996210
65 adults with type
1 and type 2
diabetes who had
been on insulin
treatment for at least
3 months
Aged 19–72 years
5 centres in the UK
Patients were
receiving Humulin
S and Humulin I by
self-mixture or
fixed-mixture
morning and
evening
Outcomes
Results
Comments
Design
EL
After a 3-month run-in period 1) HbA1c
allocated by computergenerated numbers to
treatment regimens for 9
months
1) During the run-in period HbA1c showed a
statistically significant improvement in
groups B (from 11.0 ± 4.2% to 9.0 ± 3.0%,
p < 0.005) and C (from 10.5 ± 4.2% to
8.6 ± 3.0%, p < 0.005) but not in group A
(from 9.3 ± 3.6% to 8.9 ± 4.2%, p > 0.05)
Financial support from
Lilly Industries UK
RCT
Ib
A: mixture (flexible – premixed insulin adjusted for
different ratios of soluble and
intermediate insulin for both
morning and evening dose)
There was a statistically significant
improvement in HbA1c levels during the 9month trial in group C (from 8.6 ± 3.0% to
7.6 ± 3.6%, p < 0.05) but not in groups A
(from 8.9 ± 4.2% to 8.9 ± 5.3%, p > 0.05) or
B (from 9.0 ± 3.0% to 8.5 ± 3.6%, p > 0.05)
B: mixture (fixed – single
fixed preparation of the same
ratio both morning and
evening)
26 of the 91 patients
originally recruited
dropped out: this was
mainly due to failure to
attend clinic. Similar
number of patients
dropped out of each
group
2) No significant difference in the number of
hypoglycaemic episodes among the groups
C: S + I (free mixing – selfmixed)
Cucinotta et al, 20 adults with type
1991215
1 diabetes
Aged 19–72 years
Italy
After a 2-week run-in period
After 4 weeks the patients
treatment
A: continue previous
Patients had been
treatment (self-mixed)
receiving soluble
and isophane
B: human pre-mixed insulin
human insulin
injected before
breakfast and dinner
1) 6-point blood glucose profile
1) Blood glucose profiles did not change
during the study compared with the run-in
period and did not show any difference
(graded I – mild, II – moderate, III between the pre-mixed insulin and the self– severe and IV – severe including mixed insulin
hospitalisation)
The mean daily glycaemia with pre-mixture
3) Preference for future treatment (139.7 ± 2.4 mg/dl) was similar to that of the
self-mixture (137.5 ± 2.9 mg/dl)
2) No difference was observed in the
number or severity of the hypoglycaemic
episodes between the two treatments. No
adverse events were reported during the
study
3) 18/20 patients declared their preference
for the pre-mixture for safety and use
simplicity reasons
RCT crossover Ib
Unknown methods of
delivery
Type 1 diabetes
84
Study
Population
Corcoran and 12 patients with
Yudkin, 1986211 type 1 diabetes
Unknown age
UK
Intervention
Outcomes
Porcine soluble and isophane Mean blood glucose
insulin twice daily
HbA1c
versus
Results
Comments
Design
EL
No significant difference (numbers not given No description of how
RCT crossover Ib
– presented as a graph)
pre-mixed Porcine soluble
and isophane insulin twice
daily
versus
porcine soluble and insulin
zinc suspension twice daily
versus
beef ultralente (crystalline
insulin zinc suspension) in
morning and three purified
porcine soluble before meals
Trial length: four 8-weeks
periods
Kinsley and
McKenna,
1999214
600 patients with
type 1 diabetes
Mean age: premixed 42 ± 1.6,
separate insulin
preparations
40 ± 0.7 years
Ireland
Survey
Pre-mix insulin
versus
separate insulin preparations
(2, 3 and 4 injections a day)
HbA1c
Patients aged < 35:
Cohort
IIb
7.8 ± 0.2% (n = 62) vs. (2 separate insulin
preparations) 6.9 ± 0.2% (n = 85), p < 0.001
preparations) 7.6 ± 0.2% (n = 38), p = NS
preparations) 7.3 ± 0.2% (n = 83), p < 0.05
Patients > 35:
7.5 ± 0.2% vs. 7.5 ± 0.1% (all numbers of
insulin injection)
Evidence tables
85
Study
Population
Intervention
Outcomes
Results
Comments
Design
Scheen et al,
1999184
15 adults with type
1 diabetes
Inject short-acting insulin 5
min before each of three
main meals (n = 15)
Mean ± SE:
RCT crossover Ib
2) Basal plasma glucose
1) 7.6 ± 0.2% vs. 7.5 ± 0.2% (NS)
Support from Novo
Nordisk
versus
3) Post-breakfast maximum
glucose increase
2) 9.65 ± 0.83 vs. 9.94 ± 0.96 mmol/l (NS)
inject short-acting insulin 30
min before each of three
main meal (n = 15)
4) Mean daily glucose profile
Support from Novo
Nordisk
RCT crossover Ib
Aged 40 ± 2 years
Belgium
periods
Danne et al,
2003186
42 children (6–12)
and 34 young
people (13–17)
Preprandial insulin aspart
(immediately before the start
of the meal)
Mean age 12.2 ± 2.8 versus
years
postprandial insulin aspart
Germany
(immediately after meal or a
maximum of 30 min after
start of the meal)
periods
5) Average 0–90 min post-meal
glucose rise
EL
3) 3.02 ± 0.61 vs. 2.61 ± 0.90 mmol/l (NS)
4) 10.0 ± 0.7 vs. 9.8 ± 0.8 mmol/l (NS)
5) 2.6 ± 0.7 vs. 0.9 ± 0.9 mmol/l (p = 0.07)
6) Total number of hypoglycaemic 6) 1.7 ± 0.6 vs. 2.0 ± 0.9 per 6 weeks (NS)
episodes
1) Glycaemic control (assessed by
fructosamine and HbA1c)
1) Fructosamine: preprandial 378.0 ± 89.7
vs. postprandial 385.4 ± 77.3 mol/l (NS)
2) 7-point blood glucose
HbA1c: preprandial 8.0 ± 1.5 vs. postprandial No description of
8.3 ± 1.5% (NS)
randomisation
3) Hypoglycaemia
4) Parent satisfaction with insulin
treatment (WHO diabetes
treatment satisfaction
questionnaire)
2) 7-point blood glucose: Only statistically
significant difference was a lower
postprandial glucose level 120 min after
breakfast for preprandial vs. postprandial
Mean blood glucose: difference
–0.71 ± 0.33 mmol/l, p = 0.08
3) Hypoglycaemia: preprandial 544 vs.
postprandial 451 episodes during treatment
period (NS)
4) Parent satisfaction: preprandial 5.11 vs.
postprandial 4.79, mean difference 0.36,
95% CI –0.03 to 0.75, p = 0.09
Kinmonth and
Baum, 1980185
9 children with type Inject short-acting and
1 diabetes
5 min before breakfast (n = 9)
Aged 10.3–16.7
years
versus
UK
inject 30 min before breakfast
(n = 9)
Trial length: single dose, study
days were separated by 7
days
Postprandial glucose concentration Mean postprandial glucose concentration:
(at 90, 120, 150 and 180 min)
90 min 16.8 vs. 19.4 mmol/l (NS), 120 min
14.4 vs. 17.6 mmol/l (p < 0.05), 150 min
12.9 vs. 16.6 mmol/l (NS), 180 min 12.6 vs.
14.8 mmol/l (NS)
Support from Novo
Laboratories
RCT crossover Ib
Type 1 diabetes
86
What is the optimum timing of injecting short-acting insulin before a meal in children with type 1 diabetes?
What is the optimum timing of injecting short-acting insulin before a meal in children with type 1 diabetes? (continued)
Study
Population
Intervention
Outcomes
Rassam et al,
1999187
12 adults with type
1 diabetes
Inject rapid-acting (lispro)
insulin 30 min before meal
(–30 min) (n = 12)
1) Postprandial glycaemia
Aged 41.7 ± 2.9
years
New Mexico
versus
inject 15 min before meal
(–15 min) (n = 12)
Results
Comments
1) Postprandial glycaemia (mean ± SE): –30
min 10 ± 0.6 vs. –15 min 11 ± 0.3 vs. 0 min
10.3 ± 0.4 vs. +15 min 9.8 ± 0.5 mmol/l
3) > 1.4 mmol/l increase in plasma (p = 0.13)
glucose concentration after nadir
2) 1 subject in +15 min group
Design
EL
RCT crossover Ib
3) 2 subjects in the – 30 min group
versus
inject at start of meal (0 min)
(n = 12)
versus
inject 15 min after meal (+15
min) (n = 12)
Trial length: single dose at
breakfast on study day, the 4
study days were separated by
at least 7 days
Strachan and
Frier, 1998188
20 adults with type
1 diabetes
Inject rapid-acting (lispro)
insulin 10 min before meal
(n = 10)
Ages: 10 min before
meal 29.3 ± 2.9, 10 versus
min after meal
inject 20 min after meal
27.6 ± 3.1 years
(n = 10)
UK
breakfast on 4 study days
1 day high carbohydrate
liquid meal (CL), 1 day high
carbohydrate solid meal (CS),
1 day high fat liquid meal
(FL), 1 day high fat solid meal
(FS)
1) Blood glucose (measured at 15, 1) Blood glucose showed a significant
30, 45, 60, 75, 90, 105, 120 min) difference between 10 min before meal and
20 min after meal: for CL meal at 30, 45, 60
2) Peak rise in blood glucose
and 75 min, for CS meal at 15, 45 and 60
min, for FL meal at 30, 45, 60 and 75, for FS
meal at 15, 30, 45, 60, 75, 90 and 105 min
Study has two different
interventions, diet types
as well as timing of
insulin injection
RCT crossover Ib
2) For CL 2.0 vs. 5.6 mmol/l (p < 0.05) no
confidence intervals given, for CS 1.0 vs.
3.5 mol/l (p < 0.01), for FL (rise in blood
glucose for postprandial glucose to peak
5.2 mmol/l but decrease in preprandial)
Evidence tables
87
Study
Population
Schernthaner et 18 adults with type
al, 1998189
1 diabetes
Aged 35 ± 7 years
Austria
Intervention
Outcomes
Results
Comments
Design
6 interventions tests (n = 18)
Postprandial blood glucose
excursions (mmol/l/hour)
Postprandial blood glucose excursions at 60
min:
A (SA –40) 0.84 ± 1.52 (p < 0.05 vs. D RA
–20)
B (SA –20) 1.84 ± 1.65 (p < 0.05 vs. D RA
–20 and E RA 0)
C (SA 0) 2.16 ± 1.70 (p < 0.05 vs. D RA –20
and E RA 0)
D (RA –20) –1.12 ± 2.13
E (RA 0) 0.19 ± 1.72 (p < 0.05 vs. D RA –20)
F (RA +15) 2.20 ± 1.49 (p < 0.05 vs. D RA
–20 and E RA 0)
Support by Eli Lilly
RCT crossover Ib
A: Short-acting insulin
(soluble) 40 min before the
start of the meal (SA –40)
versus
B: short-acting insulin
(soluble) 20 min before the
start of the meal (SA –20)
versus
C: short-acting insulin
immediately before meal (SA
0)
versus
D: Rapid-acting insulin
(lispro) 20 min before start of
the meal (RA –20),
versus
E: Rapid-acting insulin (lispro)
immediately before meal (RA
0)
versus
F: Rapid-acting insulin (lispro)
15 min after meal (RA +15)
lunch on 6 study days
EL
Postprandial blood glucose excursions at 90
min:
A (SA –40) 0.65 ± 1.72 (p < 0.05 vs. D RA
–20 and E RA 0)
B (SA –20) 1.05 ± 2.20 (p < 0.05 vs. D RA
–20 and E RA 0)
C (SA 0) 1.67 ± 2.55 (p < 0.05 vs. D RA –20
and E RA 0)
D (RA –20) –1.27 ± 1.89
E (RA 0) –1.44 ± 1.60
F (RA +15) 0.02 ± 1.99
Postprandial blood glucose excursions at
120 min:
A (SA –40) 0.67 ± 1.69 (p < 0.05 vs. E RA 0)
B (SA –20) 0.74 ± 2.40 (p < 0.05 vs. E RA 0)
C (SA 0) 1.02 ± 2.73 (p < 0.05 vs. D RA –20
and E RA 0)
D (RA –20) –0.99 ± 1.89
E (RA 0) –1.79 ± 1.66
F (RA +15) –0.37 ± 2.05
(p values shown if < 0.05, all others
differences were not significant)
Ahmed et al,
2000190
88 insulin-treated
Survey
Interval between insulin
diabetes
injection and meal (advised
Mean age 48 ± 14
to be given 20 min or more
before meal)
UK
Timing of insulin administration in 84% < 20 min
relation to meal
26% ≤ 5 min
Survey
III
Type 1 diabetes
88
What is the optimum timing of injecting short-acting insulin before a meal in children with type 1 diabetes? (continued)
4.4
Methods of delivering insulin
Should a pen or syringe and needle be used for insulin therapy delivery in the treatment of children with type 1 diabetes?
Study
Population
Intervention
Outcomes
Murray et al,
1988220
78 adults with type
1 diabetes
patients were randomised in
blocks of six, and were then
followed for 20 weeks
Comments
Design
1) No significant difference in glycated
RCT
haemoglobin values between the two groups randomisation took place
(syringe 10.9 ± 2.0% vs. pen 11.2 ± 2.0%)
Aged 18–60 years
One group received
2) Blood glucose profiles not statistically
different insulin to the
Ireland
(classified
in
grades;
I
–
mild,
II
–
A: continued twice-daily
different apart from the pre-dinner blood
other, main effect could
moderate
and
III
–
severe)
regimen of fast- and
glucose values, which were lower at 26
be due to insulin regimen
All patients were
not delivery mechanism
using a twice-daily intermediate-acting insulin in 4) Acceptability of multiple-insulin weeks in the pen group (p <0.05)
regimen of fast- and disposable syringe
regimen
intermediate-acting B: multiple-injection regimen
hypoglycaemic attacks between the two
5) Adverse effects
insulin administered using three-times-daily
groups
with a disposable
human soluble insulin from
syringe
4) 95% of pen group expressed preference
pen injector injected 5–30
for the multiple-injection regimen for future
min before meal and a single
management of their diabetes
injection of human ultralente
19 adults with type
1 diabetes
Aged 20–65 years
Taiwan
treatment
A: injector pen
B: continued using existing
insulin regimen with syringes
and vials
The type of insulin pen was
selected according to their
previous insulin regimen
EL
Ib
2) Blood glucose profile
insulin (crystalline insulin
zinc suspension) before bed
Chen et al,
1999217
Results
5) 1 drop-out in pen group, 1 pen group
patient had to change site of injection due to
burning sensation
1) Blood glucose measurements
1) No significant difference in mean blood
glucose (pen 158.5 vs. syringe, 168.7 mg/dl,
p = 0.541) or maximum blood glucose (pen
206 vs. syringe 222 mg/dl, p = 0.352)
2) pen 7.7% vs. syringe 7.9%, p = 0.085
5) Acceptability of new insulin
delivery system
hypoglycaemic episodes was observed
between the two regimens (p = 0.860)
2) HbA1c
RCT crossover Ib
5) 84% of patients preferred to continue
medication with injector pen
Evidence tables
89
Study
Population
Kølendorf et al, 19 patients with
1988218
type 1 diabetes
Aged 16–69 years
Denmark
Intervention
Outcomes
Results
treatment
1) 7-point blood glucose profiles
3) Total daily insulin dosage
1) Mean blood glucose: penfill 10.7 ± 4.1 vs. No description of how
RCT crossover Ib
vial 10.1 ± 2.9 mmol/l, p > 0.05
within-patient
2) HbA1c: penfill 7.9 ± 2.5% vs. vial
comparison
8.0 ± 2.3%, p > 0.05
4) Frequency of hypoglycaemic
episodes
3) Total daily insulin dosage: 30.6 ± 17.0 vs.
vial 30.5 ± 17.2 units/24 hours, p > 0.05
5) Acceptability and convenience
of delivery system
4) Number of hypoglycaemic episodes was
too small for statistical analysis
A: protaphane HM in penfill
B: protaphane HM in vials
2) HbA1c
Comments
Design
EL
5) 17/19 patients found pen easer and
quicker to use than conventional syringe,
17/19 reported an improved quality of life
with pen, at completion of the study 18/19
patients preferred to continue with pen
Jorgensen et al, 50 adult patients
1988219
with type 1 diabetes 3 months of one treatment
then swapped to the other
Aged 18–56 years
treatment for 3 months.
Denmark
A: pen injector of isophane
insulin
Patients already
using multipleB: traditional syringe of
injection therapy as isophane insulin
3–4 daily injections
of soluble insulin by
means of a pen
injector with a
single injection of
isophane insulin at
bedtime using a
conventional
syringe
1) HbA1c
3) Insulin antibodies
4) Insulin dosage
No significant differences were observed
between the two groups in HbA1c, fasting
blood glucose or mean blood glucose at the
end of the treatment periods
1) penfill 8.0 ± 1.0% vs. syringe 8.1 ± 1.0%,
p > 0.05
6) Reactions at injection site
2) Fasting blood glucose: penfill 9.9 ± 3.4 vs.
syringe 8.9 ± 2.7 mmol/l, p > 0.05
7) Patient preferences for future
devices and significance of pen
Mean blood glucose: penfill 9.2 ± 1.9 vs.
syringe 8.9 ± 1.9 mmol/l, p > 0.05
3) No significant difference between the two
groups
groups
5) The mean number of hypoglycaemic
episodes during the last week on each
regimen was 1.3 for pen and 1.7 for syringe,
p > 0.05
groups in local reactions
7) 86% of patients found the pen injection
less complicated to use. 48/50 indicated that
they would wish to use the pen in the future
RCT crossover Ib
Type 1 diabetes
90
Should a pen or syringe and needle be used for insulin therapy delivery in the treatment of children with type 1 diabetes? (continued)
Study
Population
Korytkowski et 121 patients with
type 1 and type 2
al, 2003221
diabetes
Intervention
Outcomes
Results
Comments
Design
EL
4 weeks of one treatment
treatment for 4 weeks.
Patient preferences
Preferred pen 78/105 vs. preferred syringe
21/105
RCT crossover Ib
1) HbA1c
1) No difference
2) No difference
RCT crossover Ib
Mean age 57 (range
28–81 years)
A: pre-filled disposable pen
injector
USA
B: traditional syringe and vial
Engstrom,
1990222
40 patients with
type 1 diabetes
12 weeks of one treatment
treatment for 12 weeks
Mean age 36 years
3) Patient preferences
for pen group and
34 years for syringe A: ppen injector
group
B: traditional syringe and vial
Sweden
Dahl-Jorgensen 10 adult patients
Syringes used for more than a 1) HbA1c (mean ± SD)
et al, 1986225
with type 1 diabetes year (retrospectively)
21–34 years
pen (NovoPen) for 6–9
Norway
months, pen could only
deliver short-acting insulin in
2-unit doses
3) 38/40 patients chose to continue with
pens at end of study
1) 3–0 months syringe 8.9 ± 1.8%, 0 month No description of how
Before/after
syringe 8.8 ± 1.9%, 1–3 months pen
randomisation took place trial
9.2 ± 1.9%, 4–6 months pen 9.3 ± 1.8%, 7–9
Early model of the pen so
months pen 9.3 ± 1.9%
the frequent technical
Blood glucose control deteriorated with pen difficulties have been
(p < 0.01)
resolved for currently
available pens
2) All patients wanted to continue using pen
after the end of the study
IIb
All but one patient experienced technical
difficulties and 10 pens had to be replaced
for 7 patients
No serious hypoglycaemic episodes or
diabetic ketoacidosis occurred
Evidence tables
91
Study
Population
Gnanalingham No patients
et al, 1998223
Intervention
Outcomes
Accuracy and reproducibility Weight of dose and intended and
of small doses delivered 1, 2, actual dose compared
5 and 10 units of soluble
insulin from:
5 new NovoPen (1.5 ml) vs. 5
BD-Pen (1.5 ml)
Results
Mean ± SD (range):
NovoPen: I unit 0.89 ± 0.04 (0.85–0.95), 2
units 1.90 ± 0.03 (1.85–1.93), 5 units
4.87 ± 0.03 (4.84–4.91), I0 units 9.80 ± 0.09
(9.72–9.94)
Comments
Design
EL
Equipment
evaluation
IIa
Equipment
evaluation
IIa
BD-Pen: I unit 0.92 ± 0.03 (0.87–0.95), 2
units 1.90 ± 0.05 (1.82–1.94), 5 units
4.87 ± 0.07 (4.77–4.94), I0 units 9.86 ± 0.09
(9.73–9.96)
versus
syringes (30-unit)
Delivered by nurses
30-unit syringe: 1 unit 1.23 ± 0.09
(1.16–1.37), 2 units 2.24 ± 0.09 (2.15–2.35),
5 units 5.18 ± 0.06 (5.10–5.26), I0 units
10.07 ± 0.07 (9.97–10.14)
Accuracy and reproducibly of
5 units of soluble insulin from
cartridges until the cartridge
was empty, for NovoPen and
BD-Pen
30-unit syringe delivers significantly higher
dose than pen injectors (p < 0.01). The %
error in the delivery of 1 unit dose was
significantly greater then the % error of 2, 5
and 10 units (p < 0.05), coefficient of
variation was significantly higher in the 1
unit dose as well (p < 0.01)
There was no difference in insulin delivered
from the four different quarters of the insulin
cartridges (p = 0.7)
Lteif and
Schwenk,
1999224
48 subjects, 32
patients and a
parent of an
additional 16
patients
Measure out insulin dose 3
times, dispense into silicon
vial. Statistical analysis to
determine accuracy and
precision
24 patients on
multiple daily
injections (mean
age 14.1 years)
Pen
24 children on
mixed split regimen
(mean age 9.8
years), for 16 of
these subjects the
parent gave insulin
and performed the
study
USA
versus
syringe
Accuracy
Dose soluble insulin ≤ 5 units (n = 9, 27
observations): absolute error 4.9 ± 1.6% vs.
9.9 ± 2.4% (p < 0.01)
Dose soluble insulin > 5 units (n = 15, 45
observations): absolute error 2.2 ± 0.4% vs.
3.2 ± 0.6% (NS)
Isophane insulin similar increase in accuracy
of insulin pen for high- and low-dose insulin
(n = 24, 72 observations): mean percent error
5.6 ± 1.1% vs. 7.5 ± 1.5% (p < 0.01)
Children compared with caregivers, dose ≤ 5
units (children n = 5, parents n = 14): mean
percent error 14.5 ± 5.4% vs. 11.6 ± 4.2%
Type 1 diabetes
92
Study
Population
Intervention
Outcomes
Bohannon et
al, 2000227
315 patients (136
New pen (Humalog Pen®)
Patient preference and physician
with type 1 diabetes given to patients,
view
and 179 with type 2 questionnaire after 6 weeks
diabetes)
33 physicians also completed
Mean age
a questionnaire
49.2 ± 16.37 years
Indiana
Results
Comments
Design
EL
Patients previously using syringe (n = 194):
probably or definitely would continue to use
pen 76.5%, probably or definitely would
recommend pen 78.8%
Before the study 62%
used syringe and vials,
28% used insulin pen
device, 10% insulin
naïve.
Noncomparative
trial
multicentre
III
All patients (n = 315): strongly or somewhat
agreed that they prefer pen to syringe 74%,
strongly or somewhat agreed that easier to
comply with insulin treatment when using
pen 61%, strongly or somewhat agreed that
more comfortable in public with pen than
syringe 67%, strongly or somewhat agreed
that easer to use pen than syringe 79%,
strongly or somewhat agreed that pen more
convenient than syringe 84%
Physician questionnaire (n = 33): strongly or
somewhat agreed that less time need to
teach to use pen compared with syringe
88%, strongly or somewhat agreed that that
it was easier to start patients new to insulin
with pen compared with syringe 91%,
strongly or somewhat agreed that more
confident in patients’ ability to deliver insulin
dose with pen compared with syringe 85%
Evidence tables
93
Study
Population
Intervention
Outcomes
Perry, 1993216
113 children with
type 1 diabetes (for
125 recruited)
Preloaded pen
1) Satisfaction questionnaire (score 1) Convenience of treatment
on scale 0–6, mean ± SD )
(0 = more):1.5 ± 1.5 vs. 3.9 ± 1.7, p < 0.001
Aged 8–18 years
conventional syringe and vial
UK
periods
versus
2) Pen acceptability
3) HbA1
4) Adverse events
Results
Flexibility of treatment (0 = more): 2.2 ± 1.3
vs. 3.7 ± 1.4, p < 0.001
Demands of treatment (0 = more): 4.0 ± 1.4
vs. 2.6 ± 1.5, p < 0.001
Glycaemic control: no statistical difference
Number of recent hypoglycaemia events: no
Unacceptably high blood sugar: no statistical
difference
Understanding of diabetes: no statistical
difference
2) 88.5% preferred the disposable pen to
syringes and vials
90.3% would continue using the pen if it
became available
3) 10.58 ± 2.40% vs. 10.27 ± 2.59%
4) Hypoglycaemic events (all levels): 350
events reported by 60 patients vs. 289 events
by 54 patients
Severe hypoglycaemic events: 8 vs. 13
Redness and swelling: 5.3% vs. 0.9%, NS
Lipohypertrophy: 15.0% vs. 18.6%, NS
Comments
Design
Not published
RCT crossover Ib
multicentre
Randomisation by sealed
envelopes containing
allocation
Analysis of HbA1 unsure
EL
Type 1 diabetes
94
Additional devices to be used with pen injectors
Study
Population
Intervention
Diglas et al,
1999226
57 adult patients
NovoPen 3
versus
Aged 19–60 years
NovoPen 3 with PenMate®
Austria
periods
Outcomes
Results
Comments
1) Glycaemic control (mean
HbA1c)
1) 8.2 vs. 8.1% ( p = 0.2)
Comparative
multicentre
crossover
Ib
Outcomes
Results
Comments
EL
2) Pain perception: 14.9 vs. 19.9 mm
2) Pain perception (measured on a (p = 0.005)
100 mm visual analogue scale of
Experienced pain 3–6 times a week: 10.5%
pain perception)
vs. 22.8%
3) Hypoglycaemia
3) 62 vs. 66 (p = 0.3)
Design
EL
Disposable or reusable insulin pens
Study
Population
Intervention
Steel et al,
1997228
110 patients who
used a pen to
administrator a
fixed mix of insulin
(31 had type 1
diabetes and 79 had
type 2 diabetes)
Interview patients asked what All patients:
they did when they no longer
1) Mean wastage insulin
had enough insulin on the
pen for the next injection
2) Approximate cost of waste
All patients:
Compare 1.5 ml cartridge pen 3) No. wasting over 10% insulin
users (n = 22) to 3 ml
disposable pen users (n = 88) Patients avoiding waste:
4) No. giving two injections
3) 8 vs. 4
5) Other ways of avoiding waste
while giving correct dose
5) 2 vs. 0
Mean age 55.8,
range 15–90 years
UK
Design
Observational III
1) 2113 vs. 831 units/patient/year
2) £31 vs. £22 waste/patient/year
Patients avoiding waste:
4) 4 vs. 23 (24.5%)
6) 1 vs. 4 (4.5%)
6) Avoiding waste giving incorrect
dose
330 patients with
type 1 or type 2
diabetes who inject
insulin
Aged 18–81 years
95
Croatia
Interview on patient
acceptance of new disposable
pen device compared with
old reusable pen
Disposable pen was rated as a significant or
modest improvement over previous pen by
70% of the patients, 76% preferred the new
device
Unknown if preference
was for new pen design
or whether it made a
difference that the pen
was pre-filled and hence
disposable
Noncomparative
study
multicentre
III
Evidence tables
Sucic et al,
2002229
Study
Population
Intervention
Outcomes
Results
Aziz, 1984245
14 children with
type 1 diabetes
Patients given same
disposable syringe-needle
unit repeatedly for a total of
seven times
Unit reuse
Average unit use 6.3 times range of 1–16
times
Aged 7 to 18 years
USA
Schuler et al,
1992246
20 (13 patients with
type 1 diabetes and
7 patients with type
2 diabetes)
Patients given 5 sterile
Bacterial culture of the needle
numbered needles which had
to be used for 1, 3, 6, 9 or 12
injections if possible
Mean age 35 (range
18–74 years)
Comments
Patients were free to
change to a new unit if
the needle got dull, bent
No incidents of infection requiring antibiotic or broken, the skin got
therapy, one incidence of redness lasting 1
infected, markings got
day
blurred or insulin got
cloudy
Culture from insulin bottles were negative
12 of 14 patients continued to reuse their
needles multiple times after completing the
study
1 patient dropped out of
the study due to
apprehension due to
needles being dull
7/20 patients completed the protocol and
used the needles repeatedly up to 12 times
before bacterial assessment. Other patients
use needles up to 9 times but then due to
dullness needles could not be reused again
Before experiment 59/20
patients reused needles
2–5 times, 9/20 patients
reused needles 5–10
times, 2 patients reused
needles > 10 times
No signs of local infection
Design
EL
NonIIb–III
controlled
trialobservational
Nonrandomised
trial
IIa
Staphylococcus was detected on one needle
that had been reused 3 times. All other
needles were sterile
50.6% of the needle plastic group points
were contaminated with coagulase-negative
Staphylococcus, Corynebacterium or haemolytic Streptococcus. No relationship
seen between the contamination and the
frequency of daily insulin injection or
between contamination and the kind of
insulin administered or the location of the
injection sites
Alexander et
al, 1987247
179 patients with
diabetes
Questionnaire on syringe
reuse
Use of syringes more than once
Asked if syringes were obtained free on
Observational III
prescription: 86% said they would continue
Same
paper
as
disposal
of
to reuse their syringes, 13% said they would
sharps paper below
use them only once
Type 1 diabetes
96
Reuse of needles in children with type 1 diabetes
Disposal of sharps
Study
Population
Intervention
Outcomes
Results
Comments
Design
Alexander et
al, 1987247
179 patients with
diabetes
Questionnaire on disposal of
sharps
1) Methods of disposal
1) 100% replaced guard before disposal
Observational III
2) Use of syringes more than once 78% used household waste
UK
EL
Unknown age
78% considered their method of disposal
safe
75% thought sharp bin provision was a
reasonable idea
2) Asked if syringes were obtained free on
prescription: 86% said they would continue
to reuse their syringes, 13% said they would
use them only once
Crawshaw et
al, 2002248
144 patients with
diabetes
Age range 0–59
years
UK
Questionnaire on disposal of
sharps
Information on sharps disposal
Use of sharps bin or needle
clippers
Recall receiving information on the disposal
of sharps: 14% for disposal of needles and
34% for the disposal of lancets
Observational III
Needle clippers or a sharps box were used
by 64% of the people for needle disposal
and 30% of the people for lancet disposal
If the person had remembered receiving
information they were more likely to use
needle clippers and/or a sharps bin for
needle (34/39 vs. 31/60, OR 6.4, 95% CI 2.2
to17.8) and lancet disposal (13/31 vs. 3/67,
OR 15.4, 95% CI 4.2 to 55.8). OR
calculated from numbers given
Evidence tables
97
Study
Population
Tubiana-Rufi et 50 children with
type 1 diabetes
al, 1999230
Aged 3–18 years
BMI between 3rd
and 60th centiles
for age and sex
(slim/thin children)
France
Intervention
Outcomes
Results
2 injections performed on
each child by nurse on 2
groups of children
Frequency of intramuscular
injections
With 12.7 mm needles 86% of insulin
RCT
injections were performed intramuscularly
open label
(88% in the arm and 84% in the thigh), 38%
crossover
of insulin injections with 8mm needle were
visualised into muscle (48% in the arm and
28% in the thigh region), reduction with
8 mm needle significant in arm p < 0.01 and
thigh p < 0.001
Insulin leakage
first group of 25 children
(randomised then crossed
over to opposite):
A: 12.7 mm in thigh
Comments
Design
EL
Ib
B: 8 mm in thigh
2nd group of 25 children
(randomised then crossed
over to opposite):
C: 12.7 mm in arm
D: 8 mm in arm
What is the ideal type of needle for the injection of insulin in children with type 1 diabetes?
Study
Population
Intervention
Edsberg et al,
1987231
10 adult patients
Each patient received two
with type 1 diabetes injections at separate sites on
the abdominal wall at same
Aged 19–50 years
time
Denmark
A: 25 mm multi-injection
needle (14 holes)
B: conventional needle
Outcomes
Results
Comments
Design
EL
Residual radioactivity at the
injection site – from this the
percentage dose absorbed in 30
min periods was calculated
The sprinkler needle gave rise to a
significantly lower residual activity from
20–70 min after the insulin injection
(p < 0.05)
Site of injection was
chosen at random
RCT
IIa
randomisation of site took
The initial dose absorbed during consecutive place, same patients for
30 min periods showed absorption in the
intervention A and B
first period to be significantly faster with the
sprinkler needle than the conventional
needle injection
Type 1 diabetes
98
What is the ideal length of needle for the injection of insulin in children with type 1 diabetes?
What is the ideal technique for the injection of insulin in children with type 1 diabetes?
Study
Population
Intervention
Smith et al,
1991235
32 children with
No intervention
diabetes who inject
insulin (unspecified
type of diabetes)
Aged 4.3–17.9,
mean 11.3 years
Outcomes
Results
Comments
Design
Distance from skin to muscle
fascia was measured by
ultrasonography at standard
injection sites on outer arm,
anterior and lateral thigh,
abdomen, buttock and calf
Distances were greater in girls than boys,
p = 0.03 in calf and p < 0.001 for all other
injection sites
Results displayed in
graphs
Observational III
nonintervention
study
UK
In most boys the distance was less than the
length of the needle (12.5mm) at all sight
apart from the buttock
EL
In girls most distances were greater than
12.5 mm except the calf
25/32 (78%) injected at an angle of 90
degrees, 24/32 (75%) raised a skin fold
before injecting
Vaag et al,
1990234
10 adult patients
Short-acting insulin
4 days subcutaneous (SC)
Aged 21–55 years. insulin injection
Denmark
versus
4 days intramuscular (IM)
insulin injection
Blood glucose 7 times a day
Variation in blood glucose
Pain (by anonymous
questionnaire)
Hypoglycaemia
Drop outs
Mean blood glucose levels were not
statistically different: SC 9.9 ± 1.5 vs. IM
9.8 ± 1.0 mmol/l
RCT crossover Ib
Lower coefficient of variation of blood
glucose was seen in IM than SC: SC
42.6 ± 3.3% vs. IM 32.9 ± 3.6%, p < 0.01
7/8 patients reported that IM was no more
painful than SC injection
2 patients were excluded due to
hypoglycaemic attacks at the same time on 2
consecutive days, 1 from SC group and 1
from IM group
Vaag et al,
1990233
11 adult patients
Two injections of long-acting
with type 1 diabetes insulin 125I labelled given at
the same time
Mean age 30.9 ± 2.7
years
intramuscular (IM) insulin
injection
Denmark
versus
subcutaneous (SC) insulin
injection
2) SC injection of long-acting insulin caused
a more constant rate of absorption
throughout the 24-hour study period, with
only a minor plateau in absorption rate 3–9
hours after injection
99
3) Intra-patient variation of absorption was
significantly lower for SC than IM injected
insulin: variation at time when 25% of
insulin was absorbed 26.4 vs. 20.0 hours,
when 50% of insulin was absorbed 29.8 vs.
18.4, and when 75% of insulin was
absorbed 42.5 vs. 19.5
Intervention
study
IIa
Evidence tables
Trial length: 4 days
1) Time till 25%, 50% and 75% of 1) IM injected long-acting insulin was
Both IM and SC given at
insulin was absorbed
absorbed much faster than SC injected
the same time
insulin. Time till 25% of insulin was
2) Insulin absorption rate
absorbed 2.7 vs. 5.8 hours, time till 50% of
3) Intra-patient variation of insulin insulin was absorbed 5.3 vs. 10.3, and time
till 75% of insulin was absorbed 8.5 vs. 16.3
absorption
Study
Population
Intervention
Outcomes
Results
Polak et al,
1996236
64 children with
diabetes treated
with insulin
Measurement of where
insulin was deposited
1) Number of injections that were
intramuscular
1) 18/59 injections were in the intramuscular Age unknown
tissue
2) Analysis of children who had an 2) Children who had an intramuscular
intramuscular injection by sex,
injection has a significantly lower percentage
BMI and skin surface to muscle
BMI (mean ± SE, 47 ± 8% vs. 72 ± 4%,
fascia thickness
p = 0.004), significantly lower distance from
skin surface to muscle fascia without a skin
fold (5.6 ± 0.6 vs. 11 ± 0.7 mm, p < 0.0001),
and a lower distance from skin surface to
muscle fascia with a skin fold (8.1 ± 0.9 vs.
15.9 ± 0.8 mm, p < 0.0001) than children
who has a subcutaneous insulin injection
France
Fleming et al,
1997237
42 adults with type Injection technique through
1 diabetes or type 2 clothing
diabetes (insulinversus
treated)
conventional subcutaneous
Age range 23–63
injection
years
USA
1) Adverse events
Approximately 13 720 injections
2) Glycated haemoglobin levels
1) No subjects experienced erythema,
induration or abscess at injection sites
3) Problems with injection
Comments
Design
EL
Observational III
nonintervention
study
RCT crossover Ib
2) No difference in glycated haemoglobin
levels between regimens
3) No significant difference in the number of
problems with injecting. Reports of blood
stains on clothing and bruising with injecting
through clothing
Benefits of injection through clothing
1.34 ± 1.11 vs. 0, p < 0.01, reported benefits
of convenience and saving time
Engstrom and
Bergman,
1993238
28 adults
Mean age 38.5
years
Sweden
New injection technique for 1) HbA1c
pen device (patient grasps
skin fold, inserts needle at an 2) Fructosamine
angle of 45 degrees, releases 3) Weight
the grip on the skin fold and
4) Fasting insulin dosage
injects insulin)
5) Mild hypoglycaemia
versus
conventional injection
technique for pen device
(patient grasps skin fold,
inserts needle perpendicularly
and injects insulin while still
grasping skin fold)
periods
7) Ease of learning technique: 19 found new
injection technique easier, 9 found no
difference, none found old technique easier
Ease of technique: 21 found new injection
technique easier, 7 found no difference,
none found old technique easier
25/28 continued to use new injection
technique after study ended
RCT crossover Ib
Type 1 diabetes
100
What is the ideal technique for the injection of insulin in children with type 1 diabetes? (continued)
What is the ideal technique for the injection of insulin in children with type 1 diabetes? (continued)
Study
Population
Intervention
Strauss et al,
2002232
1002 patients who
inject insulin with
type 1 or type 2
diabetes (58% type
1)
Survey of injection technique
Aged 13–89, mean
46.9 years
Sweden, Belgium,
Germany, France,
Italy, Spain, UK
Outcomes
Results
Comments
70% used pinch up technique, patients who
used the pinch technique had lower HbA1c
than those who did not (7.9% vs. 8.2%,
p = 0.032), no association with
lipohypertrophic lesions
Possible bias between
Observational III
confounding factors,
survey
unknown what
adjustments were made,
raw figures not given,
results just quote p values
There was a significant relationship between
leaving the pen in for longer and lower
HbA1c (p = 0.001), no association with
lipohypertrophic lesions
Design
EL
Patients who regular inspected injection sites
had a lower HbA1c (p = 0.03)
HbA1c was not associated with injection
perpendicularly into the abdomen, nor
pinching up in the thigh
38% reported rotating injection sites each
time they injected soluble insulin, this was
not associated with HbA1c, or
lipohypertrophic lesions (p = 0.088)
Lipohypertrophy was not associated with the
length of the needle, the presence of bruising
at site of injection, the sex of the patient,
angle of injection, disinfecting the skin
before injecting
There was a possible relationship between
patients who reused needles and
lipohypertrophic lesions (p = 0.067)
Those who inject into smaller zones (5 cm
by 4 cm) and reused needles had a higher
risk of lipohypertrophic lesions (p = 0.0001)
Needle length was not related to bruising
Evidence tables
101
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Witt et al,
1983242
23 children with
type 1 diabetes
2-day trial, early (≥ 15 min in
proportion to the fasting
blood glucose concentration)
and late (5 min before
breakfast) insulin injections
Plasma glucose
Fasting plasma glucose and free insulin
concentrations were not significantly
different between the groups on either study
day.
‘Patients were divided
into two groups’,
unknown method
Nonrandomised
controlled
trial
IIb
Aged 7.7–18.6
years
USA
Free insulin determination
In the extremity-administered insulin the
mean free insulin concentration did not
change significantly between 07:00 and
08:00 on the late insulin day, but the mean
plasma glucose concentrations increased
from 146 ± 24 to 173 ± 19 mg/dl (p < 0.01). In
the abdominal wall-administered insulin the
mean free insulin concentration did not
change significantly between 07:00 and
08:00 on the late insulin day, and the mean
plasma glucose concentrations were not
significantly different (197 ± 31 to
217 ± 27 mg/dl)
A: normal morning insulin
dose administered in
extremity
B: normal morning insulin
dose administered in
abdominal wall
After breakfast the mean free insulin
concentrations were not significantly
different between the two interventions at
any time on the late insulin day
Koivisto and
Felig, 1980239
7 adults with type 1 Insulin absorption and blood
diabetes
glucose control associated
with varying insulin (125I
Aged 24–49 years
labelled rapid-acting insulin)
injection site in patient with
USA
diabetes
Abdominal wall
versus
leg
versus
arm
Trial length: 3 days, 1 site test
per day
1) Insulin absorption
2) Blood glucose control
1) Amount of insulin absorbed from the
abdomen was significantly greater than
insulin absorbed from the leg at 90 to 135
min after the insulin injection (p < 0.005), by
135 min after injection 86% more insulin
had been absorbed
Amount of insulin absorbed from the arm
was significantly greater than insulin
absorbed from the leg at 90 to 135 min after
the insulin injection (p < 0.05), by 135 min
after injection 41% more insulin had been
absorbed
Amount of insulin absorbed from the
abdomen was significantly greater than
insulin absorbed from the arm at 90 to 135
min after the insulin injection (p < 0.05)
2) The mean rise in plasma glucose above
fasting levels was 30 to 50 mg/dl less after
abdominal than leg injection (p < 0.02)
RCT crossover Ib
Type 1 diabetes
102
What is the ideal anatomical place for the injection of insulin in children with type 1 diabetes?
What is the ideal anatomical place for the injection of insulin in children with type 1 diabetes? (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Bantle et al,
1993240
22 adults with type
1 diabetes
Injection of isophane and
soluble insulin in to:
Peak postprandial increment in
plasma glucose
RCT crossover Ib
Aged 20–44 years
abdomen
The peak postprandial increment in plasma
glucose after abdominal injection was
3.1 mM or 29% lower than the thigh
(p < 0.001)
USA
versus
1) Serum fructosamine
1) Not significantly different
RCT
2) Blood glucose excursions
2) Blood glucose excursions were larger
when insulin was injected into the thigh
compared with abdomen
thigh
Trial length: 2 days, 1 site test
per day
Henriksen et
al, 1993241
35 adults with type
1 diabetes
Subcutaneous injection into
the thigh (n = 18)
Aged 18–57 years
versus
Denmark
subcutaneous injection into
the abdominal wall (n = 17)
3) Low nocturnal blood glucose
values (< 4 mmol/l)
3) A higher number of measured low
nocturnal blood glucose values were seen
when insulin was injected into the thigh
compared with abdomen (34/86 vs. 21/81,
p < 0.05)
Monaco et al,
1996244
58 children with
type 1 diabetes
Method of teaching children
to identify injection sites
Aged 6–11 years
Injection bares
USA
versus
Ib
1) Accuracy scores in injection site 1) Total errors including date on aid, body
identification
location, exact site: (mean ± SD) 7.02 ± 4.36
vs. 13.4 ± 5.67, p = 0.0001 (significance
remained when stratified into 2 age groups)
No detail about
randomisation
NonIIa
randomised
controlled
trial crossover
2) All children: 37 preferred bare vs. 21
preferred chart, p = 0.036
injection chart
6–8 year old group: 21 preferred bare vs. 8
preferred chart, p = 0.016
9–11 year old group: no significant
preference
Girls: 22 preferred bare vs. 7 preferred chart,
p = 0.005
Boys: no significant preference
12 adults with type
1 diabetes
Aged 19–56 years
USA
Rotating injections
(predetermined to arm,
abdomen or thigh)
versus
abdominal injections
103
Trial length: two 3-days
periods
1) Mean SD of plasma glucose
level
2) Mean variation of plasma
glucose level
1) Higher in the rotating injections group
than the abdominal injection group:
3.7 ± 0.3 vs. 2.7 ± 0.2 mmol/l, p < 0.001
2) Higher in the rotating injections group
than the abdominal injection group:
17.4 ± 2.2 vs. 9.2 ± 1.4 mmol2/l2, p < 0.001
RCT crossover Ib
Evidence tables
Bantle et al,
1990243
Study
Population
Intervention
Outcomes
Results
Comments
Houtzagers et
al, 1988249
14 adults with type
1 diabetes, 6 with
needle phobia
Jet injector (Medi-jector II)
1) Drop outs
versus
1) 5 patients dropped out – due to technical
problems, haematomas, insulin leakage
and/or pain
Aged 19–66, mean
33 years
conventional syringes
3) Hypoglycaemic reactions
frequency
Needle-phobic patients
RCT crossover Ib
50.0 ± 13.1 vs. 57.4 ± 6.0
(no significant difference) open
No details of
randomisation or power
calculation
Netherlands
periods
4) Anxiety test
2) 9.8 ± 1.2% vs. 9.1 ±1.1% p < 0.05
3) Grade I 0.4 ± 0.3 vs. none found
Grade II 3.7 ± 3.0 vs. 3.2 ± 1.4
Grade III 0.1 ± 0.1 vs. 0.4 ± 0.3
Design
EL
Devices supplied by
Health Care Systems,
Europe
4) Non-needle-phobic patients 33.5 ± 2.1 vs.
30.3 ± 2.1 (no units) (no significant
difference)
Rayman et al,
1989251
10 adults with type
1 diabetes
Aged 21–71 years
Jet injector
1) Drop-outs
1) 2 patients dropped out, due to instruments
failure
Evaluation
study
III
Evaluation
study
III
Evaluation
study
III
2) 1/8 vs. 7/8
Questionnaire on experiences
UK
Gonzalez et al, 14 children with
New device
1998254
type 1 diabetes
already using Medi- versus
jector
old device (Medi-jector
Aged 3–18 years
USA
Baseline psychological
response and follow-up 2
weeks later
1) Compliance
1) Number of times skipped injections in last
2 weeks – once or twice: 7% vs. 29%
2) Reported difficulties with device p = 0.08
3) Pain
Did injecting go wrong in the last 2 weeks –
4) Local reactions
yes: 36% vs. 57% p = 0.30
3) Sometimes, often or always painful: 64%
vs. 28%, p = 0.01
Very, quite or reasonably painful: 28% vs.
8%, p = 0.02
4) Number of times in last week jet injector
caused bruising: no statistical difference
Stephens et al,
2003252
10 patients with
type 1 diabetes
One-off trial of device
Jet injector (J-Tip)
Mean age 37.5,
range 22–71 years
versus
UK
pen
Patient preference
7/10 preferred pen, 3/10 no preference,
none preferred jet injector
Type 1 diabetes
104
Jet injectors
Jet injectors (continued)
Study
Population
Intervention
Denne et al,
1992250
42 patients with
Questionnaire
type 1 diabetes, all
patients used needle
and syringe before
moving on to the jet
injector
Outcomes
Results
1) Number returned to syringe
after trial of jet injector
1) 46% (50% stopped due to breakage of
device, 45% because they did not like it, 5%
because told to by medical professional)
2) Preference
Comments
Design
EL
Evaluation
study
III
Evaluation
study
III
2) 70% preferred jet injector
Aged 20–53, mean
35 ± 8 years
USA
Schneider et al, 41 children with
1994253
type 1 diabetes
Insulin administration by
jet injector by doctor
Aged 9.3–21.1,
mean 14.45 years
versus
Austria
syringe by doctor
One-off trial
1) Pain (using visual pain scale,
139 mm long)
2) Adverse events
1) Mean pain score in mm: 53.54 vs. 43.48
2) Jet injector produced: lesions in 25/41
patients, bleeding in 21/41, leakage in 11/41,
painful infiltrate in 4/41, wheal in 3/41,
haematoma and delayed pain in 2/41. No
comparison with syringe
Evidence tables
105
Study
Population
Intervention
Outcomes
Results
Comments
Royle et al,
2003 255
6 RCTs, total 1191
participants with
type 1 and type 2
diabetes, mainly
adult population
Inhaled insulin
1) Glycaemic control
1) All trials showed glycaemic control to be
comparable for inhaled insulin compared
with entirely subcutaneous regimen
Insufficient information to Systematic
determine study quality
review
versus
2) HbA1c
insulin
3) Patient satisfaction
Trial length: at least 10 weeks
4) Quality of life
6) Weight change
7) Adverse effects
2) 3 trials, 2 in patients with type 2 diabetes
and 1 in patients with type 2 diabetes, had
sufficient information to allow meta-analysis
of HbA1c change from baseline (WMD –0.12,
95% CI –0.28 to 0.03)
3) 5 trials reported patient satisfaction, all 5
reported significantly greater satisfaction
with inhaled insulin
4) 3 trials reported outcomes for quality of
life, all showed significant improvements in
the inhaled insulin group compared with the
subcutaneous insulin group
5) There was little or no difference in the
total hypoglycaemic episodes in any of the
trials
4 trials reported the rates for severe
hypoglycaemic episodes, 3 found no
statistical difference and 1 trial in patients
with type 1 diabetes found an increased in
severe hypoglycaemic episodes in patients
treated with inhaled insulin (RR 1.97, 95%
CI 1.28 to 3.12)
6) 3 trials reported no difference in weight
change, one trial reported a significantly
smaller increase in body weight in patients
treated with inhaled insulin compared with
subcutaneous insulin injections.
7) 3 studies reported greater incidence of
cough in those using inhaled insulin
RCTs: Belanger 2002259,
Cefalu 2001260,
Hermansen 2002261,
Quattrin 2002256, Skyler
2001257, Skyler 2002258
Design
EL
Ia
Type 1 diabetes
106
Inhaled insulin
Inhaled insulin (continued)
Study
Population
Intervention
Outcomes
Results
Skyler et al,
2001257
73 patients with
type 1 diabetes
Inhaled insulin (n = 35)
1) HbA1c
versus
2) Changes in fasting and
postprandial glucose
concentrations
1) At 12 weeks 7.9 ± 0.1% vs. 7.7 ± 0.9% (no Study included in above
significant difference), difference 0.2% (95% systematic review. 1
CI –0.2 to 0.5)
dropped out of
conventional
subcutaneous insulin
3) Number with mild hypoglycaemia: 33/35 group
vs. 31/37 (no significant difference)
Supported by Pfizer
Aged 18–55, mean
age for inhaled
insulin group
35.4 ± 9.0, for
subcutaneous
insulin group
39.7 ± 8.6 years
USA
insulin (n = 37)
Trial length: 12 week
3) Occurrence and severity of
hypoglycaemia
4) Body weight
5) Pulmonary function
Comments
Design
EL
RCT parallel
open label
multicentre
Ib
Number with severe hypoglycaemia: 5/35
vs. 5/37 (no significant difference)
Number of mild episodes: 550 vs. 547 (no
Number of severe episodes: 8 vs. 10 (no
Mild episodes per patient month: 5.5 vs. 5.3
Severe episodes per patient month: 0.08 vs.
0.10 (no significant difference)
5) Stable over study period
No serious or major adverse events
6) 85% of patients already on inhaled insulin
elected to continue on a long-term extension
with inhaled insulin
Evidence tables
107
Study
Population
Lalej-Bennis et 16 patients with
type 1 diabetes
al, 2001262
Mean age 38 ± 2
years
France
Intervention
Outcomes
Results
Comments
Design
Preprandial gelified nasal
insulin (n = 16)
1) Drop-out
1) 4 patients withdrew because of nasal
burning and persistent sinusitis
No details of
calculation
RCT crossover Ib
1) 12 patients withdrew: 6 because of
No details of
metabolic dysregulation, 4 due to lack of
compliance with nasal mucosa investigation, calculation
1 due to hypoglycaemia
RCT crossover Ib
versus
preprandial insulin injections
(n = 16)
periods
Hilsted et al,
1995263
31 patients with
type 1 diabetes
Mean age 32 ± 2
years
Denmark
2) HbA1c
2) At 6th month: 8.3 ± 0.1% vs. 8.6 ± 0.1%
(capillary glucose value ≤ 5.5 mM)
3) 87.9 ± 2.5 vs. 87.7 ± 2.5 (no significant
4) Weight gain
difference)
EL
4) 1.6 ± 0.4 vs. –0.8 ± 0.1 kg, p < 0.05
first dose preprandial nasal
insulin (50%), 30 min later
second dose (50%) (n = 19)
1) Drop-out
versus
2) HbA1c
2) At 1 month 8.1% vs. 7.8% (p < 0.01)
reprandial insulin injections
(n = 19)
3) no significant difference
periods
Indwelling catheters
Study
Population
Intervention
Outcomes
Results
Hanas et al,
2002 264
41 patients with
type 1 diabetes
Indwelling catheter
1) Pain
versus
2) Use after end of study
1) Lower pain for the group treated with
Intranasal insulin than insulin pens (median
0.8 cm vs. 1.5 cm, p = 0.006)
Aged 8.1 ± 3.7 years
Sweden
insulin pen with standard
needle
Trial length: at least 10 weeks
2) 16/20 chose to remain using indwelling
catheters after study ended, 9/20 were still
using indwelling catheters after 6 months
Comments
Design
EL
RCT parallel
Ib
Type 1 diabetes
108
Nasal insulin
4.5
Non-insulin agents (oral antidiabetic drugs)
Is there a role for other oral hypoglycaemic agents combined with insulin therapy in the treatment of children with type 1 diabetes?
Acarbose
Study
Population
Intervention
Hollander,
1997267
264 (236 analysed)
adult patients with
type 1 diabetes.
Treatment three times daily at Primary outcomes: HbA1c, mean
the beginning of each meal
percentage change in total daily
insulin requirements from
A: acarbose, the dosage
baseline, mean change from
titrated at 6-week intervals:
baseline of hypoglycaemic
50 mg 3 times a day (baseline episodes at the treatment endpoint
week 0), 100 mg 3 times a
day (baseline week 6),
Secondary outcomes: mean
200 mg 3 times a day
change from baseline in meal
(baseline week 12) and
tolerance test variables, glucose
300 mg 3 times a day
Cmax and glucose rise, serum lipid
(baseline week 18)
levels, total daily insulin
requirements at each of the 6B: Placebo
week visits
At 6-week intervals patients were
USA
Exclusion criteria:
conditions that
complicate the
diabetes state,
adherence to the
protocol,
gastrointestinal
disease
Outcomes
Results
Comments
Design
EL
Acarbose treatment was associated with a
RCT
Ib
significant reduction in mean HbA1c levels of randomisation took place
double blind
0.48% compared with placebo
(6.28 ± 0.08% vs. 6.77 ± 0.08%, p < 0.05)
HbA1c levels showed significant reductions in
all time points for acarbose treatment
compared with baseline (all p ≤ 0.05), in
contrast the placebo-treated patients showed
an increase in HbA1c levels over the
treatment period
109
Evidence tables
Acarbose was associated with significant
reductions in all plasma glucose variables
that were measured (relative to placebo).
Fasting plasma glucose levels were reduced
evaluated for: dosage titration,
by 26 mg/dl, p ≤ 0.05. Postprandial plasma
clinical and laboratory assessment, glucose levels were reduced by 59, 47 and
reporting of any adverse effects,
41 mg/dl at 60, 90 and 120 min following
adjustment of insulin dosage, and meal (all p ≤ 0.05)
assessment of protocol compliance
There was no statistically significant change
Plasma glucose measurements
in the difference between treatment groups
were taken before the test meal
in either the mean change in total daily
and at 60, 90 and 120 min after
insulin dose or in the number of
meal, body weight and other vital hypoglycaemic episodes. Also no significant
signs, fasting blood chemistry,
differences between the treatment groups in
urinalysis, haematology counts
the body weight, fasting triglycerides, total
HDL and LDL cholesterol
HDL cholesterol was measured at
baseline and at the end of the
49% of placebo and 84% of acarbose
treatment period
treatment group reported an adverse event;
this was a statistically significant difference
(p = 0.01) (mainly gastrointestinal symptoms).
5% of placebo and 19% of acarbose
treatment group discontinued therapy due to
adverse events (p = 0.0004)
Study
Population
Intervention
Outcomes
Results
Riccardi,
1999268
121 adult patients
aged 30.0 ± 2.5
(range 18–65 years)
in Italy, with good
glycaemic control
6-week run-in period whilst
receiving placebo taken with
breakfast, lunch and dinner,
then randomisation into one
of the following treatments,
again taken with breakfast,
lunch and dinner
1) 2-hour postprandial plasma
glucose levels
1) 2-hour postprandial plasma glucose levels No description of how
RCT
Ib
were lower in the acarbose group compared randomisation took place
multicentre
with the placebo group: 12.2 ± 0.8 vs.
Sponsored by Bayer SpA double blind
14.9 ± 0.9 mmol/l, p < 0.02
Inclusion criteria:
type 1 diabetes for
at least 1 year,
BMI ≤ 30 kg/m2,
stable body weight,
HbA1c ≥ 7% and
≤ 12%, receiving
insulin therapy at
least 2 injections
per day for at least
3 months
Exclusion criteria:
digestion
disturbances,
pregnancy, points
detailed in the
paper
A: acarbose (50 mg 3 times a
day for first 2 weeks then
100 mg 3 times a day) and
high-fibre diet
B: acarbose (50 mg 3 times a
day for first 2 weeks then
100 mg 3 times a day) and
low-fibre diet
C: placebo and high-fibre diet
D: placebo and low-fibre diet
2) HbA1c
4) Adverse events
5) Daily insulin dose, fasting
glycaemia, total cholesterol,
triglycerides, HDL cholesterol
2) No statistically significant difference
between the adjusted mean HbA1c values:
8.7 ± 0.1% vs. 8.9 ± 0.1%, p = 0.23
No difference in HbA1c or postprandial
plasma glucose level reductions between
patients who had a higher or lower
carbohydrate intake
3) Similar between the two groups
4) 75% in acarbose and 39% in placebo
(mainly mild gastrointestinal. 5/60 in the
acarbose group and 1/60 from the placebo
group withdrew from the study due to
adverse events
5) Daily insulin dose, fasting glycaemia, total
cholesterol, triglycerides did not show any
difference between the treatment groups.
Significantly lower HDL cholesterol levels
were seen in the acarbose group compared
with the placebo: 1.39 ± 0.03 vs.
1.50 ± 0.03 mmol/l, p < 0.02
Comments
Design
EL
Type 1 diabetes
110
Acarbose (continued)
Study
Population
Intervention
Marena et al,
1991270
14 adult patients
with type 1 diabetes patients received 6 weeks of
both treatments in random
Aged 35.1 ± 13.2
order at beginning of each
years
meal
Italy
A: acarbose 100 mg 3 times a
day
BMI
22.5 ± 2.4 kg/m2,
B: placebo 3 times a day
7.9 ± 5.9 years,
HbA1c 9.6 ± 0.9%,
fasting plasma Cpeptide
0.08 ± 0.08 nmol/l,
insulin dosage
46.9 ± 13.2 units/
day
Outcomes
Results
HbA1c
Fasting and mean daily blood glucose levels No description of how
were statistically significantly decreased after randomisation took place
acarbose compared with placebo. (7.4 ± 0.5
vs. 10.7 ± 0.5 mmol/l, p < 0.001 and 8.5 ± 0.3
vs. 9.7 ± 0.3 mmol/l, p = 0.002)
Occurrence of adverse effects
Adherence to treatment
Blood glucose profile
Decrease in HbA1c compared with baseline
Insulin requirement (artificial B(8.5 ± 0.2% vs. 9.6 ± 0.2%, p < 0.001) and
cell)
compared with placebo (8.3 ± 0.2% vs.
Total cholesterol, HDL cholesterol, 9.4 ± 0.3%, p < 0.001)
triglycerides
35% reduction in insulin requirements with
acarbose (p < 0.001)
Haematology and liver function
tests
Plasma triglycerides were lower after
acarbose than placebo (1.2 ± 0.2 vs.
1.4 ± 0.2 mmol/l, p = 0.006). There were no
other changes in laboratory measurements
Comments
Design
EL
RCT
Ib
crossover,
double blind
No wash-out
period
Adverse effects: 2/14 abdominal discomfort,
2/14 asymptomatic fasting hypoglycaemia in
acarbose treatment, 1/14 flatulence in
placebo
Insulin was given 3
times a day, no
changes intended
No residual B-cell
function
Viviani and
Camogliano,
1987271
30 (26 after drop3 times a day for 1 month:
outs) adult patients
with type 1 diabetes A: acarbose 100 mg 3 times a
day with meals
Mean age
B: placebo 3 times a day with
38.4 ± 11.3 years
meals
Italy
Low-carbohydrate
diet
1) Glucose profiles
2) HbA1c (said measured but not
reported)
4) Adverse effects (including
hypoglycaemia)
4) 4 drop-outs (2 for personal reasons and 2
due to adverse effects, 1 whilst receiving
acarbose treatment and 1 whilst receiving
placebo). Gestational adverse effects were
more common in acarbose than placebo
(10/14 vs. 5/12)
More cases of hypoglycaemia in acarbose
compared with placebo, (5/14 vs. 2/12)
111
Evidence tables
3) Other biochemical
measurements: plasma bilirubin,
transaminases, gammaglutaminetranspeptidases, alkaline
phosphatase,
lacticodehydrogenase, creatine
and proteins, albumin, total
globulins, blood urea, nitrogen,
serum iron, uric acid, calcium,
sodium, potassium, phosphorum,
triglycerides, total and HDLcholesterol
1) Acarbose significantly lowered the plasma No description of how
RCT
Ib
glucose values, glycaemic control worsened randomisation took place
crossover
during placebo treatment (p < 0.05)
double blind
2) No variations were seen in other
biochemical measurements, body weight or
arterial pressure
Study
Population
Intervention
Koch et al,
1999266
15 adult outpatients Treatment periods of 14 days,
with type 1 diabetes 3 tablets a day taken with
main meals, random order of
Germany
treatments with 7 days washout period in between each
Inclusion criteria:
well controlled on treatment
insulin therapy and A: injection–meal interval 10
individual diet,
min and treatment with
aged 18–70 years,
acarbose (Acarbose dosage
had type 1 diabetes increased stepwise: 3 days of
for at least 1 year,
150 mg increasing to 300 mg
blood glucose
for the remaining 11 days)
levels, insulin
dosage, HbA1c
B: no injection–meal interval
levels, Broca index and treatment with acarbose
values stated in
(Acarbose dosage increased
paper, well
stepwise 3 days 150 mg
educated on
increasing to 300 mg for the
diabetes, able to
remaining 11 days)
monitor own blood
C: injection–meal interval 10
glucose
min and treatment with
Exclusion criteria:
placebo
digestion
D: no injection–meal interval
disturbances,
pregnancy, acarbose and treatment with placebo
hypersensitivity,
other serious
illnesses, other
points detailed in
the paper
Outcomes
Results
Patient monitoring at the start and
end of every treatment stage
Comments
Design
EL
No statistical difference in the mean 1-hour No description of how
RCT
Ib
glucose values between the treatment groups randomisation took place
crossover
(p = 0.835)
Primary outcome: 1-hour
double blind
postprandial (breakfast) blood
Out of 22 original patients there were 36
glucose concentration
adverse events: 26/22 in acarbose-treated
and 10/22 in placebo-treated (majority were
Secondary outcome: blood
gastrointestinal). There were 8 reported
glucose values taken at 0.5, 2 and hypoglycaemic episodes (in 6 patients), 3
3 hours after breakfast, heart rate
confirmed by blood glucose: 7 with
and blood pressure, compliance
treatment with acarbose and 1 with
(number of tablets returned)
treatment with placebo
Adverse events or unusual events 7 drop-outs, none due to adverse events, 5
Clinical biochemical and
homological parameters
due to other reasons, 2 due to noncompliance to treatment (unknown treatment
group)
No significant differences found in the vital
signs and other physical findings between
treatment groups
Type 1 diabetes
112
Study
Population
Intervention
Damoiseaux et 7 adult patients with Treatment A: insulin and
type 1 diabetes in
acarbose for 5 days, 200, 100
al, 1983269
hospital
and 100 mg before breakfast,
lunch and dinner, respectively
Mean age 45 ± 6
years, duration of
B: insulin and placebo
diabetes from 1 to
25 years, 3 female, 3 patients received placebo
tablets for the first 4 days,
4 male
followed by acarbose for 5
Belgium
days; the remaining 4 patients
received acarbose for the 5
initial days followed by 4
days of placebo
Outcomes
Results
Plasma glucose 7 times daily,
mean circadian glycaemia and
mean values at each time point
were recorded
The mean circadian plasma glucose was
significantly reduced during acarbose
treatment (8.2 ± 0.4 to 10.1 ± 0.6 mmol/l,
p ≤ 0.05). Postprandial plasma glucose levels
decreased due to acarbose at 10:30 (from
14.0 ± 0.7 to 10.4 ± 0.6 mmol/l, p < 0.05) and
at 20:30 (from 12.0 ± 0.7 to 8.7 ± 0.7 mmol/l,
p < 0.02), at other times no significant
difference was observed
Quality of glucose control – ‘M
value’
Mean amplitude of glycaemic
excursions (MAGE) index (an
estimate of the blood glucose
fluctuations)
Comments
Design
EL
RCT
Ib
crossover
double blind
No wash-out
period
The M index was significantly reduced
during acarbose administration (36 ± 6 to
45 ± 6, p ≤ 0.02), whilst no significant
modification of the MAGE value was
recorded. Plasma glucagon levels and insulin
dosage were not affected by the drug
Hypoglycaemic episodes were more
frequently recorded during the acarbose
administration (n = 21 vs. 10)
No gastrointestinal symptoms were reported
Frank et al,
1998272
Blood glucose profile (area under
curve from first breakfast to 3.5
hours later)
No significant difference in area under the
curve blood glucose profile between
acarbose and placebo
90 min post first breakfast blood
glucose level
There was a statistically significant difference
in the mean blood glucose level 90 min after
the first breakfast between acarbose and
placebo (increase from baseline +1.09 vs.
+1.05 mmol/l, p = 0.0034)
90 min post first breakfast serum
insulin concentration
RCT of single Ib
randomisation took place dose
Sponsored by Bayer AG
crossover
double blind
1 week washout period
between days
Safety outcomes: heart rate, blood The mean increases in serum insulin for the
pressure, adverse events and
regimens were not significantly different
withdrawals.
All adverse events reported were of
Haematological parameters, urine flatulence: 9/24 in acarbose, 2/24 in
analysis and biochemical
placebo. No hypoglycaemic events recorded
parameters all detailed on the
paper
No significant differences in safety outcomes
Adverse events
113
Evidence tables
20 adult patients
Each patient received the
with type 1 diabetes different regimens on 4
different days separated by a
Germany
week each
Inclusion criteria:
A: 1 breakfast and acarbose
aged 18 years or
(100 mg)
older, HbA1c value
less than 9.5% over B: 1 breakfast and placebo
preceding 3
C: 2 breakfasts and acarbose
months, must be
(100 mg)
receiving flexible
insulin therapy
D: 2 breakfasts and placebo
basal–bolus regimen
Randomisation to treatment A
or dietary
or B on first day, second day
adjustment
received opposite to first day
Exclusion criteria:
Randomisation to treatment C
diabetic
or D on third day, fourth day
complications,
received opposite to third day
pregnant women,
specific drugs listed
in paper
Study
Population
Juntti-Berggren, 10 Adult patients
2000265
with type 1
diabetes. Sweden
Closed loop insulin
infusion system to
normalise blood
glucose levels.
(artificial pancreas)
Intervention
Outcomes
Results
Comments
Treatment single dose:
Postprandial triglycerides glucagon
and gastrointestinal peptide levels,
gastric empting and rates of
carbohydrate and lipid oxidation
were assessed
Blood glucose measurements were used to
assess the level of glycaemic control: area
under curve values showed no statistically
significant difference between acarbose and
placebo.
RCT of single Ib
A: Acarbose 100mg
B: placebo
Cannulas used to stabilise
blood glucose at target
4–5 mmol/l
Statistically significantly less insulin was
required in the Acarbose group compared
with the placebo (5171.7 ± 2282.6 mU vs.
8074.5 ± 3045 mU, p = 0.003)
Inclusion criteria:
18–65 years of age
have had type 1
diabetes for at least
3 years, receiving
intensive insulin
therapy (4 doses of
insulin a day) have
an HbA1c value of
6–8.5% and a body
mass index of 30 kg
or less
crossover,
double blind
Washout
period of
10 ± 3 days
Statistically significant changes in plasma
GIP levels were seen: AUC and Cmax values
were lower in acarbose compared with
placebo, (AUC 7259 ± 1973 vs.
10 560 ± 3962, p = 0.006 and Cmax
61.8 ± 20.8 vs. 91.7 ± 49.3 p = 0.022). The
tmax values were not significantly different
GLP-1, glucagon and postprandial
triglyceride levels, carbohydrate, lipid
oxidation rates, gastric empting profiles were
not significantly affected by acarbose
treatment compared with placebo
7 adult male
diabetes with good
glycaemic control
Single drug treatment given
with meal. 30 min exercise
was performed, 90 min after
treatment
Aged 30.0 ± 2.5
years
A: acarbose 100 mg
Canada
EL
No significant period effect or treatmentperiod interaction, thus no carry-over effect
was present.
Exclusion criteria:
pregnant women,
gastrointestinal
disease. Paper
details further
criteria
Rabasa-Lhoret
et al, 2001273
Design
B: placebo
1) Glucose turnover by tracer
2) Intestinal glucose absorption
3) Hypoglycaemia (< 3.5 mmol/l)
1) Acarbose treatment resulted in a
significantly lower postprandial plasma
glucose rise at 90 min after treatment
(peaking above baseline at 2.9 ± 0.6 vs.
placebo 5.0 ± 0.7 mmol/l, p < 0.005)
2) Glucose absorption was statistically
significantly higher in the placebo than the
acarbose (acarbose 8.6 ± 0.9 vs. placebo
10.8 ± 1.9 mol/kg, p < 0.005)
3) Out of a total of 7 patients in the study
there were 3 hypoglycaemic incidents in 2
subjects after acarbose and 6 hypoglycaemic
incidents in 4 subjects after placebo
RCT of single Ib
crossover
single blind
Type 1 diabetes
114
Glibenclamide
Study
Population
Intervention
Burke and
20 adult patients
Treatment
Hartog, 1984277 with type 1 diabetes
A: insulin and glibenclamide
Mean age 28 (range 15 mg daily
20–36 years),
duration of diabetes B: insulin and placebo
0.75 to 14 years, 6
female, 14 male
Results
Comments
Diabetes control – patient
collecting own capillary blood
glucose samples, capillary blood
spot filter paper method
In the C-peptide secretors, there were
differences in the glibenclamide compared
with the placebo group: mean daily blood
glucose (7.4 ± 1.5 vs. 8.4 ± 1.7 mmol/l,
p = 0.02), mean index of blood glucose
variation (140 ± 132 vs. 202 ± 180, p = 0.05),
HbA1 (7.5 ± 0.9% vs. 8.1 ± 0.5%, p = 0.05)
RCT, double Ib
randomisation took place blind
crossover trial
Sponsored by Hoechst
(UK) pharmaceuticals
3 months 1
therapy, 1
month washout, 3 months
other therapy
Mean daily blood glucose
Mean index of blood glucose
variation
Plasma C-peptide area during OGTT and
fasting plasma glucose C-peptide ratio both
significantly improved whilst on
Fasting blood glucose before GTT glibenclamide and insulin treatment.
(47.5 ± 28.4 vs. 32.3 ± 16.0 nmol min,
Oral 50 g glucose tolerance test
(OGTT), area blood glucose during p = 0.01 and 49 ± 33 vs. 72 ± 47 mmol/nmol
p = 0.008, respectively)
OGTT, plasma C-peptide area
during OGTT, fasting plasma
No significant difference in the fasting blood
glucose C-peptide ratio
glucose before GTT and the area blood
glucose during OGTT
Bristol, UK
Design
EL
HbA1 at end of period
Trial length 3
months
Inclusion criteria:
no ketoacidosis in
the previous 6
months
C-peptide secretors
(0.07 nmol/l) and Cpeptide nonsecretor individuals
analysed separately
Stocks et al,
1988274
Outcomes
In the C-peptide non-secretors, there was no
significant difference in any of the outcomes:
HbA1 (8.6 ± 0.3% to 8.9 ± 1.5%, p > 0.05),
mean daily blood glucose (8.9 ± 2.3 to
9.5 ± 2.8 mmol/l, p > 0.05), mean index of
blood glucose variation (352 ± 264 to
309 ± 205, p > 0.05)
6 adult patients with 3 times a day for 1 month:
type 1 diabetes
A: oral weight adjusted
Australia
glibenclamide 10 mg
B: placebo
At end of treatment period 24-hour
glucose profile, free insulin level
every 15 min, both to give area
under curve
Glycated haemoglobin level
No significant difference was observed
between the net effect of the placebo or
glibenclamide treatment on the glycated
haemoglobin level, (0.4 ± 0.4% vs.
–0.2 ± 0.3%, p > 0.05), the daily insulin
requirement (3.0 ± 5.0 vs.
–1.0 ± 2.5 units/day, p > 0.05), the areas
under the glucose curve (–12.3 ± 12.2 vs.
–13.2 ± 8.2, p > 0.05), and free insulin curve
(–35.9 ± 51.1 vs. 47.5 ± 107.1, p > 0.05)
RCT double
placebocontrolled
crossover
study
Ib
4 weeks
wash-out
period
Evidence tables
115
Study
Population
Intervention
Kabadi et al,
1995275
10 men with type 1 3-phase trial, each lasting 3
diabetes
months. First stage was a runin stabilisation, and then
Aged 31–66 years
patients were randomised to
additional treatments, after 3
USA
months patients were crossed
over to the other treatment
A: glibenclamide 5 mg 2
tablets twice daily
B: placebo
Outcomes
Results
Comments
1) HbA1 and blood glucose levels
monthly
1) No significant difference in HbA1
(glibenclamide 6.5 ± 0.2 vs. placebo,
9.9 ± 0.2%)
RCT crossover Ib
2) Fasting serum cholesterol and
triglycerides
3) Number of hypoglycaemic
events (< 2.8 mmol/l)
The 24-hour average capillary blood glucose
level as well as the difference between the
mean postprandial and the preprandial
blood glucose concentrations were
significantly lower during the treatment with
glibenclamide treatment (all values are given
as; mean ± SEM):
24-hour average capillary blood glucose
level:
glibenclamide 7.4 ± 0.4 vs. placebo
8.7 ± 0.5 mmol/l, p < 0.05
Difference between the mean postprandial
blood glucose concentrations: glibenclamide
8.7 ± 0.4 vs. placebo 10.8 ± 0.5 mmol/l,
p < 0.01
Difference between the mean preprandial
blood glucose concentrations: glibenclamide
6.6 ± 0.4 vs. placebo 8.2 ± 0.5 mmol/l,
p < 0.05
Fasting plasma glucose was not significantly
different between different treatment groups:
glibenclamide 6.3 ± 0.5 vs. placebo
7.0 ± 0.6 mmol/l)
2) Fasting serum cholesterol and triglycerides
were not significantly different between the
treatment groups:
Cholesterol: glibenclamide 4.8 ± 0.3 vs.
placebo 5.5 ± 0.3 mmol/l
Triglycerides: placebo 1.3 ± 0.2 vs.
glibenclamide 1.3 ± 0.2 mmol/l
3) Hypoglycaemic episodes were
significantly reduced in the glibenclamide
treatment group: glibenclamide 1.8 ± 3 vs.
placebo 3.8 ± 0.8 mmol/l, p < 0.01
Design
EL
Type 1 diabetes
116
Glibenclamide (continued)
Glibenclamide (continued)
Study
Population
Intervention
Bieger et al,
1984276
21 patients with
type 1 diabetes
Run-in period for 2 weeks
1) HbA1c
following normal regimen
2)
Self-monitored blood glucose
with the addition of treatment
for 6 weeks
Aged 41.8 ± 11.1
years
Germany
Outcomes
A: glibenclamide 10 mg
Results
Comments
Design
1) No significant difference in HbA1c
RCT
between the treatment groups: glibenclamide randomisation took place
10.4 ± 2.1% vs. placebo 12.0 ± 1.5%
EL
Ib
2) No significant difference in mean blood
glucose levels between the treatment groups
B: placebo
Gliclazide
Study
Population
Fallucca,
1996278
Treatment
22 young patients
newly diagnosed
with type 1 diabetes A: insulin and gliclazide
160 mg/24 hours
Aged 12–25 years
B: insulin and placebo
Italy
Studied every 6
months for 18
months
Outcomes
Results
Plasma glucose
Insulin need was the same in the 2 groups
RCT, single
for time 0 but thereafter it steadily decreased randomisation took place blind
in the gliclazide group, becoming at 6, 12
and 18 months respectively 54%, 42% and
39% that of the placebo group, these
differences were statistically significantly
(p < 0.003, p < 0.001 and p < 0.001
respectively)
C-peptide
HbA1c
Insulin need
No statistically significant difference in the
metabolic control (glycated haemoglobin
and plasma glucose p > 0.05 for all time
periods) between the 2 groups
117
The gliclazide group had statistically
significantly higher C-peptide levels, which
was about double those of the placebo
group (p < 0.003)
Comments
Design
EL
Ib
Evidence tables
Intervention started
from the third week
since the onset of
the disease
Intervention
Study
Population
Intervention
In addition to usual diet and
Goldman et al, 28 adult patients
with type 1 diabetes insulin dosage for a period of
1984280
24 weeks, one tablet before
Aged 23–65 years
breakfast of:
Michigan, USA
A: placebo
Exclusion criteria:
B: glyburide (5 mg)
diabetic
complications,
pregnant women,
specific drugs listed
in paper
Outcomes
Results
Comments
At beginning and end of study,
tests performed were: ECG, serum
samples for insulin antibodies and
plasmapheresis for insulin receptor
studies
There were no statistically significant
differences in plasma free C-peptide
concentration, insulin antibody titres, mean
plasma glucose concentrations, plasma
cholesterol, triglyceride concentrations,
cholesterol-lipoprotein fractions
RCT double
randomisation took place blind.
Every 6 weeks of the study tests
performed were: fasting blood
glucose, triglycerides, total
cholesterol, cholesterol-lipoprotein
fractions, HbA1c, total glycated
haemoglobin, BUN, creatinine,
liver function tests
Design
EL
Ib
Statistically significant difference in total
glycated haemoglobin and HbA1c between
glyburide and placebo only at 6-week stage,
(p < 0.05 in both), otherwise no significant
differences seen
Clinical evaluations were also
carried out every 6 weeks during
the study
Gums et al,
1992281
46 adult patients
12-week run-in period then
with type 1 diabetes randomisation to treatment
for 12 weeks
Aged 18–68 years
A: glyburide 10 mg/day
USA
B: placebo
1) Glucose measurements
2) Serum lipids
3) HbA1c
1) Glucose concentrations were significantly No description of how
RCT
different before the start of the study so little randomisation took place
conclusion can be drawn from the glucose
measurements
2) No statistically significant differences in
the plasma lipids were found between the
placebo and the glyburide groups
3) No statistically significant differences in
the HbA1c were found between the placebo
and the glyburide groups
Ib
Type 1 diabetes
118
Glyburide
Tolazamide
Study
Population
Sanders et al,
1990282
24 children newly
15 months of daily morning
diagnosed with type dose:
1 diabetes
A: oral weight adjusted
Mean age 9 ± 4
tolazamide
years
B: placebo
USA
Kabadi and
Birkenholz,
1988283
Intervention
15 men with type 1 After initial examination and
diabete
conformation of diagnosis,
12-week study
Aged 36–66 years
A: tolazamide 500 mg
USA
B: placebo
Outcomes
Results
Comments
HbA1 and blood glucose levels
monthly
The placebo group had a greater insulin
dosage requirement during the entire 15
months of the study (difference
0.17 ± 0.9 units/kg/day, p < 0.001)
RCT double
randomisation took place blind Ib
Fasting serum C-peptide
Design
Mean daily insulin dose
No statistically significant difference in the
fasting serum C-peptide, blood glucose
levels (at 15 months 135 ± 13 vs.
140 ± 37 mg%, p > 0.05), or HbA1 (at 15
months 10.77 ± 4.98% vs. 9.09 ± 2.01%,
p > 0.05)
HbA1c
Fasting plasma glucose was significantly
RCT
lower in tolazamide group by 3 weeks The
maximum lowering of glucose was measured
by 9 weeks, and was sustained until the end
of the study period (tolazamide 6.7 ± 0.4 vs.
placebo 11.9 ± 1.0 mmol/l)
Self-monitored blood glucose
levels
Hypoglycaemia with blood
glucose level
Fasting plasma glucose
EL
Ib
HbA1c concentration was significantly lower
in the tolazamide group by 6 weeks, there
was a maximum decline occurring by 9
weeks and then it remained steady until the
end of the study (tolazamide 9.6 ± 0.5% vs.
placebo 10.8 ± 0.9%)
3/8 subjects in the tolazamide group had
their total daily insulin dose lowered to
avoid recurrent hypoglycaemic episodes. No
significant alterations were made in the
placebo group
Evidence tables
119
Study
Population
Lins et al,
1986279
9 adult patients with After an overnight fast the
type 1 diabetes
patients were given a single
treatment in random order at
Aged 19–37 years
least 1 week apart
Sweden
Glipizide 5 mg
No C-peptide
response
Intervention
Outcomes
Results
Comments
Design
EL
Blood glucose
Glipizide did not alter the blood glucose
curve or the area under it
RCT crossover Ib
Outcomes
Results
Comments
1) HbA1c (change from baseline)
1) HbA1c (change from baseline) mean ± SD:
–0.3 ± 0.7% vs. 0.3 ± 0.7% (p = 0.03)
Additional patient
RCT crossover Ib
withdrew due to vomiting
in metformin group
versus
placebo
Metformin
Study
Population
Intervention
Hamilton et al, 27 young people
Metformin
2003284
versus
Aged 12–17 years
placebo 3 months
Canada
2) Fasting glucose levels (change
from baseline)
3) BMI (change from baseline)
2) Fasting glucose levels (change from
baseline): –0.9 ± 3.8 vs. –0.5 ± 3.2 mmol/l
(p = 0.04)
Design
EL
4) Mild hypoglycaemic
3) BMI (change from baseline): –0.05 ± 1.0
5) Severe hypoglycaemic episodes vs. 0.2 ± 0.5 kg/m2 (p = 0.35)
6) Gastrointestinal discomfort
4) Mild hypoglycaemic: 1.75 ± 0.8 vs.
0.9 ± 0.4 events/patient/week (p = 0.03)
5) Severe hypoglycaemic episodes: 2/14 vs.
1/13
6) Gastrointestinal discomfort: 6/11 vs. 5/13
Särnbald et al,
2003285
26 young people
Metformin
versus
Aged 16–20 years
placebo 3 months
Sweden
HbA1c (change from baseline)
Change in HbA1c, –0.9%, 95% CI –1.6 to
–0.1, p < 0.05 vs. 0.3%, p > 0.05
2 young people were
RCT crossover Ib
excluded due to nonadherence to treatment
protocol, both from
intervention group, one of
these had nausea
Type 1 diabetes
120
Glipizide
Metformin (continued)
Study
Population
Gin, 1985286
10 patients with
type 1 diabetes
Intervention
Randomised to a treatment
for 1 week then a wash-out
interval of 10 days before
Aged 40.8 ± 4 years swapping to the next
treatment, insulin therapy
France
remained constant, patients
were placed on an artificial
pancreas for a euglycaemic
hyperinsulinaemic clamp
Outcomes
Results
1) Glucose infusion rate by
artificial pancreas for a
euglycaemic hyperinsulinaemic
clamp
1) The mean value of glucose infusion
RCT crossover Ib
increased with metformin: with metformin
3.71 ± 1.06 vs. without 3.4 ± 1.06 mg/kg/min,
p < 0.001. This was not found in three
patients
2) Lactate, total cholesterol,
triglycerides
Metformin 850 mg twice daily
versus
Comments
Design
EL
2) Changes in other plasma values were not
significant: lactate (1 ± 0.07 vs.
1.1 ± 0.06 mmol/l), total cholesterol
(4.7 ± 0.20 vs. 4.7 ± 0.25 mmol/l), and
triglycerides (1.18 ± 0.15 vs.
1.15 ± 0.10 mmol/l)
placebo
Coscelli et al,
1984288
15 patients with
type 1 diabetes
Italy
3 days on insulin alone, 5
days on treatment metformin
850 mg twice daily, then 2
days on insulin alone
Group A (10 patients): diurnal
plasma glucose profile, the
difference between maximum and
minimum glucose level and
glycaemic control index
Group A: significant difference in diurnal
glycaemic profile at 2/7 time points (at 13:00
insulin alone 13.4 ± 1.1 vs. insulin and
metformin 8.8 ± 1.0, p < 0.01, and at 18.00
insulin alone 10.7 ± 1.3 vs. insulin and
metformin 7.9 ± 1.2 mmol/l, p < 0.01)
Non-randomised and not Noncontrolled
controlled
intervention
Unknown how glycaemic study
control index was
measured
IIb
Group B (5 patients): fasting blood
glucose level
Group A: significant difference in the
difference between maximum and minimum
glucose level (insulin alone 10.1 ± 1.5 vs.
insulin and metformin 6.8 ± 1.5 mmol/l,
p < 0.01)
Group A: significant improvement in the
glycaemic control index with metformin
(insulin alone 10.1 ± 1.5 vs. insulin and
metformin 6.8 ± 1.5, p < 0.01)
Group B: significant decrease of glucose
levels when metformin added (values not
given as shown in graph)
Evidence tables
121
Study
Population
Intervention
Outcomes
Results
Comments
Janssen and
Rillaerts,
1991290
12 patients with
type 1 diabetes
All patients were given
850 mg metformin twice a
day for a 6-week period
HbA1c
Total cholesterol, HDL cholesterol
and triglycerides
HbA1c: start 9.5 ± 2.3% vs. metformin
9.1 ± 2.0%
controlled
intervention
Unknown age
study
IIb
Fasting glycaemia
No significant differences in any of the
measures after 6 weeks of metformin
treatment.
Unknown if the study was Crossover
randomised
controlled
trial
IIa
controlled
intervention
study
IIb
Belgium
Design
EL
Fasting glycaemia: start 205 ± 83 vs.
metformin 185 ± 75 mg %
Total cholesterol: start 187.3 ± 39.5 vs.
metformin 185.5 ± 38.0 mg/dl
HDL cholesterol: start 55.9 ± 12.6 vs.
metformin 53.4 ± 11.5 mg/dl
Triglycerides: start 80.3 ± 63.6 vs. metformin
82.3 ± 29.9 mg/dl
Pagano et al,
1983287
14 patients with
type 1 diabetes
Aged under 60
years
Italy
After initial control period
patients were given one
treatment for 4–6 weeks then
swapped over to the other
treatment
Metformin 850 mg 3 times a
daily before main meals.
1) Test period at end of treatment:
an artificial pancreas control was
administered and plasma glucose
measured
2) Total cholesterol, HDL
cholesterol and triglycerides
3) Adverse effects
versus
placebo
1) Mean plasma glucose values were
statistically significantly lower after
metformin administration than placebo
(placebo 5.88 ± 0.18 vs. metformin
5.25 ± 0.20 mmol/l)
2) No significant differences were found in
the measurements of total cholesterol
(placebo 4.7 ± 0.25 vs. metformin
4.7 ± 0.26 mmol/l), HDL cholesterol (placebo
1.15 ± 0.07 vs. metformin 1.26 ± 0.6 mmol/l)
or triglycerides (placebo 1.14 ± 0.10 vs.
metformin 1.18 ± 0.15 mmol/l)
3) Transient abdominal pain and nausea was
noted for the first week of metformin
treatment
Gómez et al,
2002289
10 young people
After a 3-month run-in
and young adults
period, treatment of
with type 1 diabetes metformin 250 mg 2 times a
day for week 1 was given.
Aged 19.1 ± 3.4
Increasing dosage up to
(range 14–45 years) 2500 mg was given every
week if no change in blood
USA
glucose level or intestinal
upset was reported
HbA1c
No statistical change in HbA1c, (start
10.94 ± 0.6% vs. metformin 10.39 ± 1.39%)
Type 1 diabetes
122
Metformin (continued)
4.6
Monitoring glycaemic control
What are the ideal parameters for measuring glycaemic control?
Monitoring of blood glucose
Study
Population
Coster et al,
2000291
8 controlled trials
Self-monitoring of
(4 in children) in
blood glucose
patients with type 1 (SMBG)
diabetes
Largest trial n = 181,
smallest n = 16, the
rest n < 40
16 non-controlled
studies
Intervention
Outcomes
Results
Comments
Design
EL
Clinical and cost effectiveness of
different methods for monitoring
blood glucose control in diabetes
mellitus. Self-monitoring by
patients and near-patient or
laboratory testing in healthcare
settings were considered
Metabolic control: None of the studies were set up to
test the effect of monitoring vs. no monitoring. 1 of 8
RCTs demonstrated an effect of SMBG on blood
glucose control looking at the before and after levels
(but it is unknown if any testing was performed before
the start of the study – this is not grade 1b evidence).
The study, in children trained in blood glucose testing,
found mean (SEM) HbA1c decreased from 11.88%
(0.28) to 11.0% (0.26) and in urine testing HbA1c
decreased from 12.04% (0.31) to 11.88% (0.32) (note
group allocation not accounted for in analysis). The
other studies showed no effect on glycated
haemoglobin of SMBG, from looking at the before and
after trial GHb results
Health Technology
Assessment
Systematic
review
Ia
Blood glucose control
Patient satisfaction
Health status
Health-related quality of life
Costs, including treatment costs
and patient costs
RCTs included Mann
1985316, Gordon 1991317,
Miller 1983318, Worth
1982319, Daneman
1985320, Carney 1983321,
Starostina 1994322, Terent
1985323
Meta-analysis of 4 RCTs (n = 181, of which 144 were
children and young people) of the combined
estimated treatment effect on glycated haemoglobin
from blood monitoring compared with urine
monitoring showed combined effect of –0.567% (95%
CI –1.073 to –0.061 (assuming correlation of 0.7)) or
–0.584% (95% CI –1.190 to 0.023 (assuming
correlation of 0.5)). The meta-analysis was difficult
due to different study designs, subject selection and
forms of intervention, 4 studies were excluded leaving
4 studies, 3 in children and 1 in adults. Making
different assumptions the pooled estimates decrease to
–0.547% (95% CI –1.139 to 0.044 (assuming
correlation of 0.7)) or –0.545% (95% –1.163 to 0.073
(assuming correlation of 0.5))
123
Patient outcomes: It was not possible to combine
findings of the 6 RCTs which looked at patient
outcomes. 1 study through comprehensive
questionnaire found that 50% thought that blood testing
was superior to urine testing for assessing metabolic
Evidence tables
Hypoglycaemia: 3 studies found that the frequency of
occurrence of hypoglycaemia was low and not
different in SMBG and control groups. 1 study
reported that blood monitoring confirmed
symptomatic hypoglycaemia in up to 2% of
measurements and revealed asymptomatic
hypoglycaemia at some time in 11 of the 16 children
in the study
Monitoring of blood glucose (continued)
Coster et al,
2000291
Population
Intervention
Outcomes
Results
control, 40% thought a combination of blood and urine
testing was better. No patients thought that urine alone
was superior. No clear preference on visual strips or
strips with meters. A second study gave questionnaires
to patients and found 84% preferred blood monitoring
alone and 10% preferred a combination of urine and
blood testing, again no patients preferred urine testing
alone. Problems included not being able to obtain a
blood sample, sore fingers and difficulty with visual
interpretation of strip results. Although no patients
preferred urine testing at the end of the study 10%
wanted to continue urine testing alone, 37% blood
testing alone and 47% wanted to continue with urine
and blood testing, the remaining 6% expressed no plans
to continue home testing. A third study found families
preferred blood to urine testing and intended to
continue this after the trial. Overall the systematic
review concluded that both children and adults prefer
blood monitoring or a combination of blood and urine
testing to urine testing alone, however these
conclusions are limited as the preference questionnaires
were not carried out before the intervention as well as
after, apart from in one limited study
Cost effectiveness: Only one study set in Russia
considered the cost effectiveness of different forms of
intervention. It was found that the benefits outweighed
the overall cost of the urine-monitoring supplies, but
for blood monitoring the benefits only accounted for
half the cost of blood-monitoring supplies, a degree of
caution should be exercised when generalising these
findings to different national settings
Laboratory testing of blood glucose: The RCTs found
provide evidence that GHb assays should be used to
monitor blood glucose control, indirect evidence
suggests that this will be cost effective
Comments
Design
EL
Type 1 diabetes
124
Study
Monitoring of blood glucose (continued)
Study
Population
Intervention
Jefferson et al,
200318
1998 survey of 302 Questionnaire
paediatricians
identified as
providing care for
children with
diabetes aged under
16 years; 244
returned
questionnaire
Outcomes
% paediatricians
Results
88% of respondents indicated that glycated
protein is routinely measured at each clinic
who provide care for children with visit
diabetes
84% using HbA1c, 4% using HbA1, and 1%
who work at clinics where there is using fructosamine
glycated protein monitoring
86% of those who measured HbA1c level
What sort of monitoring?
used capillary method
Comments
Design
EL
Children and young
people cared for
n = 17 192
Survey
III
UK
Evidence tables
125
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Grieve et al,
1999312
599 patients of all
ages with type 1 or
type 2 diabetes
Near-patient testing
by nurse of HbA1c,
lipids and creatinine
1) HbA1c
1) No statistically significant differences in metabolic
control between the groups.
Controlled
trial
IIa
UK
versus
Patents were not
randomised. The
different treatment
groups were at two
different hospitals
conventional
laboratory testing
2) Number of management
changes
4) Patient perceived frequency of
hypoglycaemia
5) Health service professionals’
views
6) Quality of results
2) Number of changes in management was increased
with near-patient testing (total of all patients in the
study OR 1.52, 95% CI 1.02 to 2.26). When split into
poorly managed and well managed: in the poorly
managed group there was an increase in management
changes with near-patient testing (OR 1.75, 95% CI
1.12 to 2.72), but in the patients with good glycaemic
control there was no statistically significant change in
number of management changes (OR 0.918, 95% CI
0.35 to 2.44). There was little evidence that
management changes were made due to information
regarding triglycerides and creatinine levels
3) No statistically significant difference in the median
total treatment satisfaction with the different testing
methods. However, two of the individual parameters
which did show a statistically significant difference
between the two clinics was satisfaction with the test
information given by the staff (75% vs. 60% recorded
at least a satisfaction level of 4, p = 0.004) and
satisfaction with the way in which the patient was
treated by the staff (p = 0.04)
At both hospitals there was strong agreement among
patients that the immediate feedback of HbA1c is
important because it allows patients to discus their
results with the doctors at the clinic
4) The patients who attended the near-patient testing
clinic had a higher perceived frequency of
hypoglycaemia than their counterparts (p = 0.005)
5) The clinicians had a positive attitude to near-patient
testing for HbA1c
6) The quality control of results for abnormal samples
for the isophane equipment had a coefficient of
variation less than 6%, and the internal quality control
for these samples compared favourably with the
standard maintained at the central laboratory. For
normal samples the quality of the near-patient testing
was comparable to central laboratory testing of HbA1c,
lipids and glucose. However, for creatinine samples
measured on the Spotchem machines the coefficients
of variation were very high
Type 1 diabetes
126
Near-patient testing
Near-patient testing (continued)
Study
Population
Intervention
Outcomes
Cagliero et al,
1999313
113 adults with type HbA1c levels determined at the Change in HbA1c from start of the
1 diabetes
time of the visit with bench- study
top analyser, so results
Mean age 49 ± 16
available at consultation
years
versus
USA
HbA1c measured by usual
laboratory results not
available in the consultation
Results
Comments
Design
EL
Change in HbA1c from start of the study:
0.34 ± 1.06% vs. 0.24 ± 1.03% (NS)
Study looked at type 1
diabetes and type 2
diabetes: this has been
split to report just type 1
diabetes here
RCT
Ib
Noncontrolled
intervention
study
III
Holman et al,
1987314
146 adults with type Patients given equipment to
1) Number of samples that were
1 diabetes and 54
take blood sample and post to feasible for analysis
with type 2 diabetes laboratory to be analysed so
2) Mean HbA1c
the result was available by
Mean age
the next clinic visit
47.9 ± 17.3 years
Trial length: five 3-month
USA
periods
1) Number of samples that were feasible for
analysis: 1984 Jun–Aug 145/209, 1984
Sep–Nov 149/218, 1984/5 Dec–Feb
166/214, 1985 Mar–May 155/199, 1985
Jun–Aug 151/206
2) Mean HbA1c: 1984 Jun–Aug 10.8 ± 2.3%,
1984 Sep–Nov 10.2 ± 2.2%, 1984/5
Dec–Feb 9.8 ± 2.2% (compared with first
reading in 1984 Jun–Aug p < 0.001), 1985
Mar–May 10.1 ± 1.9% (p < 0.05), 1985
Jun–Aug 10.1 ± 2.2% (p < 0.05)
Evidence tables
127
Study
Population
Intervention
Outcomes
Results
Comments
Design
Singh et al,
1997296
122 patients with
type 1 diabetes
None
HbA1
Annual mean HbA1 ranged from 8.4% to
9.3% with large standard deviations
(1.7–2.0%), indicating a marked variability
among individuals. Fluctuations of more
than ± 1% HbA1 occurred in 50% of the
patients year to year, over 9 years minimum
and maximum range was > 3% and > 5%
HbA1 in 55% and 11% of patients,
respectively. In 1 year, 22–43% of patients
had HbA1 < 8%, but over 9 years only 3.3%
were consistently < 8%
Observational study
Retrospective III
analysis over
9 years
None
HbA1c
A significant correlation was seen between
HbA1c and the actual metabolic control. A
seasonal variation was seen: lowest level of
HbA1c seen in June and July
Observational III
study over 18
months
Study:
Correlation with mean glucose
concentration
HbA1c has been suggested to be preferable to Non-systematic review.
HbA1 as a parameter for assessing glycaemic Possible bias in articles
control. As when plotting the mean blood
presented
glucose concentration against the glycated
haemoglobin fractions, the slope is greater in
HbA1c than the HbA1 and lowest for the
HbA1a+b. Also, there is a positive correlation
between HbA1a+b and age and the increase of
HbA1a+b with storage of samples
Review article III
of
observational
studies
Aged 44 ± 12 years
UK
Mortensen et
al, 1982292
92 children with
type 1 diabetes
Median age 7,
range 1–18 years
EL
Denmark
Mortensen,
1985293
Two observational
studies
HbA1c
versus
HbA1
Type 1 diabetes
128
HbA 1c
Fructosamine
Study
Population
Intervention
Outcomes
Results
Cefalu et al,
1988302
27 patients with
None
type 1 diabetes, and
35 patients with
type 2 diabetes
Correlation between serum
fructosamine and other indicators
of glycaemic control. HbA1c,
fasting glucose levels and mean
preprandial blood glucose over a
3-day period
Fructosamine was found to be highly
correlated with HbA1c (r = 0.70, p < 0.001).
Mean daily preprandial blood glucose was
found to be correlated with fructosamine
(r = 0.53, p < 0.005) and HbA1c (r = 0.47,
p < 0.005)
See if therapeutic alterations made
to control the blood glucose
concentration have an effect on
the fructosamine level
The mean preprandial blood glucose level
dropped from the initial value of 205 ± 17 to
162 ± 17 mg/dl at the end of the first week
and continued to drop to 134 ± 10mg/dl by
week 3. Compared with the initial value
(3.96 ± 0.19 mM), a significant decrease in
serum fructosamine was achieved at both
the second week (3.33 ± 0.15 mM, p < 0.02)
and third week (3.19 ± 0.13 mM, p < 0.005).
The HbA1c level was found to decrease every
week but was not found to approach a
significant decrease until the end of the third
week of study (8.73 ± 0.49% vs.
7.23 ± 0.47%, p < 0.02)
None
Correlation between fructosamine
and HbA1
Fructosamine level was 3.44 ± 0.65 mM,
HbA1 level was 11.6 ± 1.8%. There was no
correlation between fructosamine and HbA1
in any of the patients with diabetes (r = 0.17,
NS) or in just patients with type 1 diabetes
(r = 0.2) or type 2 diabetes (r = 0.03)
Observational III
study
None
Correlation between fructosamine
and HbA1
Fructosamine correlated with HbA1 (r = 0.86)
and with the average glucose measured over
a 30-day period (r = 0.83)
Observational III
study
Aged 11–73 years
USA
Dominiczak et 77 patients with
al, 1988305
type 1 diabetes or
type2 diabetes
UK
Hindel et al,
1986303
57 children with
type 1 diabetes
Aged 4–17 years
100 patients with
type 1 diabetes
Design
EL
Observational III
study over 3
weeks
HbA1 correlated with average glucose
measured over a 60-day period (r = 0.7)
UK
Smart et al,
1988308
Comments
None
Fructosamine correlated moderately well
with HbA1 (r = 0.8)
Aged 16–82 years
HbA1
UK
Plasma glucose
70% of the patients were placed in the same
category (good moderate to bad glycaemic
control) with fructosamine and HbA1
Glycated plasma proteins
Fructosamine
Observational III
study
129
Evidence tables
Correlation analysis between the
following outcomes:
Study
Population
Intervention
Outcomes
Results
Watts et al,
1989310
172 patients with
type 1 diabetes
None
HbA1
There was significant between-subject
Long-term study looking Observational III
correlation of HbA1 and fructosamine
at within-patient variation study
(r = 0.68, p < 0.001). However, the withinsubject correlation of HbA1 and fructosamine
was not as strong (r = 0.21, p < 0.05)
Fructosamine
Aged 12–60, mean
31.4 years
Over 12 months 7 measurements
were taken
UK
Winocour et al, 100 patients with
1989306
type 1 diabetes
Aged 15–69, mean
40.3 ± 1.1 years
UK
Comments
Design
EL
Within-subject variance of fructosamine was
47% compared with just 17% for HbA1
Study over a 6-week period
while attempts were made to
maximise glycaemic control
HbA1
Glycated serum albumin
Fructosamine
Fasting blood glucose
Mean blood glucose levels
All levels of glycaemic control improved
significantly: HbA1 (from 9.1 ± 0.2% to
8.0 ± 0.1%), glycated serum albumin (from
9.8 ± 0.4% to 7.3 ± 0.3%), fructosamine
(from 3.92 ± 0.08 to 3.42 ± 0.07 mM), fasting
blood glucose (from 11.1 ± 0.6 to
8.1 ± 0.7 mM), mean blood glucose levels
(from 12.5 ± 0.3 to 8.8 ± 0.5 mM), the M
value (from 118 ± 7 to 40 ± 3 u)
Mean percentage changes in direct measures
of glycaemia (32–66%) and GSA (29%) were
greater than for fructosamine (11%) or HbA1
(12%) (p < 0.001)
Correlations between change in glycated
serum albumin and changes in direct
measures of glycaemia over initial 2-week
period were significantly different from the
corresponding correlations between direct
measures of glycaemia and fructosamine
over this period (p < 0.05–0.01). Changes in
glycated serum albumin correlated more
closely with direct measures of glycaemia,
than HbA1 or fructosamine after 4 and 6
weeks
The Spearman rank-correlation coefficient of
absolute changes in glycated serum albumin,
fructosamine, and HbA1 after 2–6 weeks
ranged from 0.27 to 0.57, confirming that
the three measures respond differently to
changing glycaemic control
Glycated serum albumin appears to be a
more sensitive indicator of short-term
improvement in glycaemic control than
fructosamine or HbA1
Observational III
study
Type 1 diabetes
130
Fructosamine (continued)
Fructosamine (continued)
Study
Population
Intervention
Outcomes
Results
Shield et al,
1994307
147 children with
diabetes
None
Fructosamine and glycated
haemoglobin
The sensitivity and specificity for predicting
poor control in the determination of glycated
haemoglobin greater than 12% using a
fructosamine concentration greater or equal
to 3.5 mmol/l were respectively 88% and
68%
Mean age 14.6
years
UK
Comments
Design
EL
Observational III
study
The prevalence of poor control defined by
glycated haemoglobin concentration in the
study population was 29%. The positive
predictive value of fructosamine was 54%.
Furthermore, 44% of all the measurements
reflecting good long-term control by glycated
haemoglobin analysis corresponded to a
fructosamine concentration in either the bad
or moderate control range. Fructosamine
values other than 3.5 mmol/l were also used
to define the lower limit for bad control to
determine glycated haemoglobin values
greater than 12%, but all proved to have
greater rates of error, suggesting that
fructosamine is a poor indicator of actual
glycated haemoglobin values
Glikmanas et
al, 1988304
120 patients with
type 1 diabetes or
type 2 diabetes
None
HbA1c
Fructosamine
France
Hom et al,
1998309
450 patients with
type 1 diabetes or
type 2 diabetes
USA
None
HbA1c
Fructosamine
Serum fructosamine correlated with HbA1c
(r = 0.80) and gave at least as good a
separation of patients from normal controls
as did HbA1c
Observational III
study
There was a significant correlation between
fructosamine and HbA1c (r = 0.80, p < 0.001),
and also fasting glucose (r = 0.74, p < 0.001,
n = 222). The correlation of HbA1c with
fasting glucose was lower (r = 0.68,
p < 0.001, n = 222)
Observational III
study
131
Evidence tables
There were significant differences in the
error proportions between HbA1c and
fructosamine in discriminating poor-to-fair
vs. good-to-excellent control (p < 0.01)
Study
Population
Intervention
Outcomes
Results
Carney et al,
1983321
43 children with
type 1 diabetes
Training in blood glucose
testing
HbA1c
Mean age
14.0 ± 2.8, range
7.9 – 19.5 years
versus
Significant difference in HbA1c after 6 months Pseudo randomised
between children who were trained in blood though sequential
glucose monitoring compared with normal
appointments
urine monitoring (intention to treat analysis):
blood glucose trained HbA1C: before
11.88 ± 0.28% vs. after 11.0 ± 0.26%, urine
testing HbA1C: before 12.04 ± 0.31% vs. after
11.88 ± 0.32%, difference p < 0.05.
USA
patients who tested urine
sugars
Comments
Design
EL
Controlled
trial
IIa
When results for HbA1c were split by
whether the child maintained blood
monitoring at least 2 times a day (81%) from
those who did not maintain blood glucose
monitoring at least 2 times a day, the
difference in HbA1c increased only in the
children who maintained blood monitoring
at least 2 times a day
Worth et al,
1982319
38 patients with
type 1 diabetes
Mean age 34 ± 9
years
UK
Urinary glucose monitoring
versus
Urinary glucose
visual blood glucose
monitoring
Mean preprandial blood glucose
versus
meter blood glucose
monitoring
Trial length: three 3-month
periods
Frequency of hypoglycaemia
(mean ± SD):10.5 ± 2.0% vs. 10.6 ± 2.1% vs.
10.4 ± 1.9% (NS)
Urinary glucose (median (range)): 59 (1–903)
vs. 82 (0–680) vs. 84 (0–1009) mmol/24
hours
Mean preprandial blood glucose
(mean ± SD): 8.6 ± 3.6 (n = 38) vs. 8.0 ± 2.9
(n = 32) vs. 8.0 ± 3.6 (n = 33) mmol/l (NS)
Frequency of hypoglycaemia (median
(range)): 0.4 (0–7) vs. 0.4 (0–10) vs. 0.7 (0–4)
per fortnight
Patient preference: ‘best’ urine tests 0/37 vs.
blood tests 21/37 vs. combination of urine
and blood tests 15/37 vs. none 1/37, ‘most
practical’ urine tests 8/37 vs. blood tests
14/37 vs. combination of urine and blood
tests 15/37 vs. none 0/37
Paper included in the
Coster systematic
review291
RCT crossover Ia
Type 1 diabetes
132
Urinary glucose
Glycated serum proteins (GSP)
Study
Population
Intervention
Beisswenger et 9 patients with type None
1 diabetes and 21
al, 1993299
Lebanon
Outcomes
Results
Glycated serum proteins (GSP) vs.
HbA1c
Analysis of the relationship between patterns
of glycaemic control and GSP and HbA1c
demonstrated that subjects with type 1
diabetes and type 2 diabetes appeared
similar when the more traditional indicators
of glycaemic control such as mean blood
glucose level (166.9 ± 20.9 vs.
177.4 ± 39.6 mg/dl) or HbA1c (83.57 ± 12.8
vs. 80.24 ± 15.7 mmol hydroxymethyl
furfuraldehyde/mol haemoglobin) were used.
However, when GSP levels or the standard
deviation of mean glucose levels were used
to assess glycaemic control, higher levels
were found in subjects with type 1 diabetes
(52 ± 10.3 mg/g protein and
28.59 ± 7.60 mg/dl) vs. subjects with type 2
diabetes [44.6 ± 15.2 mg/g protein and
21.6 ± 15.9 mg/dl])
Comments
Design
EL
Observational III
study
This suggests that GSP may be more
sensitive than HbA1c assay to the greater
fluctuations in blood glucose levels generally
associated with type 1 diabetes
Evidence tables
133
Study
Population
Winocour et al, 113 patients with
1989298
type 1 diabetes (98
completed the
study)
Mean age
40.36 ± 1.1, range
15–69 years
UK
Intervention
Outcomes
Results
58 weeks follow-up
Evaluation of glycaemic control:
fasting blood glucose, HbA1c,
fructosamine and direct measures
of blood glucose control
Significant changes were observed in all
measures of blood glucose control mainly
during the 6-week period of intensified
management (p < 0.001). Following this
period, and despite little further change in
HbA1 or direct measures of blood glucose,
GSA and fructosamine levels rose
significantly
Glycated blood glucose levels were
significantly correlated more often with
levels of mean blood glucose and M values
(on 4–7 occasions, r = 0.30–0.58) than with
fasting blood glucose levels (on only 2–3
occasions, r = 0.34–0.44). Fructosamine
estimations correlated significantly with
mean blood glucose levels on 4/14
occasions (r = 0.30–0.50) and with HbA1 on
6 occasions (r = 0.36–0.54)
Correlations between glycated blood
proteins confirmed a significant association
throughout the year by HbA1 and GSA
(r = 0.47–0.68) and between GSA and
fructosamine (r = 0.48–0.76). The
correlations between HbA1 and fructosamine
were less clear (r = 0.38–0.44) and no
significant correlation was seen either at the
point of randomisation or 3 months after
Comments
Design
EL
Longitudinal
cohort study
IIb
Type 1 diabetes
134
Glycated serum proteins (GSP) (continued)
What are the ideal targets of glycaemic control in children with type 1 diabetes?
Study
Population
Intervention
Outcomes
Results
Butler et al,
1995324
3200 people with
diabetes on lists of
37 general
practitioners
None
Last glycated haemoglobin level
for 1992
The rate of data capture of HbA1 was 75.7% Adults and children
Observational III
and the mean level for study samples was
study
Comments made are
10.5% at one laboratory and 10.0% at the
‘Targets
for
clinical
care
other
that are set in the absence
These mean levels of HbA1 are poor or very of normative data and
poor according to published standards
local feasibility
assessment to be treated
with caution.’
None
Glycaemic control
The DCCT has provided evidence for
Mainly adult population
desirable glycaemic control targets in
patients with type 1 diabetes and defines the
benefits of good glycaemic control in terms
of HbA1c. There has been a suggestion that
classification of glycaemic control according
to numbers of standard deviations from a
local, non-diabetic population mean
UK
Kilpatrick et al, 339 people with
1998325
type 1 diabetes
Mean age 36, range
15–74 years
UK
Comments
Design
EL
Observational III
study
Comparing the two methods, SD guidelines
(using age-matched controls (HbA1c 4.02%,
SD 0.28%, n = 106)) classified 1% of patients
as having good (HbA1 < 3 SD from reference
mean), 4% as borderline (3–5 SD) and 95%
as poor (5 SD) glycaemic control
When calibrating the same instrument to the
DCCT analyser (r = 0.996), 37% of patients
had HbA1c results lower than the 7% median
value found in the intensively treated DCCT
group, while only 12% of patients had
values greater than the 9% conventionally
treated median HbA1c. DCCT subjects with
HbA1c values of less than 8% belonged
predominantly to the intensively treated
group. In this study, 71% of patients fell into
this category
135
Evidence tables
Thus, guidelines based on the number of SD
away from a non-diabetic mean may
overestimate the glycaemic control required
to reduce microvascular complications in
patients with type 1 diabetes
Comparison of self-monitor blood glucose with no self-measurement of blood glucose
Study
Population
Intervention
Hanson et al,
1996330
288 young people
Structured questionnaire,
with type 1 diabetes including question on use of
home blood glucose
Mean age 12.5 (SD monitoring
3.7), range 4.1–20.0
years
Outcomes
Results
Correlation between question and
HbA1c
Correlation between question and HbA1c:
13 patients with
unstable type 1
diabetes (11 had
received kidney
transplants in the
previous year)
Design
EL
Survey
III
Noncontrolled
trial
III
Noncontrolled
trial
III
Nonrandomised
crossover
study
IIa
Frequency of glucose testing –0.20,
p < 0.001
Actual frequency vs. suggested frequency
–0.20, p < 0.001
USA
Barbosa et al,
1980331
Comments
Frequency of urine testing –0.07, p > 0.05
Questionnaire on blood
glucose monitoring (with
Ames Dextrostix/Eyetone®)
75% thought blood glucose monitoring was
a ‘great help’, 25% thought it was a
nuisance but of some help
33% had more hypoglycaemic reactions,
50% had fewer hypoglycaemic reactions
92% thought that their metabolic control
had improved
Age range 22–54
years
USA
Evans and
Pohl, 1980332
7 patients with type Home blood glucose monitor Basal HbA1c compared with HbA1c All 7 patients had a lower HbA1c after 2
1 diabetes
after 2 months with home blood
months of home blood glucose monitoring
Trial length: 2 to 9 months
glucose monitoring
than at baseline: mean 10.5% vs. 13.9%
Mean age 27, range
17–48 years
USA
Daneman et al, 16 children with
1985320
type 1 diabetes
Mean age 13.1,
range 9.8–17.2
years
Canada
Group A. urine testing with
self-monitoring of blood
glucose, then urine testing
only
Group B. urine testing only
then urine testing with selfmonitoring of blood glucose
periods
GHb at baseline, after 12 weeks
urine testing with self-monitoring
of blood glucose and after 12
weeks urine testing only
Group A:
Urine testing with self-monitoring of blood
glucose 10.9 ± 0.6%
Urine testing only 10.7 ± 0.6%
Baseline 10.5 ± 0.6%
Group B:
Urine testing with self-monitoring of blood
glucose 10.1 ± 0.4%
Urine testing only 10.2 ± 0.4%
Baseline 9.5 ± 0.3%
None of the results were statistically
significantly different from each other
Type 1 diabetes
136
What is the optimum monitor for home blood glucose monitoring in children with type 1 diabetes?
Comparison of self-monitor blood glucose with no self-measurement of blood glucose (continued)
Study
Population
Intervention
Outcomes
Results
Yeo et al,
1985333
40 patients with
type 1 diabetes
Home blood glucose
monitoring (n = 38)
Fasting blood glucose
concentration
Fasting blood glucose concentration
Between-group
(improvement from/to): intervention 126 ± 11 comparisons not
to 122 ± 8 mg/dl vs. control 151 ± 19 to
calculated
160 ± 20 mg/dl
19–76 years
control (n = 12)
Singapore
HbA1
Clinical complications
Comments
Design
EL
Nonrandomised
intervention
study
IIa
HbA1: 10.3 ± 0.4% to 9.3 ± 0.3% (p < 0.01
from baseline) vs. 10.6 ± 0.7% to
10.4 ± 0.6%
Clinical complications (% of patients with
complications):
Neuropathy: 32.4% to 35.0% vs. 16.7% to
41.7%
Nephropathy (albuminuria ≥ 1): 15.8% to
15.8% vs. 25% to 16.7%
Retinopathy: 30% to 30% vs. 16.7% to 25%
Comparison of self-monitor blood glucose visual sticks with the laboratory standard measurement of blood glucose
Population
Intervention
Outcomes
Results
Comments
Design
EL
Clark et al,
1983345
117 blood glucose
measurements
Self-monitor blood glucose
with visual strip (Visidex®
strip)
Correlation between visual strip
method of self-monitor blood
glucose and glucose oxidase
analyser
r = 0.95, a = 22.2 mg/dl, b = 1.14
Test
evaluation
study
IIb
UK
versus
glucose oxidase analyser
(laboratory standard)
measured by trained nursing
staff
137
117 strip tests blood glucose
range from 5 to 775 mg/dl
Evidence tables
Study
Study
Population
Intervention
Kirk et al,
1986346
160 children with
type 1 diabetes
with visual strip
Outcomes
Results
Comparison between self49% of the self-monitored readings were
monitoring blood glucose with
within 2 mmol/l of the laboratory reading
visual strip and laboratory standard
50% of children detected hypoglycaemia
measured
2.4–19.9 years
(less than 3 mmol/l) or hyperglycaemia
laboratory standard measured
(13 mmol/l or more). For the detection of
UK
hypoglycaemia: sensitivity 44% and
specificity 95%. For the detection of
5402 reagent strip
hyperglycaemia: sensitivity 54% and
readings
specificity 86%
Comments
Design
EL
Test
evaluation
study
IIb
Test
evaluation
study
IIb
Accuracy did not correlate with the child’s
age, sex, social class, time of day or season
of year
Silverstein et
al, 1983344
159 children with
type 1 diabetes
USA
Blood glucose with
Visidex® visually read
versus
Chemstrip® visually read
versus
glucose analyser meter
(laboratory method),
measured by physicians
Measured once at camp and
once 4 months later
Comparison of correlation
between laboratory standard and
visual stick methods
% of readings 20% outside
reference range
Correlation coefficients at camp: Visidex
strips r = 0.893, Chemstrip strips r = 0.857
Correlation coefficients at clinic: Visidex
strips r = 0.939, Chemstrip strips r = 0.976
Readings 20% outside reference range:
Underestimated: Chemstrip strips at camp
12% and at clinic 46%, Visidex strips at
camp 0.6% and at clinic 24%
Overestimated: Chemstrip strips at camp
14% and at clinic 4.4%, Visidex strips at
camp 69% and at clinic 18%
At the camp the Visidex strips and Chemstrip
strips were significantly less reliable than the
laboratory method: Visidex strips vs.
laboratory p < 0.001, Chemstrip strips vs.
laboratory p = 0.016, Visidex strips vs.
Chemstrip strips p < 0.001. However, this
was not apparent when the tests were
repeated in the clinic
Type 1 diabetes
138
Comparison of self-monitor blood glucose visual sticks with the laboratory standard measurement of blood glucose (continued)
Comparison of self-monitor blood glucose with meter with the laboratory standard measurement of blood glucose
Study
Population
Trajanoski et al, 15 patients during
1996334
hypoglycaemic–
hyperinsulinaemic
clamps (6 patients
and 9 healthy
volunteers)
Austria
Intervention
Outcomes
Results
663 blood glucose monitor
readings and 119 reference
values ranging from 2.28 to
3.89 mmol/l
1) Comparison of correlation
self-monitor blood glucose meter
1) Correlation coefficients:
One Touch II: 0.91
Companion II: 0.81
Reflolux: 0.78
Accutrend: 0.88
Elite: 0.78
HemoCue: 0.93
Analysed by six blood
glucose monitors, compared
with laboratory reference
method (Beckman Glucose
Analyzer 2):
2) % of readings 10% and 20%
within reference range
3) % of readings 40% outside
reference range
One Touch II®
Companion II®
Reflolux®
Accutrend®
HemoCue®
180 blood samples
UK
Analysis of blood glucose
monitor Reflocheck®
compared with laboratory
reference method, by ‘skilled
operator’
Design
EL
Test
evaluation
study
IIb
Test
evaluation
study
IIb
2) % of readings 10% and 20% within
reference range (10% then 20%):
One Touch II: 78.0%, 99.2%
Companion II: 58.0%, 88.2%
Reflolux: 34.5%, 85.0%
Accutrend: 14.5%, 46.0%
Elite: 39.5%, 75.6%
HemoCue: 80.5, 96.6%
3) % of readings 40% outside reference
range:
One Touch II: 0%
Companion II: 2.5%
Reflolux: 0.9%
Accutrend: 6.6%
Elite: 4.2%
HemoCue: 0%
Elite®
Rayman et al,
1984335
Comments
Correlation coefficient: r = 0.996
Evidence tables
139
Study
Population
Lehmann et al, 55 patients with
2001336
type 1 diabetes and
40 patients with
type 2 diabetes
760 blood glucose
monitor readings
ranging from 2.6 to
20.0 mmol/l
Intervention
Outcomes
monitor (MediSense Precision between laboratory standard and
QID®) compared with
laboratory reference method
Patient preference
Blood glucose monitor
measurement was performed
by patient and by nurse
Correlation coefficient: r = 0.97, p < 0.0001
(n = 95)
monitors (Glucoscan I®)
reference method
Glucoscan I: correlation coefficient:
r = 0.847 (n = 28)
Aged 19–79 years
Switzerland
Laus et al,
1984337
12 patients with
type 1 diabetes
28 blood glucose
monitor readings
USA
Results
by nurse
Number of acceptable values
< 15% deviation from reference
Of blood glucose meter readings
< 3.9 mmol/l (but > 2.6 mmol/l), 64% were
within ± 10% and 100% were within ± 20%
of the reference reading
Comments
Design
EL
Test
evaluation
study
IIb
Test
evaluation
study
IIb
The glucose measuring system and test strips
received an overall rating of good to very
good (although this was not compared with
any other glucose monitoring systems)
10/28 values were considered unacceptable
(> 15% deviation from reference, maximum
deviation seen 55%)
Type 1 diabetes
140
Comparison of self-monitor blood glucose with meter with the laboratory standard measurement of blood glucose (continued)
Study
Population
Intervention
Outcomes
Results
Laus et al,
1984337
3 blood samples of
different glucose
concentrations,
tested 9 different
times
monitors (Glucoscan I® and
Glucoscan II®) looking at
variations in test procedure:
Variation of the different methods
and significant differences
Glucoscan I:
From: 1) completely coat the
reaction pad with blood, 2)
wait exactly 60 seconds, 3)
wash for 2 seconds, 4) blot
reaction pad firmly, 5) inset
test strip into meter and read
For Glucoscan I the
procedure was varied in
several ways: 1) sample
volume varied from 5 l to
50 l (but so pad is
completely covered at all
times), 2) reaction time varied
from 40 to 70 seconds, using
5 l sample, 3) wash time
varied from 1 to 4 seconds, 4)
blotting pressure and
technique were interpreted
three different ways
For Glucoscan II the
procedure was varied in
several ways: 1) sample
volume varied from 5 l to
50 l (but so pad is
completely covered at all
times), 2) timing of blotting
varied from 35 to 45 seconds,
using 5 l sample, 3) blotting
pressure and technique were
interpreted in two different
ways, 4) total reaction time or
reading time varied from 60
to 80 seconds
1) Increasing sample volume from 5 to 50 l
led blood glucose measurements to vary
from 38.0 ± 6.5 to 86.0 ± 1.5 mg/dl, p < 0.05.
However, there was no difference in blood
glucose measurements at sample volumes of
10, 20, 30, 40 or 50 l, p > 0.05
Comments
Design
EL
Test
evaluation
study
IIb
2) Varying reaction time from 40 to 70
seconds led blood glucose measurements to
vary from 60.3 ± 2.4 to 90.7 ± 4.4 mg/dl,
p < 0.05
3) Varying washing time from 1 to 4 seconds
from 88.3 ± 0.9 to 62.7 ± 1.2 mg/dl, p < 0.05
4) Varying blotting pressure and technique in
three different ways led blood glucose
measurements to vary from 85.3 ± 3.5
(gentle) to 64.7 ± 1.2 mg/dl (extra firm),
p < 0.05
Glucoscan II:
1) Increasing sample volume from 5 to 50 l
from 91 to 97 mg/dl, p > 0.05
2) Varying reaction times from 35 to 45
seconds led blood glucose measurements to
vary from 89.0 ± 1.0 to 96.0 ± 3.5 mg/dl,
p > 0.05
3) Varying blotting pressure and technique in
three different ways led blood glucose
measurements to vary from 67.5 ± 1.7
(gentle) to 69.5 ± 2.8 mg/dl (firm), p > 0.05
4) Varying delay in reading led blood
glucose measurements to vary from
94.0 ± 4.6 to 97.7 ± 4.2 mg/dl, p > 0.05
Evidence tables
141
Study
Population
Intervention
Outcomes
Results
Nelson et al,
1983338
41 adults with
diabetes
monitors (Glucometer®,
Glucoscan® and Hypocount
B®) compared with
venous serum glucose
assayed by the hexokinase
method and the capillary
whole blood glucose
determined by the glucose
oxidase method (Yellow
Springs Instrument)
between laboratory standard
(hexokinase method) and selfmonitor blood glucose meter
Correlation coefficients:
Glucometer: r2 = 0.92
Glucoscan: r2 = 0.86
Hypocount B: r2 = 0.92
Glucose oxidase method: r2 = 0.95
No significant difference between them
101 blood glucose
monitor readings
Canada
by experienced nurse
Sensitivity and specificity
Sensitivity and specificity:
Glucometer: 95.9%, 82.4%
Glucoscan: 87.8%, 90.2%
Hypocount B: 89.8%, 96.1%
Accuracy of meters within 10% of the
laboratory hexokinase method < 100 mg/dl:
Glucometer: 45.5%
Glucoscan: 54.6%
Hypocount B: 18.2%
Accuracy of meters within 10% of the
laboratory hexokinase method > 180 mg/dl:
Glucometer: 86.1%
Glucoscan: 36.1%
Hypocount B: 69.4%
Comments
Design
EL
Test
evaluation
study
IIb
Type 1 diabetes
142
Study
Population
Intervention
Kolopp et al,
1983339
30 blood glucose
monitor readings for monitors (Hypocount®
each monitor
Glucocheck®, Glucometer®
Dextrometer® and Eyetone®)
France
reference method (Beckman
BGA II®)
Two monitors were tested for
each blood glucose monitor
type, except for Eyetone
where only one monitor was
tested
Outcomes
Results
Coefficients of variation for
0–3.82, 3.83–8.38 and
≥ 8.39 mmol/l, and for all blood
glucose concentrations
In all meters there was a statistically
significant correlation with the reference
measure (p < 0.001)
Comments
Design
EL
Test
evaluation
study
IIb
Coefficients of variation for 0–3.82 mmol/l
(for each meter):
Hypocount: 10.8, 7.1
Glucocheck: 30.3, 11.2
Glucometer: 8.6, 5.1
Dextrometer: 8.8, 12.6
Eyetone: 17.5
Beckman BGA II: 2.4
Coefficients of variation for
3.83–8.38 mmol/l:
Hypocount: 7.9, 8.4
Eyetone: 11.1
Beckman BGA II: 1.7
Coefficients of variation for ≥ 8.39 mmol/l:
Hypocount: 6.2, 6.8
Eyetone: 7.1
Beckman BGA II: 1.3
Coefficients of variation for all blood glucose
concentrations:
Hypocount: 8.3, 7.4
Eyetone: 11.9
Beckman BGA II: 1.8
Evidence tables
143
Study
Population
Gifford37 adult and
Jorgensen et al, paediatric patients
1986340
with diabetes
USA
Intervention
Outcomes
Results
monitors (Accu-Chek®,
Glucochek II®, Glucochek
Dextro®, Glucometer® and
Glucoscan II®) compared
with laboratory reference
method (Beckman Astra 8®)
Coefficients of variation blood
glucose 60–180, 181–300 and
301–400 mg/dl
Coefficients of variation for 60–180 mg/dl:
Accu-Chek: 3.31
Glucochek II: 1.38
Glucochek Dextro: 3.85
Glucometer: 4.09
Glucoscan II: 5.47
Comments
Design
EL
Test
evaluation
study
IIb
Test
evaluation
study
IIb
Test
evaluation
study
IIb
Accu-Chek: 2.84
Glucochek II: 2.84
Glucometer: 3.13
Glucoscan II: 6.41
Blood samples tested 8 times
on each meter within 30 min
of blood being drawn
Accu-Chek: 2.61
Glucochek II: 4.71
Glucometer: 4.09
Glucoscan II: 7.84
Kyvik et al,
1990341
50 patients with
insulin-treated
diabetes
Aged 18–79 years
Denmark
1) 3 blood samples of
approximately 4, 10 and
20 mmol/l measured with 6
ExacTech® meters compared
with laboratory standard
Coefficient of variation
1) Coefficient of variation: 10.28%, p > 0.05
(n = 63)
(n = 45)
(n = 60)
2) blood sample from each
patient analysed with
with laboratory standard,
tested by study staff
3) blood sample from each
patient analysed with
with laboratory standard,
tested by patient
Merino-Torres
et al, 2003342
25 adults with type
1 diabetes
62 measurements of HbA1c
Patients monitored for 3–9
Aged 17 to 34 years months
Spain
Linear regression calculated
between HbA1c and mean blood
glucose for the 60 days before
HbA1c sampling
r = 0.71, r2 = 0.497, p = 0.000
Type 1 diabetes
144
Self-monitoring of blood glucose with a meter or a visual stick
Study
Population
Intervention
Outcomes
Results
Peterson et al,
1984354
24 adults with type
1 diabetes
Self-monitor blood glucose:
HbA1
HbA1 (mean (SD)):
Mean age 39.35,
range 15–65 years
USA
A. by meter then switched to
visually read strips
Meter group A 7.8% (1.75%), group B 7.6%
(1.05%)
B. by visually read strips then
switched to meter
Visual test group A 7.96% (0.99%), group B
8.41% (2.18%)
C: measured urine for whole
study period
Urine group 9.99% (2.72%)
Germer and
Campbell,
1985352
20 young people
with type 1diabetes with meter
Aged 12–19 years
versus
Canada
self-monitor blood glucose
with visual strip
32 patients with
type 1 diabetes
with meter
Aged 13–60 years
versus
UK
self-monitor blood glucose
with visual strip
Design
EL
RCT crossover Ib
No statistical difference in HbA1 between the
groups (p values not given)
periods
Shiffrin et al,
1983353
Comments
Correlation between method of
self-monitor blood glucose and
capillary plasma glucose, glucose
oxidase method (laboratory
method)
Meter: r = 0.96, p < 0.0001
Test
evaluation
study
IIb
Patient preference
Patient preference (patients preferred
method): 19/32 vs. 9/37
Nonrandomised
intervention
study
crossover
IIa
meter and visual stick method
Correlation coefficients 0.96 vs. 0.95, p > 0.5
Test
evaluation
study
IIb
Test
evaluation
study
IIb
Visual strip: r = 0.96, p < 0.0001
periods
Rayman et al,
1984351
101 blood samples
from patients with
diabetes
UK
Aziz and
115 blood samples
Hsiang, 1983350 from outpatients
Simultaneously obtained
finger prick blood samples
tested by two types of meter meter and visual stick methods
and two types of visual stick
compared with venous blood
(laboratory standard)
Correlation coefficients all very similar
Meter Glucometer® r = 0.921
Meter Accu-Chek® r = 0.955
Visual strip Visidex® r = 0.955
Visual strip Chemstrip® r = 0.963
Not clear if blood
samples came from
patients who had type 1
diabetes or not
145
Evidence tables
UK
Simultaneously obtained
finger prick blood samples
tested by meter and visual
stick compared with venous
blood (laboratory standard)
Study
Population
Anderson et al, 10 children and
young people with
1986349
type 1 diabetes
Aged 9–14 years
Australia
Intervention
Outcomes
Self-monitor blood glucose:
Results
Visidex-2® strip visually read meter and visual stick methods
versus
Correlation coefficients:
20–800R® reagent strips
visually read
Ames B.G. strips with Glucometer meter
r = 0.92
versus
20–800R reagent strips with Reflolux meter
r = 0.73
Ames B.G. strips® read by
Glucometer® meter
Comments
Design
EL
RCT crossover Ib
Visidex-2 strips r = 0.59
20–800R reagent strips r = 0.80
versus
20–800R® reagent strips read
by Reflolux® meter
Compared with laboratory
standard test
Trial length: four 7-day
periods of testing twice a day
Chiasson et al, 100+ patients both
1984348
with and without
diabetes
Canada
Chemstrip bG (visual)
versus
Dextrostix (visual)
versus
Visidex (visual)
versus
Dextrometer –Dextrostix
(meter)
Coefficient of variation with
laboratory standard
Coefficient of variation (number of
determinates):
Chemstrip bG (visual) 15.5% (105)
Dextrostix (visual) 11.2% (43)
Visidex (visual) 16.7% (55)
Dextrometer – Dextrostix (meter) 9.5% (119)
Glucometer – Dextrostix 5.7% (55)
Reflomat – Reflotest 10.8% (63)
versus
Hypocount II-BM-strip 5.7% (53)
Glucometer – Dextrostix
Correlations: reagent strips with meters
r2 = 0.85 to 0.96, reagent strips r2 = 0.69 to
0.90
versus
Reflomat – Reflotest
versus
Hypocount II-BM-strip
all compared with laboratory
standard test
Test performed by trained
nurse
Test
evaluation
study
IIb
Type 1 diabetes
146
Self-monitoring of blood glucose with a meter or a visual stick (continued)
Self-monitoring of blood glucose with a meter or a visual stick (continued)
Study
Population
Intervention
Outcomes
Results
Kalk et al,
1985347
50 patients with
type 1 diabetes
20–800R® blood glucose
strips visually read
Correlation coefficient
South Africa
versus
Correlation of blood glucose read by meter
compared with laboratory standard: r = 0.97,
p < 0.0001
Comments
Design
EL
Test
evaluation
study
IIb
Correlation of blood glucose visually read
compared with read by meter: r = 0.921,
p < 0.001
read with meter Reflolux®
versus
laboratory standard
Comparison of blood glucose monitors with and without a memory
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Halimi and
Charpentier,
2001355
179 adults with
diabetes treated
with insulin
Monitor with memory
(1. Glucotrend Premium®,
n = 60)
1) HbA1c
Unknown the precise
difference between
monitor 1 and monitor 2
RCT
Ib
1) HbA1c (mean decrease ± SD): 0.9 ± 1.2 vs.
1.0 ± 1.1 vs. 0.6 ± 1.1% (end levels not
given)
Aged 24.4 ± 4.1,
24.6 ± 3.2 and
23.3 ± 3.4 years for
the three groups,
respectively
versus
monitor with memory
(2. One Touch Profile®,
n = 49)
4) Accuracy of capillary blood
glucose determination compared
with venous blood glucose
laboratory measurement
France
versus
3) Hypoglycaemic events: 7.9 ± 14.0 vs.
7.6 ± 18.0 vs. 3.2 ± 5.5 (p = 0.02 for monitor
1 vs. control, p = 0.08 for monitor 2 vs.
control)
147
4) Accuracy of capillary blood glucose
determination: not significant, no values
given
Evidence tables
diary for results of selfmonitored blood glucose
(no memory, n = 55)
2) Patient preference: 81 ± 18 vs. 77 ± 23 vs.
68 ± 24% (p = 0.02 for monitor with memory
1 and 2 vs. no memory)
Study
Population
Intervention
Meyerhoff et
al, 1994357
24 patients with
type 1 diabetes
(system introduced
to 98 patients, the
24 who wanted to
use the system were
entered into the
study)
Patients given memory system 1) HbA1
with meal and exercise input
option attached to monitor for 2) Blood glucose
blood glucose and followed
up. Divided into three groups:
Aged 17–50 years
patients who returned the
system within the first 4
weeks, (mean 12 days using
system, n = 8)
Germany
versus
Outcomes
Results
Comments
Design
EL
Patients wanting to try the memory meter:
24/89
Patients self-selected to
length of time using the
equipment, bias in
comparing patients
Test
evaluation
study
IIb
Before/after study
Non RCT
IIa
After 3 years only 5 patients continued to
use the meter, none used the option to input
daily meal and exercise regimen
1) HbA1 (mean, no SD given): 11.7% vs.
10.7 %vs. 7.8%
2) Blood glucose (mean ± SD): 161 ± 73 vs.
175 ± 88 vs. 121 ± 58 mg/dl
patients who used the system
for as long as it was given to
them free, (mean 45 days
using system, n = 8)
versus
patients who bought the
system after period of loan
was up (mean 33 months
using system, n = 8)
Trial length: varying for each
patient
Strowig et al,
1998356
22 adults with type
1 diabetes
Blood glucose meter with
memory (n = 22)
Aged 33.2 ± 8.2
years
versus
USA
blood glucose meter with no
memory (n = 22)
Trial length: 12 months with
non-memory meter then 12
months with memory meter
HbA1c
HbA1c: 6.4 ± 0.10% vs. 6.9 ± 0.12%
(p = 0.004)
Type 1 diabetes
148
Comparison of blood glucose monitors with and without a memory (continued)
Patient reliability in reporting self-monitoring blood glucose levels
Study
Population
Intervention
Mazze et al,
1985359
20 patients with
type 1 diabetes
Patients recorded home blood 1) Under-reporting (% number of
glucose measurements in log measurements on meter memory
book
recorded in log book)
Aged 28.1 ± 1.5,
range 14–41 years
USA
Outcomes
versus
2) Over-reporting (% number of
log book recording that
measurements were recorded corresponded to a measurement
by the memory in the monitor on meter memory)
(patients were told about this
memory, measurements were 3) Precision (% of identical
downloaded at the clinic)
recordings)
(n = 20)
Mazze et al,
1985359
13 patients with
Patients did not know that
type 1 diabetes (all monitor had a memory
also included in the
versus
above study)
patients then told that
Aged 18–41 years
monitor had a memory
USA
(n = 13)
Results
Comments
1) Under-reporting: 11/20 subjects underreported at least one measurement, average
6.8% recordings were not recorded in log
book
Design
EL
Test
evaluation
study
IIb
Non RCT
IIa
Test
evaluation
study
IIb
2) Over-reporting: 3/20 subjects overreported at least one measurement,
unconfirmed log book entry in < 0.5% of log
book recordings
3) Precision: 8/20 subjects’ values were not
all the same (no patients had more than 9%
of recordings inaccurate)
1) Under-reporting
1) 10% vs. 7% (p = NS)
2) Over-reporting
2) 34% vs. 1% (p = 0.0027)
3) Precision
3) 72% vs. 99% (p = 0.0037)
4) 179 ± 16 vs. 167 ± 16 mg/dl (p = NS)
Correlations between:
Underreporting: 13/21
Under-reporting
Over-reporting: 9/21
Over-reporting
Precision: 13/21
Precision
Over-reporting correlated with underreporting (rs = 0.56, p < 0.01)
Before/after study
Williams et al,
1988360
21 patients with
type 1 diabetes
Aged 43.2, range
17–66 years
UK
Patients did not know that
(n = 21) comparison of log
book results with memory
results
Trial length: 7 days (range
5–10)
Overall reliability (from precision
+ over-reporting)
Clinicians’ predicted rating of
patients accuracy (range 10–good
to 0–bad)
HbA1
Neither over-reporting nor under-reporting
correlated with precision
Clinicians’ prediction of the patients’
accuracy was associated with the overall
reliability scores (rs = 0.68, p < 0.01)
149
Unreliability of self-monitored blood glucose
was not correlated to age, gender, body mass
index, duration of self-monitored blood
glucose or duration of diabetes
Evidence tables
HbA1 correlated weakly with the meter
readings of self-monitored blood glucose
(rs = 0.62, p < 0.01) and overall reliability
score (rs = –0.44, p < 0.05)
Study
Population
Intervention
Outcomes
Petranyi et al,
1988358
6 patients with type Patients did not know that
Under-reporting
1 diabetes, with
Over-reporting
poor control
versus
Precision
Aged 43.2, range
patients
then
told
that
17–66 years
monitor had a memory (n = 6)
UK
periods
Results
Comments
Design
EL
Under-reporting: 6/6 (100%) vs. 4/5 (80%)
(mean of not recorded measurements were
higher than memory mean in 4/6 patients)
Before/after study
Non RCT
IIa
Over-reporting: 5/6 (83%) vs. 1/5 (20%)
(mean of phantom recorded measurements
was lower than memory mean in 4/5
patients)
Precision not 100%: 4/6 (66%) vs. 4/5 (80%)
Average number of measurements: increased
in 4/5 patients
1 patient returned the meter after being
informed that a meter would be fitted
Computer systems for assisting monitoring glycaemic control
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Balas et al,
1998361
15 RCTs that
measured the
outcome on patient
care of patientfocused computergenerated
information
Patient-focused computergenerated information
1) HbA1c
1) All 15 studies reported HbA1c levels, 6
RCTs found a significantly lower level in the
intervention group
No detail of how studies
were selected
Systematic
review
Ia
10 RCTs
investigating adults
(n = 502) and 5
RCTs investigating
children (n = 259)
13 RCTs
investigating
diabetes 1 type 2
diabetes and 1 RCT
in patients with type
1 and type 2
diabetes
versus
2) Blood glucose levels
no patient-focused computer- episodes
generated information
Sample size,
2) 3 RCTs found a significantly lower level in characteristics of patients,
the intervention group
setting, training required
on computer use,
3) 1 RCT found a significantly lower number acceptance rates of
in the intervention group
computer by patient,
description of
intervention, definition
and ascertainment of
outcomes, duration of
follow-up and validity
score were not reported
Statistical heterogeneity
was not reported
Type 1 diabetes
150
Patient reliability in reporting self-monitoring blood glucose levels (continued)
Computer systems for assisting monitoring glycaemic control (continued)
Study
Population
Intervention
Morrish et al,
1989362
18 patients with
type 1 diabetes
Outcomes
Results
Comments
Design
EL
Home blood glucose meter
1) HbA1
with computer analyser (n = 9)
2) Fructosamine
versus
1) HbA1 (absolute change during study):
–1.7 ± 0.3% vs. –1.6 ± 0.2% (NS)
Patients ranked on in
order of HbA1 and
randomly allocated in
consecutive pairs to
intervention
RCT
Ib
Home blood glucose meter
with computer storage and
analyser (n = 9)
HbA1c: 8.9% (7.2–11.0%) vs. 9.3%
(7.7–12.8%) (NS)
RCT
Ib
RCT
Ib
Aged 36.3 ± 2.8
(computer analyser)
and 43.2 ± 8.5 years conventional home blood
glucose meter (n = 9)
(conventional
meter)
2) Fructosamine (absolute change during
study): –0.2 ± 0.6 vs. –0.4 ± 0.1 mmol/l (NS)
UK
Rosenfalck and 16 male young
Bendtson,
people with type 1
1993363
diabetes and not
satisfactory control
Aged 14–20 years
Denmark
HbA1c
versus
conventional home blood
glucose meter (n = 7)
Peterson et al,
1986364
16 adults with type Computer analyser for insulin HbA1c
1 diabetes willing to adjustment (n = 7)
start to use CSII for
versus
the study
conventional algorithms for
Aged 20–62 years
insulin adjustment (n = 9)
USA
HbA1c: 6.2% vs. 7.0% (p = 0.06)
Holman et al,
1996365
6 adults with type 1 Computer-assisted insulin
diabetes
adjustment
1) Preprandial glucose (mean (SE)): 7.5 (0.4)
vs. 8.9 mmol/l (0.4) (p = 0.015)
Aged 23–48 years
versus
UK
conventional insulin
adjustment
weeks
1) Preprandial glucose
2) Fructosamine
3) HbA1c
4) Hypoglycaemia
Small numbers and short
length of study
RCT crossover Ib
2) Fructosamine (mean (SE)): 481 (34) vs.
492 mol/l (34) (NS)
3) HbA1c (mean (SE)): 9.2% (0.5%) vs. 9.2%
(0.5%) (NS)
4) Hypoglycaemia: 7 vs. 7 (NS)
Evidence tables
151
Study
Population
Intervention
Danne et al,
1992366
10 children with
Computer-assisted insulin
type 1 diabetes and adjustment based on urine
poor glycaemic
glucose measurements
control
versus
Aged 7–14 years
record urinary glucose only
Germany
periods
Outcomes
Results
1) Urine glucose
1) Urine glucose: Group A (computer then
control) 0.7 ± 0.3% vs. 1.7 ± 0.9% mean per
week (p < 0.05), Group B (control then
computer) 0.5 ± 0.2% vs. 0.5 ± 0.3% mean
per week (NS)
Comments
Design
EL
RCT crossover Ib
2) Glycated haemoglobin: Group A
(computer then control) 8.6 ± 0.8% vs.
9.0 ± 0.5% (NS), Group B (control then
computer) 10.5 ± 1.3% vs. 10.3 ± 1.3% (NS)
3) Patient preference: 9/10 improved control
with computer advice, 8/10 felt more secure
with insulin therapy, 9/10 wished to
continue using the computer
Billiard et al,
1991369
22 adults with type
1 diabetes
Aged 32 ± 14 years
France
Computerised self-monitoring HbA1c
blood glucose (n = 11)
Urine glucose
versus
conventional meter and selfmonitoring blood glucose on Patient preference
books (n = 11).
HbA1c: Group A (computer then control)
6.0 ± 1.0% vs. 6.8 ± 0.6% (p = 0.03), Group B
(control then computer) 6.7 ± 1.0% vs.
6.8 ± 0.9% (NS)
RCT crossover Ib
Analysis of variance showed no order effect
(F = 1.47, p= 0.23)
Patient could adjust their
insulin in both groups
periods
Chiarelli et al,
1990371
20 children and
young people with
type 1 diabetes
Computer algorithms
1) HbA1c levels
1) 7.7 ± 2.1% vs. 7.8 ± 1.9% (NS)
versus
2) Pre-meal glycaemia
2) 8.0 ± 1.8 vs. 7.8 ± 2.3 mmol/l (NS)
3) Frequency of hypoglycaemia
3) 1.2 vs. 2.3 events per week
Aged 7.6–11.9 years manual algorithms
Marrero et al,
1989367
57 children with
type 1 diabetes
Aged 10–18 years
USA
HbA1
memory and analysis function
(n = 29)
versus
memory (n = 28)
HbA1: 9.3 ± 1.7% vs. 9.8 ± 1.7% (NS)
RCT parallel
Ib
RCT
Ib
Type 1 diabetes
152
Study
Population
Biermann et al, 48 adults with type
1 diabetes
2000368
Aged 30.5 ± 8.6
(intervention) and
30.5 ± 8.6 years
(control)
Germany
Intervention
Outcomes
Results
Comments
Design
EL
Blood glucose measurements
sent to computer for storage,
telephone link available to
physicians and scheduled
telephone consultations
(n = 29)
HbA1c
HbA1c: 7.1% vs. 6.8% (NS)
Increased time with
RCT
physicians in intervention
group
Ib
1) HbA1c
1) 8.6 ± 1.7% vs. 8.6 ± 1.2%, p = 0.89
RCT
Ia
versus
memory (n = 28)
Chase et al,
2003372
70 young people
2 clinic visits at 0 and 6
with type 1 diabetes months. Modem
electronically transmitted
Aged 15–20, mean blood glucose information to
age 17.4 ± 1.7 in
clinic approximately every 2
intervention group weeks. The healthcare
and 17.2 ± 1.5 years provider reviewed the
in control group
information transmitted and
called the patient to make
USA
treatment changes as needed
(n = 30)
2) Blood glucose testing frequency 2) 2.9 vs. 3.0 times/day, p = 0.91
On scale 1 to 7 (1 being most favourable):
mean values 2.6 vs. 2.2, p = 0.81
versus
3 clinic visits at 0, 3 and 6
months with the option to
telephone or fax blood
glucose results to the clinic as
desired by the patient or
recommended by the
physician (n = 33)
Evidence tables
153
Study
Population
Intervention
Kaufman et al,
1999374
40 children with
type 1 diabetes
Plastic insulin dose guide and 1) HbA1c
education in its use to guide
insulin dosage adjustment
(see Comments)
3) Patient acceptability (Likert
Scale)
versus
Aged 10.6 ± 4.6,
range 4–20 years
USA
written-on-paper algorithm,
with education on how to use
algorithm dosage correction
Outcomes
4) Mean time to teach
Results
Comments
1) 7.8 ± 1.3% vs. 8.7 ± 2.1% (NS)
Two separate insulin dose RCT
guides were developed,
one for short-acting
insulin users and one for
rapid-acting insulin users
2) 166 ± 22 vs. 212 ± 28 mg/dl (9.2 ± 1.2 vs.
11.8 ± 1.6 mmol/l converted from mg/dl)
3) 5.0 vs. 3.4 (0–5 scale)
4) 18 vs. 43 min
The insulin dose guide
and algorithm seem to
have contained the same
information just displayed
in different ways
Numbers in each
treatment group were not
given
Design
EL
Ib
Type 1 diabetes
154
Plastic insulin dose guide compared with paper algorithm
What is the ideal frequency and timing of monitoring glycaemic control in children with type 1 diabetes?
Frequency of self-monitoring of blood glucose
Study
Population
Intervention
Gordon et al,
1991317
25 patients with
type 1 diabetes
Blood glucose was monitored Blood glucose control
by:
Fructosamine control
A: 4-point profile on any 2
GHb levels
non-consecutive days per
week
Frequency at which patients
B: one 4-point profile on any altered insulin dosages
Aged 31.0 ± 10.0
years
UK
day of the week
Outcomes
Patient preference
C: 2 blood glucose
measurements on each day
for 7 days per week
Trial length: three 12-week
periods
Results
Comments
Design
EL
No significant differences were found when
comparing the three protocols among any of
the laboratory measures studied: blood
glucose control, fructosamine control and
GHb levels
RCT crossover Ib
4 patients withdrew
during the study, all while
undergoing the single
The frequency at which patients altered
day/week protocol. The 2
insulin dosages was extremely variable:
patients who provided
median 3.3 (range 0.03–11.8) dosage
reasons for withdrawal
changes/week. A significant increase was seen expressed concern about
in frequency of insulin dosage changes during the infrequency of
the 2 day 4 tests/week protocol vs. 1 day monitoring during this
4 tests/week (no values given but p < 0.02)
phase
No significant relationship was seen between
the frequency at which a patient altered
insulin dosage and their metabolic control as
estimated by mean GHb. However, the lack
of differences between 1 day 4 tests/week
and 7 days 2 tests/week fails to
demonstrate clearly that alteration in
frequency of blood glucose monitoring
influences patient practice
Protocol preference: at the final visit, of the
21 patients completing the study, 18
expressed a preference: 9/18 preferred 2
days 4 tests/week, 6/18 preferred 1 days
4 tests/week, 3/18 preferred 7 days 2
tests/week. These differences were not
statistically significant
Wysocki et al,
1989326
30 young people
with type 1
diabetes.
Aged 14.3 ± 1.3
years
155
1) At 16 weeks: approximately 80% vs.
58.1%
RCT
2) 191.4 vs. 194.7 mg/dl
Unknown if patients were
given the education and
freedom to alter their
daily insulin doses in
response to their blood
glucose level, if this was
done the blood glucose
concentration and
glycated haemoglobin
level may have decreased
3) 85.1 vs. 88.3 mg/dl
4) 15.1% vs. 15.3%
Ib
Evidence tables
USA
1) Percent of days blood glucose
monetary reward, the value of was monitored twice
the reward related to the
number of days blood
concentration
glucose monitoring was
performed at least twice
3) Blood glucose variability (mean
SD of blood glucose
versus
concentration)
blood glucose meter (money
received just for turning up at 4) Mean percentage glycated
haemoglobin concentration
the clinic, not in relation to
frequency of blood glucose
monitoring)
Study
Population
Intervention
Outcomes
Schiffrin and
Belmonte,
1982327
7 patients with type Phase 1: A. CSII who selfMean blood glucose
1 diabetes
monitored blood glucose at
HbA1
least 4 times a day (n = 5)
Aged 15–36 years
versus
Canada
B. CSII who self-monitored
(Self-selected
blood glucose 2 times a day
patients as they
(n = 2)
were performing
blood glucose
Phase 2: crossover A with B
testing as often as
Phase 3: both groups measure
they considered
blood glucose at least 4 times
necessary)
a day
Trial length: phase 1 was 6
months, phase 2, was 3
months, phase 3 was 3
months
Results
Comments
Design
EL
Group A:
Small numbers
Mean blood glucose: (≥ 4 times/day)
114 ± 29 vs. (2 times/day) 156 ± 50
(p = 0.1429) (Phase 3: (≥ 4 times/day)
119 ± 30 mg/dl NS compared with phase 1
(≥ 4 times/day))
No randomisation
Self-selected IIb
crossover trial
HbA1: (≥ 4 times/day) 7.9 ± 0.4% vs. (2
times/day) 10.3 ± 0.5% (p < 0.0001) (Phase 3:
(≥ 4 times/day) 8.0 ± 0.1% NS compared with
phase 1 (≥ 4 times/day))
Group B:
115 ± 35 vs. (2 times/day) 165 ± 42
(p = 0.3251) (Phase 3: (≥ 4 times/day)
(≥ 4 times/day))
HbA1: (≥ 4 times/day) 8.2 ± 0.4% vs. (2
times/day) 10.2 ± 0.5% (p = 0.0476) (Phase 3:
(≥ 4 times/day) 8.1 ± 0.1% NS compared with
phase 2 (≥ 4 times/day))
Schiffrin and
Belmonte,
1982327
7 patients with type Phase 1: C. patients on
Mean blood glucose
1 diabetes.
multiple daily injections who
self-monitored blood glucose HbA1
(Self selected
at least 4 times a day (n = 6)
patients as they
were performing
versus
blood glucose
D. Patients on multiple daily
testing as often as
injections who self-monitored
they considered
blood glucose 2 times a day
necessary)
(n = 1)
Phase 2: crossover C with D
Phase 3: both groups measure
blood glucose at least 4 times
a day
Trial length: phase 1 was 6
months
Group C:
Small numbers
116 ± 37 vs. (2 times/day) 165 ± 52
(p = 0.0845) (Phase 3: (≥ 4 times/day)
(≥ 4 times/day))
No randomisation
HbA1: (≥ 4 times/day) 8.1 ± 0.4% vs. (2 times
/day) 10.0 ± 0.9% (p = 0.0008) (Phase 3: (≥ 4
times /day) 8.0 ± 0.6% NS compared with
phase 1 (≥ 4 times /day))
Group D:
119 ± 32 vs. (2 times/day) 158 ± 48 (Phase 3:
(≥ 4 times/day) 113 ± 30 mg/dl)
HbA1: (≥ 4 times/day) 8.6% vs. (2 times/day)
10% (Phase 3: (≥ 4 times/day) 8.7%)
Self-selected IIb
crossover trial
Type 1 diabetes
156
Frequency of self-monitoring of blood glucose (continued)
Frequency of self-monitoring of blood glucose (continued)
Study
Population
Intervention
Outcomes
Schiffrin and
Belmonte,
1982327
7 patients on
combined multiple
daily injection and
CSII
Self-monitored blood glucose Mean blood glucose
2 times a day (3 months)
HbA1
versus
Results
Comments
Design
EL
116 ± 30 vs. (2 times/day) 161 ± 51 mg/dl
(p = 0.0672)
Small numbers
IIb
No randomisation
Historical
intervention
trial
Results
Comments
Design
EL
n = 92, when using FreeStyle meter, 62 used
arm only for test site, 16 used arm and
finger, 14 used finger only
39 dropped out before
end of the study
NonIIa
randomised
crossover trial
HbA1: (≥ 4 times/day) 8.2 ± 0.3% vs. (2
times/day) 10.3 ± 0.3% (p < 0.0001)
self-monitored blood glucose
4 times a day (3 months)
What is the ideal site of blood glucose testing in children with type 1 diabetes?
Study
Population
Intervention
Bennion et al,
2002382
121 patients with
type 1 or type 2
diabetes
Meter that needs a low
Patient preference
amount of blood, so alternate
sites can be used (FreeStyle®) Number of tests per day
Influence of using alternate site
versus
(analysing patients who used arm
personal meter (finger stick
testing site exclusively or for part
meters)
of the time with FreeStyle with
their values for their normal home
blood glucose monitor)
periods
Mean age 53.7,
range 18–80 years
USA
Outcomes
Patient preference: 76% preferred the
FreeStyle meter, 20% preferred the original
meter, 4% had no preference
Alternate site analysis
may be influenced by
meter as well as site
change
Number of tests per day: 2.54 vs. 2.45
test/day (NS)
Funding by TheraSense
Inc
Influence of using alternate site: 6.93% vs.
7.08% (NS, p = 0.093)
Peled et al,
2002375
versus
157
finger capillary blood
samples, plasma glucose
concentration (by YSI
analyser ®) (n = 46)
1. Steady glycaemic state:
forearm vs. finger: correlation coefficient
0.968
Test
evaluation
trial
IIa
Evidence tables
9 patients with type 4 studies looking at alternates Correlation coefficients
1 diabetes and 37
site of testing
Aged 29–80 years
forearm capillary blood
USA
samples (using AtLast®)
(n = 46)
Study
Population
Intervention
Outcomes
Peled et al,
2002375
14 patients with
Correlation coefficients
type 1 diabetes and
palm capillary blood samples
33 with type 2
(using AtLAst®) (n = 47)
diabetes
versus
Aged 14–87 years
Results
palm vs. finger: correlation coefficient 0.987
Comments
Design
EL
Test
evaluation
trial
IIa
Test
evaluation
trial
IIa
Test
evaluation
trial
IIa
Test
evaluation
trial
IIa
analyser®) (n = 47)
Peled et al,
2002375
20 patients with
3. Random glycaemic states:
type 1 diabetes and
palm and forearm capillary
30 with type 2
blood samples (using
diabetes
AtLAst®) (n = 50)
Aged 8–64 years
versus
3. Random glycaemic states:
palm vs. finger: correlation coefficient 0.986
Peled et al,
2002375
7 patients with type 4. High glucose load:
1 diabetes and 3
with type 2 diabetes palm and forearm capillary
blood samples (using
Aged 19–62 years
AtLAst®) (n = 14)
4. High glucose load:
forearm vs. finger: correlation coefficient
0.938
versus
Peled et al,
2002375
14 patients with
5. Comfort of sampling from
type 1 diabetes and the palm of the hand:
33 with type 2
diabetes
samples (using AtLAst®)
Aged 14–87 years
(n = 46)
versus
palm capillary blood samples
(using AtLAst®) (n = 47)
Pain levels associated with
5. Patient preference:
sampling from various testing sites
76% chose palm as preferred testing site,
67% rated palm capillary blood samples
(using AtLAst) zero on pain scale
Type 1 diabetes
158
What is the ideal site of blood glucose testing in children with type 1 diabetes? (continued)
Study
Population
McGarraugh et 120 patients with
al, 2001376
type 1 diabetes or
type 2 diabetes
USA
Intervention
Outcomes
1. Single sample for each
patient of:
% of measurements within 20% of Forearm capillary blood FreeStyle vs. YSI
YSI measurement
using capillary blood from the finger: 88.5%
within 20% of YSI values
Correlation coefficient
Finger capillary blood FreeStyle vs. YSI using
capillary blood from the finger: 98.7%
within 20% of finger values. Correlation
coefficient: 0.983
samples (using FreeStyle®)
(n = 120)
versus
Results
Comments
Design
EL
Inc
Test
evaluation
trial
IIa
Test
evaluation
trial
IIa
Test
evaluation
trial
IIa
Time difference in
FreeStyle vs. YSI using
capillary blood of 5–10
min, compared with same
sample used for finger
Looking at the measurements within 20% of
capillary blood FreeStyle
the YSI measurement (88.5% vs. 98.7%) they
vs. YSI using capillary
were not statistically different. More scatter
blood from the finger
in the forearm (FreeStyle) vs. finger (YSI) than
finger (FreeStyle) vs. finger (YSI) (numbers
not given)
Rubbing test site reduced the difference
between arm and finger glucose
McGarraugh et 14 patients with
al, 2001376
type 1 diabetes
USA
2. 5–6 hour (including one
meal) testing every 15 min to
get profile of blood glucose:
Difference in arm and finger tests
as a function of rate of change in
glucose
Regression intercept = 0.8 mg/dl, slope =
–0.166, R = –0.709
Time difference in
FreeStyle vs. YSI using
capillary blood of 5–10
min, compared with same
sample used for finger
capillary blood FreeStyle
vs. YSI using capillary
blood from the finger
samples (using FreeStyle®)
(n = 14)
versus
Lee et al,
2002377
Inc
‘Bias’ mg/dl when finger result was Preprandial: mean bias of forearm – finger
≤ 100 mg/dl and % ‘bias’ from
0.62 (mg/dl or %), 95% CI 0.26 to 0.97
finger result was used when finger (n = 5523 tests)
result was > 100 mg/dl
1-hour postprandial: mean bias of forearm –
finger –6.02 (mg/dl or %), 95% CI –6.41 to
–5.63 (n = 5386 tests)
Trial length: 10 days testing at
home
2-hour postprandial: mean bias of forearm –
finger 0.68 (mg/dl or %), 95% CI 0.30 to
1.06 (n = 5357 tests)
Bedtime: mean bias of forearm – finger 0.04
(mg/dl or %), 95% CI –0.58 to 0.65
(n = 1770 tests)
Study by Roche
Diagnostic Corp
Unknown if the result of
bias is a meaningful
outcome. Confusion over
units of ‘bias’ measure
159
Evidence tables
190 patients, 30%
Forearm capillary blood
with type 1 diabetes samples (using FreeStyle®)
and 70% with type (n = 190)
2 diabetes
versus
USA
finger capillary blood samples
(using FreeStyle®) (n = 190)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Fineberg et al,
2001378
378 patients, 26%
with type 1
diabetes, 64% with
type 2 diabetes and
10% without
diabetes, from 5
different diabetes
clinics
Arm blood glucose sample
using automated device
(SoftSense®) taken by patient
1) Correlation
1) Patient measured arm blood glucose
concentration using automated device vs.
finger laboratory result: regression
slope = 0.98, r = 0.96, n = 354
Exclusion of 24 patients
due to protocol
deviations
Test
evaluation
trial
IIa
Aged 18–84 year
versus
USA
finger using automated device
Test
evaluation
trial
IIa
Test
evaluation
trial
IIa
versus
Finger using automated device vs. finger
laboratory result: regression slope = 0.96,
r = 0.97, n = 378
arm blood glucose sample
using automated device taken
by health professional
Health professional measured arm blood
glucose concentration using automated
device vs. finger laboratory result: regression
slope = 0.95, r = 0.95, n = 352
versus
2) 87% of the subjects had a successful first
attempt at arm blood glucose monitoring
finger using laboratory
reference instrument (YSI
analyser®).
Lock et al,
2002379,380
50 patients with
diabetes (28 with
type 1 and 22 with
type 2 diabetes)
Patient meal tolerance tests:
arm and finger glucose was
measured every 30 min for 4
hours
Mean age
49.7 ± 11.5, range
23 – 67 years
n = 860 pairs of blood glucose
tests
Supported by Abbott
Laboratories
(manufacturer of glucose
monitoring system)
60% of patients reported arm test was
‘painless’, 31% stated ‘much less painful’,
6% ‘less painful’ (overall 97% of patients
found arm blood glucose testing less painful)
Clarke error grid analysis for
correlation between the arm and
finger glucose measurement
92% of data points in zone A and 8% in
zone B – all found to be clinically
acceptable
Exclusion of 24 patients
due to protocol
deviations
Supported by Abbott
Laboratories
(manufacturer of glucose
monitoring system)
USA
Ellison et al,
2002381
42 adults with type
1 diabetes
Mean age
47.9 ± 12.2 years
USA
Blood glucose monitoring
pre-meal and at
approximately 60, 90, 120,
150 and 180 min post-meal:
forearm site
versus
thigh
versus
finger
Meter results
Meter finger results were accurate at all time
points Alternative sites tended to produce
lower glucose readings compared with finger
readings at times when glucose was
increasing rapidly (60 and 90 min post-meal)
Type 1 diabetes
160
Is there a role for continuous blood glucose monitoring in children with type 1 diabetes?
Invasive continuous glucose monitoring
Study
Population
Chase et al,
2001385
11 children with
type 1 diabetes
Intervention
Continuous glucose
monitoring sensors
(MiniMed®) results were
Mean age 14.8 ± 2.2 downloaded after each sensor
in continuous
use. 6 sensors were used for
glucose monitoring 18 total sensor days, within a
sensors group and
30-day period (n = 5)
12 ± 0.6 in control
group, overall range versus
10–17 years
control, at least 4 selfUSA
tests a day and fax results
every 5 days (6 times in total)
(n = 6)
Ludvigsson and 27 children, young
Hanas, 2003386 people and young
adults with type 1
diabetes receiving
intensive insulin
therapy (14 with
multiple daily
injections and 13
with CSII)
Mean age
12.5 ± 3.3, range
5–19 years
Sweden
Outcomes
Results
Comments
Design
EL
1) Fear of hypoglycaemia
1) No significant differences
Ib
No description of
randomisation
RCT
2) DCCT quality of life
3) HbA1c
3) 6 months before intervention: 9.3 ± 0.7%
vs. 8.9 ± 0.7% (p > 0.05)
Crossover
RCT
Ib
Test
evaluation
comparative
study
IIa
events detected (< 60mg/dl) during Baseline: 10.0 ± 0.7% vs. 9.0 ± 1.2%
study month
(p > 0.05)
5) Insulin dosage changes during
the month study
Small numbers
Supported by MiniMed
Inc
1 months after intervention: 9.5 ± 0.9% vs.
8.8 ± 0.4% (p < 0.01)
3 months after intervention: 8.8 ± 0.3% vs.
8.4 ± 0.2% (p > 0.05)
4) 12.8 ± 1.6 vs. 6.7 ± 1.1
Insulin dosage adjustment
performed by telephone
5) 11.5 ± 1.5 vs. 5.2 ± 0.9
CGMS sensor used for 3 days HbA1c
every 2 weeks, CGMS profile
used to adjust insulin therapy
at follow-up visits every 6
weeks
7.31 vs. 7.65%, p = 0.011
No description of
randomisation
versus
patients used CGMS sensor
used for 3 days every 2 weeks
but results were not available
to patients or diabetes team,
insulin therapy adjustments
were based solely on 7-point
blood glucose profiles
performed by the patients
periods
135 patients (87%
Continuous glucose
diagnosed with type monitoring system
1 diabetes)
(MiniMed®) for 3 days or
more
Mean age
40.5 ± 14.5 years
versus
USA
161
Correlation, linear regression,
Correlation: r = 0.91, slope = 0.93,
mean difference and % absolute
intercept = 14.5 mg/dl
Inc
difference scores, Clarke error grid
Mean
absolute
difference:
18.0%
±
19.8%
analysis
Clarke error grid analysis: 96.2% of the data
pairs falling within the clinically acceptable
patients’ home blood glucose
regions (A and B)
meter
2477 data points to compare
Evidence tables
Gross et al,
2000387
Study
Population
Intervention
Gross and
Mastrototaro,
2000388
62 patients (94%
Patients wore 5–10
diagnosed with type continuous glucose
1 diabetes)
monitoring sensors
(MiniMed®) sequentially over
Mean age 44 ± 11
a period of 15–20 days
(SD) years
versus
USA
home blood glucose testing
(Accu-Chek®, Advantage®
meter)
Outcomes
Results
Comments
1) Adverse events
2) Correlation coefficient
1) 7/415 devices were reported to cause
adverse events, all involved mild irritation of Inc
the sensor insertion site
3) Average difference
2) 0.92
4) Category agreement (low, in
target, high)
3) Average difference –5.4 ± 44.2 mg/dl,
average percent difference 0.3%
(–0.3% ± 32.4%)
Design
EL
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
4) Category agreement 87% of the analysed
pairs, 2 recordings were in extreme
disagreement
Patients were asked to
perform 11 blood glucose
meter measurements each
day – before each meal, 1
and 2 hours after and at
bedtime (sensor tested for
sensitivity by testing twice
before breakfast)
415 sensors used, mean use
of sensor was 69 hours. Total
of 1153 days
Gross and
Mastrototaro,
2000388
62 patients (94%
Comparison of day of use of
diagnosed with type sensor
1 diabetes).
Numerical agreement
Mean age 44 ± 11
(SD) years
Category agreement
Mean daily correlation (median)
No difference seen in any of the outcomes, Supported by MiniMed
performance remained stable over the life of Inc
the sensor
USA
Gross and
Mastrototaro,
2000388
62 patients (94%
Comparison of person who
1) Numerical agreement
1) NS
diagnosed with type performed the insertion of the
2) Mean daily correlation (median) 2) 0.90 (0.89) vs. 0.89 (0.88), p = 0.04
1 diabetes).
device:
3) Category agreement
3) 85.3% vs. 88.7%, p = 0.06
Mean age 44 ± 11
medical professional
(SD) years
USA
versus
patient
Inc
Type 1 diabetes
162
Invasive continuous glucose monitoring (continued)
Study
Population
Intervention
Gross and
Mastrototaro,
2000388
9 patients with type Patients used continuous
1 diabetes
glucose monitoring sensors
(MiniMed®) for two 1-week
periods, changes to diet,
insulin dosage and selfmonitoring blood glucose
schedule were made as
indicated after each week of
sensor use, adjustments made
by end of week 5, follow-up
for further 10 weeks
Outcomes
Results
Comments
Design
EL
1) HbA1c (p value of change from
baseline)
1) Baseline: 9.9 ± 1.1%
Inc
Test
evaluation
comparative
study
IIa
Inc
Test
evaluation
comparative
study
IIa
Ongoing study
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
2) Daily insulin rate
3) Amount of information so
changes to care package can be
made
Week 5: 8.8 ± 1.0%, p = 0.0006
Week 10: 8.6 ± 1.2%, p = 0.019
2) Baseline: 53.2 ± 24.2 units/day
Week 5: 55.5 ± 24.0 units/day, p = 0.428
3) Comparison to self-monitoring blood
glucose: only 1/9 patients provided enough
information for care package changes to be
made, whereas with continuous glucose
monitoring all 9 patients had enough
information for changes to be made
Comparison to 4 times daily
self-monitoring blood glucose
Gross and Ter
Veer, 2000389
238 patients, 83%
Patients used continuous
with type 1 diabetes glucose monitoring sensors
(MiniMed®) for 3 days.
21% aged under 18
years
278 sensors were inserted,
resulting in 961 days of
USA
sensor use and 4015 paired
sensor and metre values
1) 0.91
2) Median absolute percent
differences
2) 12.6%
Kerr, 2001390
46 patients with
type 1 diabetes
Profile of blood glucose
performed for patients looking
at continuous glucose
monitoring sensors
(MiniMed®) and self blood
glucose monitoring
1) Mean absolute difference
between finger stick measurement
and sensor results
1) 19%
Patients used continuous
(MiniMed®):
1) Data analysed for glucose
≤ 40 mg/dl
Aged 14–70, mean
38 years
UK
Kaufman et al,
2002391
47 patients with
type 1 diabetes
2) Proportion of time the patients
were within the target glucose
concentration set between 4 and
10 mmol/l
2) Data analysed for glucose
≤ 50 mg/dl
1) For entire night: 45% vs. 22% (p = 0.15)
21:00–01:00: 33% vs. 12% (p = 0.006)
01:00–05:00: 30% vs. 17% (NS)
05:00–09:00: 17% vs. 11% (NS)
2) For entire night: 61% vs. 29% (p = 0.001)
> 100 mg/dl
21:00–01:00: 48% vs. 17% (p = 0.0004)
Monitored for a total of 167
nights
01:00–05:00: 40% vs. 21% (p = 0.56)
05:00–09:00: 27% vs. 16% (NS)
163
Evidence tables
Mean age 11.8 ± 4.6
years
bedtime blood glucose levels
of ≤ 100 mg/dl
USA
versus
2) 35%
Study
Population
Intervention
Outcomes
Results
Kaufman et al,
2001392
35 patients with
type 1 diabetes
Followed with the continuous Comparison of the number of high 120 with continuous glucose monitoring
(> 150 mg/dl) or low (< 70 mg/dl)
sensors vs. 30 with self-monitoring blood
(MiniMed®)
glucose
glucose meter
Mean age 11.8 ± 4.6
years
versus
USA
self-monitoring blood glucose
recording in logbook
Monitored for a mean of
69.5 ± 28 hours, 18.5 ± 8.0
log book recordings
Kaufman et al,
2001392
35 patients with
type 1 diabetes
3 months before, baseline
and 3 months and 6 months
after continuous glucose
Mean age 11.8 ± 4.6 monitoring sensors, and
years
patient regimen changes
reconsidered
USA
Change in HbA1c from 3 months
before to 6 months after
(mean ± SD)
3 months before: 8.7 ± 1.6%
Baseline: 8.6 ± 1.5%
3 months after: 8.4 ± 1.3%
6 months after: 8.3 ± 1.3%
Comments
Design
EL
Patients recruited if they
had problems with
HbA1c > 8% with
management problems
(n = 35) or problems with
severe or nocturnal
hypoglycaemia with
mean HbA1c ≤ 8% (n = 12)
Test
evaluation
comparative
study
IIa
Patients recruited if they
had problems with
HbA1c > 8% with
management problems
(n = 35) or problems with
severe or nocturnal
hypoglycaemia with
mean HbA1c ≤ 8% (n = 12)
Test
evaluation
comparative
study
IIa
Type 1 diabetes
164
Study
Population
Intervention
Outcomes
Schiaffini et al, 27 children with
type 1 diabetes
2002393
Continuous glucose
monitoring sensors
(MiniMed®) inserted twice at 2) Mean absolute difference
Mean age 10.4 ± 0.8 start of study and then after 6
3) HbA1c
years
weeks
4) Fructosamine
Italy
5) Mean glycaemia
events/72 hours
7) Duration of hypoglycaemic
events
Results
Comments
1) 0.91
2) 13%
3) Before adjustments to insulin dosage vs. 6
weeks later: 7.5 ± 0.5% vs. 7.6 ± 0.7%
(n = 18) (NS)
Design
EL
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
4) Before adjustments to insulin dosage vs. 6
weeks later: 330 ± 30 vs. 349 ± 24 mol/l
(n = 18), p < 0.05
5) Continuous glucose monitoring sensors vs.
standard monitoring system: 10.58 ± 1.92 vs.
10.74 ± 1.58 mmol/l (NS)
Before adjustments to insulin dosage vs. 6
weeks later: 10.25 ± 2.03 vs.
10.01 ± 2.18 mmol/l (n = 18) (NS)
6) No symptomatically severe events
occurred
Asymptomatic median hypoglycaemic
events/72 hour: 3.6 ± 2.3 vs. 0.7 ± 0.9
(n = 23), p < 0.0001
6 weeks after dosage adjustment vs. baseline
before adjustments to insulin dosage:
2.5 ± 1.7 vs. 3.9 ± 2.2 (n = 18), p < 0.05
7) 26% of children had duration of under 30
min
44% of children had duration of 30–60 min
30% of children had duration of over 60 min
Sharp and
Rainbow,
2002394
27 patients with
type 1 diabetes
Mean age 40.2,
range 20–77 years
1) Correlation between mean
sensor glucose value and HbA1c
2) Correlation with standard
deviation of sensor glucose value
and HbA1c
1) r = 0.59, p = 0.002
2) r = 0.3, p = 0.15
2 dropped out due to
patient error
Inc
165
Evidence tables
UK
Continuous glucose
monitoring sensors
(MiniMed®) mean 2.6 days
compared with HbA1c
Study
Population
Intervention
Outcomes
Results
Comments
Boland et al,
2001395
56 children with
type 1 diabetes
Continuous glucose
monitoring sensors
(MiniMed®) for 3 days, 4
finger stick self-monitored
blood glucose samples, for
monitor calibrations
1) HbA1c
1) 7.7 ± 1.4%
IIa
2) Hyperglycaemia
2) approximately 90% of peak postprandial
glucose levels after every meal were
> 180 mg/dl
2/59 had sensor replaced Test
as it failed to meet
evaluation
performance parameters comparative
study
Inc
Sponsored by Novo
Nordisk
Test
evaluation
comparative
study
IIa
Sponsored by Novo
Nordisk
Test
evaluation
comparative
study
IIa
Sponsored by Novo
Nordisk
Test
evaluation
comparative
study
IIa
Aged 2–18 years
UK
Bolinder et al,
1992396
3) Hypoglycaemia
Almost 50% were > 300 mg/dl
Records kept of food intake,
exercise, hypoglycaemic
symptoms
3) 67.8% of children recorded
hypoglycaemia (glucose < 60 mg/dl) at least
one night
Glycaemic patterns examined
32.1% of children recorded glucose
≤ 40 mg/dl
6 patients with type Continuous subcutaneous
1 diabetes
adipose glucose monitoring
sensors, dialysate samples
Aged 19–49 years
were collected in 60 min
fractions over 10 hours
Sweden
1) Absolute glucose concentration
1) Range 87–101% of blood glucose value
2) Blood glucose compared with
the adipose tissue glucose
2) r = 0.93, p < 0.01
1) Mean tissue dialysate glucose
concentration as a % of
concentration in venous plasma
1) 93% (SE = 3)
Design
EL
(microdylasis probe CAM
research AB, microinfusion
pump MiniMed®)
Bolinder et al,
1993397
17 patients with
type 1 diabetes
Continuous subcutaneous
sensors, dialysate fractions
Mean age 37 (SE 3), collected every 1 or 2 hours
range 19–53 years for 72 hours, used to compile
24-hour glucose profile
Sweden
pump MiniMed®)
Bolinder et al,
1997398
24 patients with
type 1 diabetes
Mean age 36 ± 12,
range 19–58 years
Sweden
Continuous subcutaneous
sensors, dialysate fractions
collected every 1 or 2 hours
for 72 hours
Compared with selfmonitoring blood glucose
recorded 7 times a day
pump MiniMed®)
2) Mean 24-hour tissue glucose
concentration correlation with
glycated haemoglobin
2) r= 0.62, p < 0.01
3) Before change 10.3% (0.6%) reduced to
8.5% (0.9%) 9 months after monitoring and
insulin therapy change, p < 0.01 (n = 8)
3) HbA1c decrease after insulin
therapy adjustment due to glucose
monitoring
Inconsistencies in the selfmonitoring blood glucose
compared with the continuous
microdialysis glucose recordings
4/24 patients 0–2 inconsistencies
Type 1 diabetes
166
Study
Population
Metzger et al,
2002399
11 subjects
Intervention
Outcomes
Two CGMS (MiniMed®) worn 1) Reliability of the sensor
simultaneously during a 3-day
(6 with type 1
2) Comparison of capillary glucose
period (mean of 60.4 ± 16.9
diabetes 3 with type hours each)
and simultaneous sensor readings
2 diabetes and 2
healthy subjects)
Perform at least 4 daily finger 3) Simultaneously worn sensors
compared
stick glucose measurements
Israel
during the 3-day period
Results
Comments
Design
EL
1) 18% of sensor data was discarded for
technical reasons
Not all patients had type
1 diabetes
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
3370 data points remaining
2) correlation coefficient r = 0.93
Mean difference between meter and sensor
was 0 at all levels
3) Correlation r = 0.84
69% of measurements had differences > 10%
7% of measurements had differences > 50%
Clinical evaluation of the glucose range
provided simultaneously by two sensors was
concordant for only 65% of the evaluation
period
25% of the time one sensor showed glucose
as too high, whereas the other suggested
satisfactory. 9% of the time one sensor
showed glucose as too low, whereas the
other suggested satisfactory. In 1 case one
sensor suggested glucose as too high,
whereas the other suggested glucose was too
low
Buckingham,
2003405
91 children and
young people with
type 1 diabetes
1 or 2 CGMS (MiniMed®)
1) Mean difference
worn simultaneously during a
2) Median difference
3-day period
Mean age 9.9 ± 4.1, Blood samples obtained every 3) Percent within ± 15 mg/dl of
range 3.5–17.7
hour in day, every 30 min at blood glucose monitor value
years
night and every 5 min during ≤ 75 mg/dl
meal
4) Percent within ± 20 mg/dl of
USA
blood glucose monitor value
6778 paired CGMS–blood
≥ 75 mg/dl
glucose monitoring values
1) –2.9 mg/dl (not significantly different from
0 mg/dl)
2) 2 mg/dl
3) 59%
4) 20%
5) None reported
6) 18% (8%, 34%)
5) Adverse effects
167
Evidence tables
6) Median relative absolute
difference (25th, 75th centiles)
Study
Population
Intervention
Outcomes
Results
Amin et al,
2003 406
28 children and
young people with
type 1 diabetes
CGMS (MiniMed®) worn
continuously during a 3- day
period
1) Prevalence of hypoglycaemia
(< 60 mg/dl for > 15 mins)
1) 10.1% (mean 2.6 hours per subject per
day)
2) Prevalence of nocturnal
hypoglycaemia
2) 78% hypoglycaemia seen on at least 1 of
the 3 nights
Mean age 9.8,
range 6.9–11.8
years
Comments
Design
EL
Test
evaluation
comparative
study
IIa
43% hypoglycaemia seen on at least 2 of the
3 nights
UK
Zavalkoff and 18 children, young
Polychronakos, people and young
2002407
adults with type 1
diabetes
continuously during a 3-day
period
Correlation between CGMS and
blood glucose monitor level
r = 0.7514
Test
evaluation
comparative
study
IIa
1) Difference in HbA1c level from
baseline
1) 3 months after CGMS: –0.40 ± 0.94%
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
Compared with blood glucose
Mean age 14, range monitoring 4 times a day
7–20 years
Canada
Salardi et al,
2002408
28 children, young
people and young
adults with type 1
diabetes with high
HbA1c (≥ 8%) for at
least a year or a
history of frequent
hypoglycaemia
continuously during a 3-day
period
2) Asymptomatic hypoglycaemia
Compared with blood glucose (≤ 40 mg/dl)
monitoring 4 times a day
3) Prolonged hyperglycaemia
HbA1c
(≥ 400 mg/dl)
6 months after CGMS: –0.43 ± 0.87%
2) 12/28 patients
3) 15/28 patients
Mean age
14.8 ± 4.8, range
5.7–24.8 years
Italy
Eastman et al,
2002409
66 children and
young people with
type 1 diabetes
Mean age 11.9 ± 3,
range 7–17 years
USA
CGMS (HemoCue®)
compared with hourly blood
glucose measurements for up
to 12 hours
1) Median relative absolute
difference
2) Clarke error grid
3) Adverse effects
1) 21%
2) 95% in A or B regions
97.3% in A or B regions of consensus error
grid
3) 2 strong reactions to adhesive – ‘most skin
reactions were mild’
Type 1 diabetes
168
Study
Population
Intervention
Ishikawa et al,
1998400
20 subjects (10 with Subcutaneously implanted
type 1 diabetes and microsensor, during standard
10 healthy subjects) meal test and intravenous
glucose tolerance test
Aged 19–47 years
compared with hourly plasma
glucose measurements (for
USA
waking hours), experiments
took place over 3 days
Outcomes
Results
1) Regression analysis
1) r2 = 0.75
2) Difference between sensor and
intravenous measurement
2) –0.13 ± 0.23 mmol/l (n = 546 paired
measurements)
3) Patient discomfort
95% of estimates fell within clinically
acceptable zones (A and B) of the Clarke
error grid
Comments
Design
EL
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
Test
evaluation
comparative
study
IIa
Sensor delay time 10.4 ± 2.3 min
3) No discomfort associated with wearing
sensors reported
Shichiri et al,
1986401
5 subjects (4 with
Telemetry glucose monitoring Tissue glucose concentration
type 1 diabetes and system used for 36–144 hours
one postpancreatectomised)
6–22% lower than plasma glucose
concentrations
Japan
Jungheim et al, 23 ambulatory
2001402
inpatients with
insulin-treated type
1 and type 2
diabetes
Continuous glucose
monitoring sensors (Roche
Diagnostics), for up to 72
hours
1) Adverse events
Maran et al,
2002403
70 patients with
diabetes (43 with
type 1 diabetes and
27 with type 2
diabetes)
Subcutaneous glucose sensor
(Glucoday®) measured every
3 min
1) Patient tolerance
versus
Mean age 47 ± 17
years
venous blood glucose
measured 9 times
3) % falling within A and B regions Patient discomfort during normal daily
of error grid analysis
activities: 30/70 nothing, 27/70 mild, 9/70
moderate, 0/70 severe, 0/70 very severe.
4) % bias between two
Italy
Trial length: 24-hour period
2) Intra-individual mean absolute
difference
1) No adverse effects occurred, except mild
skin irritation to the dressing tape
Supported by Roche
Diagnostics
2) Intra-individual mean absolute difference
14.8 ± 9.9% (mean ± SD)
Short letter only
1) Patient pain sensation: 24/70 nothing,
36/70 mild, 4/70 moderate, 2/70 severe,
0/70 very severe
Multicentre study
Compared with 75 capillary
blood samples
2) Correlation
2) r = 0.9, p < 0.001 (381 data pairs)
3) 97%
6.9% in the euglycemic range
(70–180 mg/dl)
11.2% in the hyperglycaemic range
(> 180 mg/dl)
169
Evidence tables
4) –2.0% in the hypoglycaemic range
(< 70 mg/dl)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Pfeiffer et al,
1993404
10 patients with
type 1 diabetes (and
10 healthy
volunteers)
Continuous glucose
Correlation
monitoring (Glucosensor
Unitec Ulm®) over the period
of an oral glucose load
Correlation of the IV and SC concentration
of glucose measured per minute was
established as 0.78–0.93
Early trial, no clinical
outcomes evaluated
Test
evaluation
comparative
study
IIa
Germany
versus
Correlation with HbA1c
r2 = 0.22, p < 0.009
Early trial, no clinical
outcomes evaluated
Test
evaluation
comparative
study
IIa
Outcomes
Results
Comments
Design
EL
1) HbA1c
1) 8.4% vs. 9.0% (no SD given), p < 0.05
Ib
2) 59 ± 14.3 vs. 56.4 ± 9.6 (fear of
hypoglycaemia scale), NS
No description of
randomisation
RCT
2) Fear of hypoglycaemia
fingertip blood glucose
measurements
Trial length: up to 27 hours
Alemzadeh
2003410
30 children and
young people with
type 1 diabetes
continuously during a three
day period
Mean age 10.5 ± 0.7 Compared with HbA1c
years
USA
Non-invasive continuous glucose monitoring
Study
Population
Intervention
Chase et al,
2003417
40 children and
young people with
type 1 diabetes
Mean age
11.9 ± 3.3, range
7–16 years
Management with noninvasive glucose monitoring 4
times a week for 3 months
and to perform blood glucose
monitoring if glucose was
≤ 70mg/dl or ≥ 300 mg/dl
(n = 40)
USA
versus
conventional blood glucose
monitoring 4 times daily in
both groups (n = 40)
3) Quality of life
4) Frequency of detection of
hypoglycaemia (blood glucose
≤ 70mg/dl)
3) 81.3 ± 11.7 vs. 79.8 ± 15.5 (quality of life
scale), NS
4) No values given, p < 0.0003
Type 1 diabetes
170
Non-invasive continuous glucose monitoring (continued)
Study
Population
Intervention
Outcomes
Results
Tamada et al,
1999414
92 patients with
type 1 or type 2
diabetes
Continuous glucose
monitoring (GlucoWatch
biographer®)
1) Mean error
1) –0.07 mmol/l (SD 1.82 mmol/l)
Mean age 42.1 (SD
15.1), aged ≥ 18
years
versus
All subjects found continuous glucose
monitoring easy but none found the device
comfortable, all found redness (1 mid, 3
strong, 1 intensive), 4/5 found tingling (2
strong, 2 moderate), 4/5 found itching (3
strong, 1 severe)
USA
invasive non-continuous
finger prick monitoring
(HemoCue® blood glucose
analyser)
Comments
Design
EL
Of the 2507 possible data
pairs, only 2167 were
2) Mean absolute error
2) 15.6%
analysed, the others were
excluded: 153 due to
3) r = 0.88
biographer shut-off and
4) Clinical significance of
4) 70% fell in region A and 96.8% fell in
missing finger values, and
differences between the two blood region A and B (A and B regions described as 187 due to predetermined
glucose measurements
therapeutically relevant)
threshold screens
Test
evaluation
comparative
study
IIa
Patient questionnaire
Test
evaluation
comparative
study
IIa
2 biographers were worn for
15 hours, 2 finger stick
glucose measurements were
performed per hour
Lenzen et al,
2002416
5 patients with type Continuous glucose
1 diabetes
biographer® provided
Mean age 47.0
interstitial glucose values at
years (SD 7.3)
20-min intervals over a 12hour period)
UK
Each participant was given 16
auto sensors to be used over
the following 3 weeks and
instructed to undertake oncedaily fingerpick capillary
blood glucose testing
Grade of skin irritation
4-hour training session
used
Small number of patients
Usable readings: 65%
No difference seen between the glucose
readings obtained and blood glucose
measurements p < 0.44
2 out of the 5 subjects were keen to
continue using the device
Evidence tables
171
Study
Population
Intervention
Garg et al,
1999415
40 patients with
type 1 diabetes
In an outpatient clinic setting: Correlation
2 continuous glucose
Mean age 30.9 ± 6.9 monitoring (GlucoWatch
years
biographer®) on each
forearm
USA
versus
capillary blood glucose
analyser (HemoCue®) (n = 28)
In home setting:
continuous glucose
biographer®)
versus
capillary blood glucose
analyser (One Touch Profile
meter®) (n = 12) for 3
consecutive days
Outcomes
Results
In clinic setting: r = 0.90, 1554 paired data
points
In home setting: r = 0.85, 204 paired data
points
36 subjects wore two biographers at the
same time: correlation r = 0.94
> 96% of biographer glucose values
determined in the clinic or home setting
were in the clinically acceptable range
Comments
Design
EL
Test
evaluation
comparative
study
IIa
Type 1 diabetes
172
Non-invasive continuous glucose monitoring (continued)
4.7
Diet
Study
Population
Intervention
Jefferson et al,
200318
paediatricians
identified as
providing care for
children with
diabetes aged under
16 years; 244
returned
questionnaire
Outcomes
Results
Comments
Design
EL
1) % of clinics where there was a
dietitian
1) 86% of clinics regularly had dietitians
attend
Survey
III
2) Was this a paediatric dietitian?
2) 76% of dietitians were paediatric
dietitians
Children and young
people cared for
n = 17 192
% make-up of total daily energy
intake:
1) At 3 months after diagnosis: 20%
Survey
III
Survey
III
UK
Virtanen et al,
2000426
38 children newly
5-day food records during 2diagnosed with type year follow-up (n = 38)
1 diabetes
compared with control
Aged < 6 years
children (n = 66)
Finland
1) Protein
2) Carbohydrates
3) Fat
4) Sucrose
5) Total energy intake compared
with control children, mean (SD)
At 24 months after diagnosis:18%, p < 0.001
At 24 months after diagnosis: 52%, p < 0.01
At 24 months after diagnosis: 30%
% of total energy intake compared At 24 months after diagnosis: 3%, no
difference
with control children:
5) Boys: 1561 (202) vs. 1656 (297) kcal,
6) Protein
p < 0.05
7) Carbohydrates
Girls: 1389 (172) vs. 1532 (221) kcal,
8) Fat
p < 0.01
9) Sucrose
6) 19% vs. 15%, p < 0.01
7) 53% vs. 50%, p < 0.05
8) 28% vs. 35%, p < 0.001
9) 3% vs. 16%, p < 0.001
66 children with
type 1 diabetes
Aged < 10 years
USA
Dietary intake data, 3 random
days, 24 hours dietary recalls
Overall mean intake of protein and
cholesterol approximated the current
recommendations
Saturated fat exceeded recommendations
Fibre was less than recommended level
10 to 40% of the sample had inadequate
intakes of vitamin D, vitamin E and zinc
173
Evidence tables
Randecker et
al, 1996427
Study
Population
Intervention
Outcomes
Results
high monounsaturated fat
(MUFA) diet (n = 12)
1) n-9 red cell phospholipid fatty
acids (RCFAs)
Aged 14–21 years
versus
2) total plasma cholesterol
Australia
control (carbohydrate) diet
(n = 11)
3) LDL cholesterol, triglycerides
1) Significant increase: 6.8% (from 14.9% to Baseline and post21.7%) (MUFA)
intervention comparison
within groups only
2) No differences
Poor compliance to diet
3) No differences
4) HbA1c
4) No differences
5) Blood pressure
5) No differences
6) Body weight
6) No differences
7) Insulin dosage
7) No differences
Donaghueet al, 23 patients with
type 1 diabetes
2000428
Comments
Design
EL
RCT
Ib–IIb
Design
EL
RCT
Ib
What is the effect of low glycaemic index dietary advice?
Study
Population
104 children and
Gilbertson et
al, 2003434 and young people with
Gilbertson et
type 1 diabetes
al, 2001435
Aged 8–13 years
Australia
Intervention
Outcomes
Flexible low glycaemic index 1) HbA1c
dietary advice (n = 50)
2) Rates of excessive
versus
hypoglycaemia (> 15 episodes per
month)
carbohydrate exchange
dietary advice (n = 33)
(episodes per month)
4) Hyperglycaemic episodes
(episodes per month)
Results
1) 8.05 ± 0.95% vs. 8.61 ± 1.37%, p = 0.05
2) 35% vs. 66%, p = 0.006
3) 11.2 ± 9.8 vs. 16.8 ± 11.8, p = 0.06
4) 6.9 ± 6.8 vs. 5.8 ± 5.5, p = 0.37
5) No differences
Dietary fat: 34.2 ± 6.7% vs. 33.5 ± 5.6% of
energy, p = 0.65
5) Long-term macronutrient intake Carbohydrate: 48.6 ± 6.5% vs. 48.8 ± 5.4%
measured by 3-day food diary 12 of energy, p = 0.86
months after advice
Protein: 17.3 ± 3.7% vs. 17.6 ± 2.5% of
energy, p = 0.61
Total sugar: 19.5 ± 6.%1 vs. 17.7 ± 5.6% of
total energy
Total fibre: 22.5 ± 6.5 vs. 20.2 ± 5.0 g/day
Comments
Type 1 diabetes
174
What is the effect of an increased monounsaturated fat diet in people with type 1 diabetes?
How well do children adhere to dietary prescriptions?
Study
Population
Intervention
Outcomes
Schmidt et al,
1992436
69 children and
young people with
type 1 diabetes (40
inpatient and 29
outpatient)
Intensive dietary instructions
3-day food diary within 12 months 1) Inpatient: actual 2321 ± 617 vs. prescribed
of intensive dietary advice
2125 ± 545 kcal, p = 0.0001
1) Energy
2) Protein
Aged 4–18 years
3) Carbohydrate
USA
4) Fat
5) Mean daily deviation from
prescribed exchanges
Results
Comments
Design
EL
Observational III
study
Outpatient: actual 2349 ± 625 vs. prescribed
1977 ± 409 kcal, p = 0.005
2) Inpatient: actual 19 ± 2% vs. prescribed
21 ± 2% of energy, p = 0.0001
Outpatient: actual 15 ± 5% vs. prescribed
20 ± 3% of energy, p = 0.0001
3) Inpatient: actual 42 ± 4% vs. prescribed
45 ± 4% of energy, p = 0.0001
47 ± 4% of energy, NS
4) Inpatient: actua: 39 ± 6% vs. prescribed
34 ± 3% of energy, p = 0.0001
33 ± 4% of energy, p = 0.0001
5) 23.8%, which indicates that patients
added or deleted approximately 1 in 4
prescribed exchanges
What is the effect of different protein intake on renal function in people with type 1 diabetes?
Population
Intervention
Outcomes
Rudberg et al,
1988429
16 patients with
type 1 diabetes
Usual protein diet (UPD)
(20%)
Glomerular filtration rate (GFR)
Aged 15–23 years
versus
6 normal-filtering,
10 hyperfiltering
low protein diet (LPD) (10%)
175
Sweden
Results
Significantly lower GFR:
114 ± 3 ml/min/1.73 m2 (LPD)
127 ± 4 ml/min/1.73 m2 (UPD)
Comments
Design
EL
RCT crossover Ib
Evidence tables
Study
Study
Population
Loghmani et al, 10 patients with
insulin-dependent
1991430
diabetes
Intervention
Outcomes
Results
Sucrose-free diet
1) Change in blood glucose
versus
2) Urinary glucose
Area under the glucose response curve:
Aged 7–12 years
sucrose-containing diet
USA
Comments
Design
EL
RCT crossover Ib
Sucrose-free 3672 ± 240 mg/dl per hour
(204 ± 13 mmol/l per hour converted from
mg/dl per hour) vs. sucrose-containing
3575 ± 285 mg/dl per hour (199 ± 16 mmol/l
per hour)
2) Sucrose-free 35.6 ± 7.5 vs. sucrosecontaining 34.5 ± 7.5 g/day
Wang et al,
1991431
8 insulin-dependent Oatmeal alone (OM)
diabetes patients
versus
Aged 7–16 years
oatmeal + sucrose (OMS)
USA
versus
Change in blood glucose
No significant differences
Small sample size
Area under the curve:
RCT crossover Ib
Latin square
design
OM 4868 ± 1914 vs. OMS 5911 ± 1907 vs.
OMP 7831 ± 1891 vs. OMPS
6137 ± 835 mg/dl/min
oatmeal +protein (OMP)
versus
oatmeal + protein + sucrose
(OMPS)
Trial length: 4 successive
saturdays
Rickard et al,
1998432
9 patients with type Sucrose-free (2%) diet
Change in blood glucose at 4
1 diabetes
hours
versus
Aged 11–16 years
sucrose-containing (17%) diet
USA
Schwingshandl, 24 patients with
1994433
type 1 diabetes
Aged 8–26 years
Austria
Sucrose-free diet (n = 11)
1) HbA1c
versus
2) % intake of CHO, protein and
fats
sucrose-containing (5%) diet
(n = 13)
Trial length: a mean period of
observation of 83 days (range
42–127 days)
Significant difference
Small sample size
RCT crossover Ib
Area under the glucose response curve:
37 ± 3.5 vs. 42 ± 4.7 mmol/l 4 hours
1) No significant difference: sucrose-free
9.0 ± 2.5% vs. sucrose-containing 9.1 ± 1.4%
Quasirandomised
trial
Allocation
according
which one of
the two days
available for
appointment
IIa
Type 1 diabetes
176
What is the effect of sucrose in young people with type 1 diabetes?
What is the effect of sucrose snacks in young people with type 1 diabetes?
Study
Population
Intervention
Outcomes
Wise et al,
1989437
16 patients with
type 1 diabetes
Sucrose (7%) added to snacks Mean blood glucose
(n = 8)
Aged 16–39 years
versus
USA
sucrose-free (1%) (n = 8)
Results
No significant difference:
Comments
Design
EL
RCT
Ib
RCT
Ib
Number allocated to each RCT
group unknown
Ib
RCT
Ib
8.8 vs. 7.4 nM on day 5
Whincup,
1987442
29 patients with
type 1 diabetes
Aged 3–16 years
UK
10 g carbohydrate (n = 15)
versus
no carbohydrate (n = 14)
1) Blood glucose/change in blood
glucose
2) No. of patients with nocturnal
hypoglycaemia (< 3.0 mmol/l)
1) Significant difference:
bedtime CHO +1.3 vs. no CHO –2.0 mmol/l
2) 2/10 vs. 10/11
supplement
Trial length: 24 hours
Kaufman and
Halvorson,
1995438
51 patients with
type 1 diabetes
Aged 14–22 years
USA
Detlofson et al, 14 patients with
1999439
type 1 diabetes
Evening cornstarch snack
versus
standard snack
1) Incidence of hypoglycaemic
events at midnight
2) Incidence of hyperglycaemic
events at 07:00
1) Significant difference:
6/218 vs. 30/222, p < 0.001
2) 9/218 vs. 21/222, p < 0.05
Trial length: 5 nights
Cornstarch supplementation
(n = 70 nights)
Aged 2–6 years
versus
Sweden
placebo (n = 70 nights)
% of nights with low blood
Significant difference:
glucose concentration (< 5 mmol/l)
5/70 (7.1%) vs.
crossover
16/70 (22.9%)
at bedtime
Trial length: 5 occasions each
Primavesi,
1990440
18 patients with
type 1 diabetes
Morning or afternoon snacks
(554–606 kJ)
Aged 6–17 years
versus
UK
no snacks
Mean blood glucose level
RCT
Ib
Evidence tables
177
Study
Population
Intervention
DAFNE study
group, 200295
169 patients with
Training in intensive insulin
type 1 diabetes with treatment (DAFNE) from start
moderate or poor
of study (n = 69)
glycaemic control
versus
Aged ≥ 18, mean 40
no DAFNE education for first
(SD 9) years
6 months and then training in
UK
intensive treatment (n = 72)
Outcomes
Results
Comments
1) HbA1c (mean ± SD): 8.4 ± 1.2% vs.
9.4 ± 1.3% (p < 0.0001)
DAFNE is an adult
RCT
education in flexible,
intensive insulin
management programme.
(unsure if this is really
comparing intensive vs.
standard control, it may
be comparing education
with no education)
2) Severe hypoglycaemia (in last 6
months)
2) 12/67 vs. 11/72 (p = 0.68)
3) Weight
3) 81.5 ± 16.9 vs. 77.3 ± 13.4 kg (p = 0.11)
4) Quality of life: impact of
diabetes on freedom to eat as I
wish, impact of diabetes on quality
of life, present quality of life, total
wellbeing, total satisfaction,
perceived frequency of
hyperglycaemia, perceived
frequency of hypoglycaemia
4) Impact of diabetes on freedom to eat as I
wish (+ increased positive effect): –1.8 ± 2.3
vs. –4.0 ± 2.8 (p < 0.0001)
Impact of diabetes on quality of life (+
increased positive effect): –1.6 ± 1.6 vs.
–1.9 ± 1.4 (p < 0.01)
Present quality of life (+ increased positive
effect): 1.3 ± 0.9 vs. 1.0 ± 1.1 (p = 0.095)
Total wellbeing (+ increased positive effect):
24.34 ± 5.7 vs. 21.37 ± 5.5 (p < 0.01)
Total satisfaction (+ increased positive effect):
31.58 ± 3.9 vs. 22.82 ± 6.0 (p < 0.0001)
Perceived frequency of hyperglycaemia (+
4.03 ± 1.3 (p < 0.0001)
Perceived frequency of hypoglycaemia (+
2.40 ± 1.3 (p = 0.31)
Design
EL
Ib
Type 1 diabetes
178
What is the effect of training in intensive insulin management to enable dietary freedom in people with type 1 diabetes?
Fasting and feasting
Study
Population
Salman et al,
1992446
21 children and
young people with
type 1 diabetes on
twice-daily insulin
therapy
Mean age 11.5,
range 9–14 years
Intervention
Outcomes
Results
1) Mean HbA1c levels
1) Did not alter before (mean 9.9%) or after
fasting (mean 9.8%)
2) Complications
Comments
Design
Timing of insulin changed RCT
to intermediate-acting
and short-acting insulin
2) No significant complications occurred, no before evening meal and
symptomatic hypoglycaemia, biochemical
at night, before pre-dawn
hypoglycaemia was observed in 3 children
meal short-acting insulin
(2.3, 2.5 and 2.6 mmol/l)
was given
Two patients developed hyperglycaemia (23 Evening short-acting
and 27 mmol/l at night before the pre-dawn insulin dose was
meal, associated with ketonuria)
increased to 30–42% of
EL
Ib
the intermediate-acting
insulin dose
Duration of fasting varied
from 7 to 30 days, mean
of 22.4 days
Evidence tables
179
Study
Exercise
Population
Schiffrin and
7 young people
Parikh, 1985447 with type 1 diabetes
on treatment with
CSII and multiple
daily injections
(MDI)
Intervention
Outcomes
Results
When exercise was performed without
change in usual insulin dose there was a
significant fall in blood glucose in both CSII
and MDI groups
Aged 13–18 years
Investigation into the effect of
45 min of cycle ergometer
exercise at 55% VO2 on
glucose regulation 2 hours
after morning insulin and
breakfast. Studied on 5
different days in a random
order
Canada
1. Resting/control day
MDI 65 ± 10 mg/dl (mean ± SEM) p < 0.05
compared with rest, with hypoglycaemia in
3 patients
2. Postprandial exercise
preceded by the usual dose of
insulin
preceded by half the usual
dose of insulin
preceded by two-thirds the
usual dose of insulin
without the usual preceding
dose of insulin
CSII 57 ± 5 mg/dl (mean ± SEM) p < 0.05
compared with rest, with hypoglycaemia in
4 patients
When exercise was performed with half or
two-thirds of the usual insulin dose the
plasma glucose profile observed during
exercise in both groups was not statistically
different from that observed during the rest
day
When exercise was performed without the
usual insulin dose there was significant
hyperglycaemia in both groups, p< 0.01
Study conclusions: reducing insulin dose by
50–66% in anticipation of postprandial
exercise of moderate intensity resulted in
near normal glycaemia values and prevented
hypoglycaemia
With unplanned postprandial exercise of 45
min duration the intake of 25–3 g of glucose
may prevent hypoglycaemia
Comments
Design
EL
Case–control II
study
Type 1 diabetes
180
4.8
4.8
Exercise (continued)
Study
Population
Intervention
Koivisto and
Felig, 1978448
11 adults with type
1 diabetes
Effect of leg exercise on
absorption of insulin injected
to various places in the body
(leg, abdomen or arm)
Aged 20–29 years
Outcomes
Results
Comments
Insulin disappearance from the leg increased
by 135% during first 10 min of leg exercise,
p < 0.05, and remained 50% above resting
levels after 60 min, p < 0.02
USA
Design
EL
Within-person III
comparison
Leg exercise had no effect on insulin
disappearance from the arm
Insulin disappearance from the abdomen
was reduced during the post-exercise
recovery period, p < 0.02
Arm injection reduced the hypoglycaemic
effect of exercise by 57% compared with leg
injection, p < 0.02
Abdominal injections reduced the
hypoglycaemic effect of exercise by 89%
compared with leg injection, p < 0.005
Berger et al,
1977449
Campaigne et
al, 1984450
11 male patients
3-hour bicycle ergometer test
with type 1 diabetes of comparable, mild work
and 6 healthy
intensity
controls
One group of patients with
Aged 17–33 years
moderate glycaemic control
given 2/3 of their usual
Switzerland
evening insulin dose on
preceding day and the other
in ketosis due to insulin
withdrawal due to insulin
being withheld 18 to 48
hours before test
19 children with
type 1 diabetes
30-min vigorous physical
exercise (n = 9)
Aged 5–11 years
versus
USA
In patients with moderately controlled
glycaemic control, blood glucose
concentration fell and the blood fatty acid
levels increased
IIa
RCT
Ib
In patients who were in ketosis exercise led
to increases in ketone bodies, glucagon and
cortisol levels
Significant correlations were found between
the exercise effect on blood glucose and
initial blood levels of glucose, free fatty
acids, ketone bodies and branch-chained
amino acids
1) HbA1
1) 11.3 ± 0.50% vs. 13.3 ± 0.54%, p < 0.05
2) 190 ± 32 vs. 292 ± 27mg/dl, no significant
difference (mean difference –5.7 mmol/l,
95% CI –10.3 to 1.1 mmol/l, converted from
mg/dl )
3) 50.49 ± 1.30 vs. 48.20 ± 1.61 ml/kg/min,
p < 0.01
No description of
randomisation
181
Evidence tables
3) Oxygen consumption through
control group, who performed treadmill testing and analysis of
no exercise (n = 10)
expired air
Trial length: 3 times a week
for 12 weeks
Nonrandomised
controlled
trial
Study
Exercise (continued)
Population
Huttunen et al, 32 children and
young people with
1989451
type 1 diabetes
Aged 8.2–16.9
years
Finland
Intervention
Outcomes
Results
Comments
Design
EL
Training for 1 hour per week
(n = 16)
1) HbA1c
1) 10.5 ± 2.5% vs. 9.7 ± 2.2%, no significant
difference
No description of
randomisation
RCT
Ib
versus
non-physical activities for 1
hour a week (n = 16)
2) Urine glucose
3) Oxygen consumption peak
VO2max
2) 210 ± 319 vs. 244 ± 238 mol/min/m2, no
3) 43.8 ± 8.6 vs. 42.7 ± 8.0 ml/min/kg, no
Type 1 diabetes
182
4.8
4.9
Alcohol, smoking and drugs
Alcohol in children with type 1 diabetes?
Study
Population
Intervention
Outcomes
Moriarty et al,
1993454
9 patients with type Fasted overnight, followed by Blood glucose monitoring
1 diabetes
ethanol 0.5 g/kg by
intravenous bolus
Mean age 22.2 ± 1.3 0.25 g/kg/hour
(SEM) years
versus
UK
saline
Turner et al,
2001453
6 men
Dry white wine (0.75 g/kg)
1) Blood glucose
Aged 19–51 years
versus
2) Hypoglycaemia
Results
Comments
Design
EL
No change in: glucose infusion rate needed Unknown if study was
to maintain euglycaemia, initial rate of fall of randomised
blood glucose, lowest blood glucose, rate of
One-off trial
blood glucose recovery
Small numbers
Crossover
controlled
study
IIa
1) No significant difference in evening or
overnight blood glucose levels
Crossover
controlled
study
IIa
Crossover
controlled
study
IIa
Crossover
controlled
study
IIa
Unknown if study was
randomised
Morning fasting and postprandial blood
One-off trial
glucose levels were significantly lower after
consumption of wine (postprandial peak 8.9 Small numbers
(1.7) vs. 15 (1.5) mmol/l, p < 0.01)
mineral water
2) From 10:00, 5 subjects required treatment
for hypoglycaemia after wine, however no
subjects experienced hypoglycaemia after
mineral water
Koivisto et al,
1993455
10 male patients
Ethanol 1 g/kg (vodka, red
with type 1 diabetes wine and cognac)
Mean age 34 ± 3
years
versus
water
1) Diurnal glucose profile
2) Hypoglycaemia
1) No effect of alcohol on blood glucose
injections until 10:00
randomised
2) None of the patients had hypoglycaemia
(< 3 mM) during the study
One-off trial
Small numbers
Finland
Frische et al,
1995457
9 adult patients with Alcohol 0.7 g /kg at 22:00
type 1 diabetes
versus
Mean age 36.4 ± 6.1
no alcohol
years
Perceived blood glucose (accuracy 25 ± 13% vs. 28 ± 13% (NS)
index %)
randomised
One-off trial
Small numbers
Germany
Evidence tables
183
Study
Population
Intervention
Outcomes
Results
Kerr, 1990458
7 adult men with
type 1 diabetes
Ethanol 0.75g /kg with fruit
squash
Age range 19–37
years
versus
During hypoglycaemia heart rate,
finger tremor and sweat
production
During hypoglycaemia heart rate was higher Unknown if study was
after alcohol. 86.1 ± 5.5 vs. 81.0 ± 5.5
randomised
(p < 0.01)
One-off trial
During hypoglycaemia finger tremor was less
Small numbers
marked after ethanol (p < 0.05)
fruit squash only
Hypoglycaemia awareness
Nottingham, UK
Comments
Design
EL
Crossover
controlled
study
IIa
Cohort
follow-up
IIb
During hypoglycaemia sweat production
was increased after ethanol (p < 0.05)
At blood glucose of 4.5 mmol/l, drinking
ethanol was associated with an increase in
symptom score (p < 0.01) predominately due
to increased sweating, palpitation, facial
flushing and blurred vision which was
sustained during hypoglycaemia. Symptom
score did not change significantly in the
placebo group
Baseline reaction times were similar but
slowing during hypoglycaemia was more
marked after ethanol (p < 0.05)
Moss et al,
1992459
891 patients with
Baseline and 4-year follow-up Diabetic retinopathy as defined
diabetes diagnosed examination
from stereographic fundus
before the age of 30
photography
years and taking
insulin
Average (for the previous year) alcohol
consumption, as determined by
questionnaire, was inversely associated with
prevalence of proliferative diabetic
retinopathy; OR 0.49, 95% CI 0.27 to 0.92
Aged 2–78 years
Proliferative diabetic retinopathy decreased
from 43.1% in abstainers to 25.7% in heavy
drinkers
For recent consumption (average of the week
before the follow-up examination),
proliferative diabetic retinopathy decreased
from 38.2% in abstainers to 23.3% in
moderate drinkers whereafter it increased to
28.6% in heavy drinkers. However the OR
was not significant (OR 0.63, 95% CI 0.37 to
1.09)
The analysis of drinking history shows exdrinkers have the highest prevalence of
proliferative diabetic retinopathy (43.8%).
However, it was not significantly different
from non-drinkers (40.7%) (ex-drinkers OR
1.47, 95% CI 0.46 to 4.70, current drinkers
OR 1.01, 95% CI 0.35 to 2.89)
Type 1 diabetes
184
Alcohol in children with type 1 diabetes? (continued)
Alcohol in children with type 1 diabetes? (continued)
Study
Population
Cox et al,
1996460
Intervention
Outcomes
Results
154 male patients
Survey of alcohol habits and
with type 1 diabetes metabolic control
Relationship between alcohol and
compliance with insulin regimen
F(3,86) = 4.28, p < 0.01
Mean age 63.5
years (SD 8.1)
HbA1c
Comments
Design
EL
Survey
III
Design
EL
Prospective
study
IIb
(no raw numbers given)
No relationship
USA
Smoking in children with type 1 diabetes?
Study
Population
Intervention
Doll et al,
1994462
34 439 male British
doctors
Postal questionnaire in 1951. 1) All-cause mortality
Investigating excess mortality
2) Neoplastic diseases
associated with smoking
3) Respiratory disease
Annual mortality during
Aged 35–85 years
UK
1971–1991
Outcomes
4) Vascular disease
5) All medical causes not
neoplastic, respiratory or vascular
Results
1) Current cigarette smokers 3038 per
100 000 men (n = 5280) vs. former cigarette
smokers 2113 per 100 000 men (n = 4802)
vs. lifelong non-smoking 1706 per 100 000
men (n = 2215)
Comments
smokers 384 per 100 000 men (n = 885) vs.
lifelong non-smoking 305 per 100 000 men
(n = 414)
(n = 131)
185
(n = 225)
Evidence tables
smokers 1221 per 100 000 men (n = 2761)
vs. lifelong non-smoking 1037 per 100 000
men (n = 1304)
Study
Population
Intervention
Outcomes
Gay et al,
1992463
241 patients with
type 1 diabetes,
5876 control
subjects (without
type 1 diabetes)
Survey to ascertain smokingrelated morbidity
OR for comparing smokers to non- 1) OR 1.91, 95% CI 1.12 to 3.04
smokers:
2) OR 2.86, 95% CI 1.71 to 4.77
1) Hospitalisations
3) OR 3.80, 95% CI 2.09 to 6.90
2) Sick days
Aged 18–28 years at
start of follow-up
Results
Comments
Design
EL
Survey
III
Survey
III
Survey
III
Survey
III
3) Poor health
USA
Frey et al,
1997467
155 young people
Anonymous survey
Alcohol
Smoking and drug use
Aged 10–20, mean
age 14.23 years (6%
over the age of 18)
Smoke cigarettes: never 66%, ever 34%, in
the past 12 months 27%
Use a drug: never 90%, ever 10%, in the
past 12 months 8%
USA
Shaw et al,
1993465
77 teenagers with
type 1 diabetes
Questionnaire and urine
cotinine assay
Prevalence of smoking
Aged 11–18 years,
mean age unknown
99 patients with
type 1 diabetes
Aged 15–31, mean
age 21.5 (3.9) years
Liverpool, UK
5/77 definite smokers and 2/77 probable, all
were 15 years old or more: 9%
23/77 (30%) had close friends that smoked
71% were aware that smoking increased the
risk of diabetic complications
Liverpool, UK
Masson et al,
1992466
Drink alcohol: never 61%, ever 39%, in the
past 12 months 46/155 (30)
Questionnaire and urine
cotinine assay
Prevalance of smoking Prevalence
in young adult clinic 48%466
31/99 admitted smoking
A further 17/99 had levels of
cotinine over 1g/mg suggesting
active smoking
Type 1 diabetes
186
Smoking in children with type 1 diabetes? (continued)
Study
Population
Intervention
Outcomes
Sinha et al,
1997464
100 patients with
type 1 diabetes (45
smokers and 43
smokers at start
were available for
follow-up)
Questionnaire and then
followed for 6 years and
completed a second
questionnaire
1) Retinopathy (background and
proliferative)
Aged < 45 years
Liverpool, UK
Results
Comments
At start 53 were smokers, 45 smokers at start Low power due to small
were available for follow-up. Of 45 original sample size
smokers reviewed at 6 years, 12 had
2) Neuropathy (macroalbuminuria stopped,
and macroproteinuria)
Three original non-smokers had started
3) Retinopathy and/or neuropathy smoking
4) Smoking load effect on
Microvascular complications (retinopathy,
retinopathy and/or neuropathy
and increased urine albumin excretion) were
Design
EL
Cohort study IIb
more common and more severe in the
smoking group at 6 years
1) At baseline 5/53 smokers vs. 1/47 nonsmokers, p < 0.05
After 6 years 8/45 smokers vs. 5/43 nonsmokers, p > 0.05
2) At baseline 4/53 smokers vs. 2/47 nonsmokers
3) At baseline 4/53 smokers vs. 2/47 nonsmokers
4) 12/22 heavy smokers vs. 6/18 light
smokers, p < 0.05
Wakefield et al, 223 patients with
1998468
type 1 diabetes
Aged 15–40 years
Australia
54/223 were smokers
56% indicated that they would expect to
receive no more than a little encouragement
from friends and family members to quit
Crosssectional
survey
III
Approximately one-third had concerns about
weight gain and dietary adherence was a
barrier to quitting smoking
Evidence tables
187
Study
Population
Ardron, 1988469 60 patients with
diabetes
Aged < 40, mean
age 29.1 years
Liverpool, UK
Intervention
Outcomes
Results
Comments
Design
EL
Intensive advice (talk at stop
smoking clinic, interactive
session, leaflet on how to stop
smoking, visited 2 weeks later
at home, discussion, further
information for the whole
family to read) (n = 30)
1) People who stopped smoking
1) 1 patient in the routine advice group
stopped smoking after a myocardial
infarction 6 weeks into the trial
Unknown type of
diabetes
RCT
Ib
versus
routine advice (just the talk at
stop smoking clinic as above)
(n = 30)
Follow-up at 3 and 6 months
at the stop smoking clinic
2) Reasons for not stopping
smoking
3) End tidal CO concentration
4) Urinary cotinine
No patients in the intensive advice group
stopped smoking
2) Never made a serious attempt: 29/60
patients.
The reasons for this:
Unconvinced by health hazards:13 patients
Already too restricted by diabetic treatment
regimen: 10 patients
‘Don’t know’: 6 patients
Stopped smoking for a few days but restarted
after developing a craving for cigarettes:
31/60 patients
3) Baseline: intensive advice smokers 23.6
(9.6) vs. routine advice smokers 21.4 (9.6)
l/l, NS
At 6 months: intensive advice smokers 18.2
(10.0) vs. routine advice smokers 19.4 (8.9)
l/l, NS
Change from baseline to 6 months: intensive
advice p < 0.01. No change from baseline for
routine advice
4) No change in the urinary cotinine values
Recreational drugs
No information apart from case series found on drugs
Type 1 diabetes
188
4.10 Long-distance travel
Study
Population
Intervention
Gill and
Redmond,
1993471
160 consultant
physicians running
diabetes clinics,
60/160 replied to
questionnaire
Consultants were asked to
give general advice to
travellers on twice-daily
short- and intermediate-acting
insulin
UK
Example situation 1: eastward
flight Manchester to
Singapore morning departure
Outcomes
Results
Comments
Design
EL
Great variation in advice given. Many
regimens excessively complicated, 6%
unhelpful, 14% liable to cause
hypoglycaemia, 13% to change to
‘basal–bolus’ system
Survey
III
Careful planning of insulin regimen together Unknown patient age
with monitoring maintains glycaemic control
and increases patient satisfaction during
travel
Cases series
III
Example situation 2: eastward
flight Manchester to
Singapore evening departure
Example situation 3:
westward flight London to
New York morning departure
Example situation 4:
westward flight London to
New York evening departure
Sane et al,
1990472
27 patients with
type 1 diabetes
Westward travel, normal
insulin regimen until
departure and then followed
it according to local time after
landing. Additional time due
to shift in time zone were
covered with 1 or 2 injections
of short-acting insulin with
meals on plane
189
Evidence tables
Eastward travel, after
departure took dinnertime or
bedtime dose of intermediateacting insulin or a slightly
reduced dose. In addition
they took an extra dose of
short-acting insulin (2–4 units)
before the meals on the
plane, the subsequent
morning dose intermediateacting insulin was reduced
because it was taken later
than usual
Influenza and pneumococcal vaccination in children with type 1 diabetes
Study
Population
Moss et al,
1991474
Bouter et al,
1991475
Intervention
Outcomes
Results
1210 persons with None
diabetes – ‘younger
onset’ persons
diagnosed under the
age of 30 taking
insulin
Cause of death pneumonia and
influenza
Observed 2 expected 0.26
Influence of
epidemic influenza
on hospitalisations
because of
influenza,
pneumonia and
diabetic acidosis in
patients with
diabetes mellitus
compared with
patients with
duodenal ulcer
1) Relative risk for hospitalisation
1) Epidemic years: 1976 5.7, 1978 6.2
2) Relative risk for pneumonia
Non-epidemic years: 1977 1.1, 1979 1.0
3) Relative risk for death
2) Epidemic years: 1976 25.6, 1978 25.6
None
Comments
Design
EL
Cohort study III
Standardised mortality ratio 7.6, 95% CI 0.9
to 27.4
No supporting data for
95% CI
Case–control III
No power calculation,
may be biased due to
difference in risk of
patients who accepted
immunisation to those
who did not
Cohort
III
Survey
III
Non-epidemic years: 1977 20.3, 1979 15.8
3) Epidemic years: 1976 42.4, 1978 91.8
Non-epidemic years: 1977 30.9, 1979: 31.8
Epidemic
evaluations of
influenza infection
observed in 1976
and 1978 compared
with non-epidemic
years of 1977 and
1979
Netherlands
Thornton,
2000476
63 children with
diabetes contacted
inviting then to an
influenza
immunisation
All patients offered
immunisation
Unknown age of
children
versus
Influenza reported by parents
Influenza more than 3 days: 0/40 vs. 6/23
Influenza 1 to 3 days: 4/40 vs. 0/23
Received immunisation
(n = 40)
All influenza: 4/40 vs. 6/23, OR 0.31, 95%
CI 0.08 to 1.19
no immunisation (n = 23)
UK
Wahid et al,
2001478
113 patients with
type 1 diabetes
Survey of immunisation rate
Immunisation rate
50/113 (44%) had the influenza vaccine
30/83 (36%) had the pneumococcal vaccine
Type 1 diabetes
190
4.11 Immunisation
Influenza and pneumococcal vaccination in children with type 1 diabetes (continued)
Study
Population
Intervention
Colquhoun et
al, 1997477
37 patients with
None
type 1 diabetes
admitted to hospital
during influenza
epidemic of
1989–1990 or 1993
for pneumonia,
bronchitis,
influenza, diabetic
ketoacidosis, coma
and diabetes
Outcomes
Results
State of influenza immunisation
Received during 1989 or 1993: cases 3/37,
controls 24/77
Comments
Design
EL
case–control
III
Received during two preceding seasons:
cases 3/37, controls 7/77
Neither: cases 31/37, controls 46/77
Multiple logistic regression estimated that
influenza vaccination reduced hospital
admissions by 79% (95% CI 19 to 95%)
77 control patients
on the diabetes
register not
admitted to hospital
during this time
period
Age ≤85 years
insulin-dependent:
cases 18/37,
controls 21/77
UK
Evidence tables
191
5.1
Hypoglycaemia
What is the optimum treatment of hypoglycaemic coma in children with type 1 diabetes?
Intramuscular glucagon compared with intravenous glucose
Study
Population
29 insulin-treated
Patrick and
Collier, 1990484 adult patients with
diabetes presenting
consecutively to the
accident and
emergency
department with
hypoglycaemia
diagnosed on a
capillary blood
specimen
Mean age 47 for
glucagon group and
48 years for glucose
(dextrose) group)
Intervention
Outcomes
Results
Comments
A: intramuscular glucagon
(1 mg IM)
Restoration of normal conscious
level and average duration of
hypoglycaemic coma
No significant difference in Initial plasma
glucose, glycated haemoglobin and
estimated duration of coma prior to
treatment
RCT
B: intravenous glucose (50 ml
50% IV)
Severe adverse effects
Design
EL
Ib
No details of blinding of
the study
Average duration of coma: 120 min (range
‘Normal conscious levels’
60–240 min) in glucagon-treated patients,
and 120 min (range 20–480 min) in glucose- not defined
treated patients
Only rough estimation of
coma duration was
Significantly slower recovery to normal
possible in several cases
conscious levels was seen in the glucagon-
Drugs administered to right
thigh
Additional 12.5 g of glucose
by IV was administered in
absence of recovery after 15
min
treated group compared with the glucosetreated group: glucagon 9 min (range 5–30
min) vs. glucose 3 min (range 2–15 min),
p < 0.01
Outcome of time to
normal conscious level
may not be important,
can it be related to longterm outcomes?
Two glucagon patients required
administration of additional intravenous
Unknown the type of
glucose after failure to show signs of clinical diabetes the patients were
recovery within 15 min of treatment
suffering from
Scotland
No correlation was seen between time taken
to recovery of consciousness and either
initial plasma glucose concentration or
duration of hypoglycaemia
All but 1 patient in each group reported
either partial or total loss of awareness of the
onset of hypoglycaemia
Carstens and
Adults with severe
Sprehn, 1998485 hypoglycaemia
(n = 14)
1 mg intramuscular glucagon
versus
50 ml of 50% glucose
administered intravenously
Recovery time
Recovery time ranged from 821 min for
those receiving intramuscular glucagon and
1–3 min for those receiving intravenous
glucose
RCT
the study
Ib
Type 1 diabetes
192
Chapter 5 Complications and associated conditions
Intravenous glucagon compared with intravenous glucose
Study
Population
Intervention
Outcomes
Results
Comments
Collier et al,
1987486
49 consecutive
insulin-treated adult
patients with
diabetes with
hypoglycaemic
coma referred to the
accident and
emergency
department
A: intravenous glucagon
(1 mg IV)
Time taken to return to a normal
level of consciousness, adverse
effects during treatment
Patients in the two groups were comparable
in terms of initial blood glucose, prevailing
glycaemic control, age, duration of diabetes
and duration of hypoglycaemia (1.3 (range
0.3–4.0) vs. 1.5 (0.3–9.0) hours)
RCT
Mean age 39 ± 17
for glucagon group,
40 ± 14 years for
glucose group
Scotland
B: intravenous glucose (50 ml
50% IV (25g))
Consciousness assessed and
graded as 0: normal orientation in
Additional 12.5 g of glucose time and place, 1: drowsy, 2:
by IV was administered in
maximal response to minimal
absence of recovery after 15 stimuli, 3: minimal response to
min and 30 min
maximal stimuli, and 4:
unresponsive to painful stimuli
Design
EL
Ib
the study
Estimation of coma
A significant difference was seen in the
duration was
subsequent glycaemic profiles between the
two treatment groups (no raw data provided) retrospective and may not
be very accurate
The glucagon-treated group was slower to
Outcome of time to
achieve normal conscious level compared
with the glucose-treated patients. Median
time: 6.5 min (range 2–16 min) vs. 4 min
can it be related to long(range 1–15 min) (p < 0.001)
term outcomes?
All patients returned to a normal level of
Unknown the type of
consciousness within 30 min of admission,
diabetes the patients were
but 2 patients in both groups required
suffering from
additional administration of (12.5 g IV)
glucose
Plasma glucose levels at admission or
duration of hypoglycaemia did not correlate
with the time to recovery of normal
consciousness in either group of patients
One patient received SC glucagon
administration prior to admission (plasma
glucose on arrival was 56 mg/dl compared
with mean 18 mg/dl across the groups and
consciousness level was a borderline grade
3)
Evidence tables
193
Study
Population
MacCuish et al, 99 insulin-treated
1970487
patients with
diabetes (and 1
patient on
chlorpropamide)
presenting to the
diabetic or the
accident and
emergency
department with
hypoglycaemia
established by
blood glucose level.
20 out of 99 were
20 or under years
old
Scotland
Patients were
classified into three
groups: 1. violent
and/or very
confused, 2.
minimal response to
maximal painful
stimulation, 3.
totally unresponsive
to maximal painful
stimulation
Intervention
Outcomes
Results
Comments
Randomly half were given
treatment A. and the other
half treatment B
Blood glucose estimations
40 patients responded within 15 min of
treatment of one injection of glucagon. 23
had been given glucagon by intramuscular
and 18 by intravenous injection. No
significant difference between the two
treatments, RR = 0.84, 95% CI 0.61 to 1.17,
p = 0.31
RCT
A: intramuscular glucagon
(1 mg IM)
Restoration of normal conscious
level and average duration of
hypoglycaemic coma
Severe adverse effects
B: intravenous glucagon (1 mg
Approximate duration of
IV)
hypoglycaemia from witnesses
If after 15 min patient was
still comatose or unable to
take oral glucose the
treatment was repeated
If after 30 min patient still
remained comatose 25 g
glucose (50 ml 50% IV)
administered and further
protocol followed
1 patient responded within 15 min of
treatment with a second injection of
glucagon
36 patients (who had not responded within
15 min of the second injection of glucagon)
responded within 15 min of treatment with
intravenous glucose
4 patients responded within 15 min of
treatment with a second intravenous
injection of glucose
19 patients did not respond to the second
injection of glucose and were treated with
mannitol infusions. Two patients died.
The effective treatment level that patients
responded to was largely unrelated to the
initial grading of level of consciousness. The
level of consciousness was not always
reflected in the admission blood glucose
unless it was < 20 mg/dl
the study
Only rough estimation of
coma duration was
possible in several cases
Outcome of time to
can it be related to longterm outcomes?
Unknown the type of
diabetes the patients were
suffering from
Design
EL
Ib
Type 1 diabetes
194
Intravenous glucagon compared with intramuscular glucagon
Intravenous glucagon compared with intramuscular glucagon (continued)
Study
Population
Intervention
Namba, 1993488 15 adult patients
with type 1 diabetes 2 treatments
Mean age 51.9 ± 3.3 A: intramuscular biosynthetic
in the I.M group
glucagon (1 mg IM)
and 48.4 ± 4.1 years
B: intravenous biosynthetic
in the IV group
glucagon (1 mg IV)
Japan
Patients were all
relatively recentonset and admitted
to the respective
hospitals for the
initial education for
their diabetes and
the establishment of
control
Outcomes
Results
Comments
Design
Plasma glucose
The plasma glucose significantly increased in
both IM and IV treatments. The increment of
plasma glucose 20 min after treatment in the
IM group was 74.7 ± 13.8 mg/dl and in the
IV group 54.7 ± 8.7 mg/dl (p < 0.05), and
after 40 min. treatment the plasma glucose
level increment in the IM group was
108.8 ± 20.4 mg/dl and in the IV group
56.8 ± 10.2 mg/dl (p < 0.05)
RCT
EL
Ib
the study
Does induced
hypoglycaemia act in the
same way as accidental
hypoglycaemia?
Hypoglycaemia was
induced through
maintaining the
patients in a fasting
state and continuing
their usual diabetic
treatment
Evidence tables
195
Study
Population
Intervention
Outcomes
Results
Comments
Aman and
Wranne,
1988489
Children and young
people with
induced
hypoglycaemia
(n = 30)
Intramuscular glucagon
20 g/kg body weight
1) Blood glucose concentrations
1) No difference
RCT crossover Ib
Age intramuscular
12.2 ± 3.0,
subcutaneous:
11.8 ± 3.2 years
Sweden
versus
subcutaneous glucagon
20 g/kg body weight
2) Plasma glucagon concentrations 2) No difference
the study
Does induced
hypoglycaemia?
Design
EL
Type 1 diabetes
196
Intramuscular glucagon compared with subcutaneous glucagon
Intranasal glucagon compared with subcutaneous glucagon
Study
Population
Stenninger and 12 children with
Aman, 1993490 type 1 diabetes
Aged 7 to 12 years
Sweden
Hypoglycaemia
(blood glucose
1.6 ± 0.1 vs.
1.8 ± 0.2 mmol/l)
induced by
continuous insulin
and variable
glucose infusions
Intervention
Outcomes
Children were randomised to
1 of 2 treatments, 1 week
later the other treatment was
received
1) Plasma glucose and glucagon
1 child was excluded due to severe
levels before glucagon and at 5,
hypoglycaemia symptoms
10, 15, 20, 25, 30, 45 and 60 min
Blood glucose concentration after 15 min of
after treatment was given
treatment were almost identical during the
2) Adverse effects: degree of
two treatments (IN 1.5 ± 0.2 mmol/l and SC
nausea was graded by each child, 1.7 ± 0.2 mmol/l p > 0.05) at 30 min the
irritation of nasal mucosa scale
increase in blood glucose tended to be lower
1–10 (1 = no nausea or no nasal
in the I. N. group, but no significant
irritation to 10 = maximal nausea
difference was detected until 45 min after
or irritation)
the treatments had been given
(1.2 ± 0.2 mmol/l, IN vs. 2.2 ± 0.4 mmol/l, SC
p < 0.05)
A: intranasal glucagon
powder with DDPC, an
absorption enhancer (1 mg
IN)
B: subcutaneous glucagon
(0.5 mg SC)
Results
Comments
Design
EL
RCT crossover Ib
the study
Does induced
hypoglycaemia?
Glucagon concentration after 5 min. of
treatment there was no significantly different
between the two treatment groups (IN 1.v0.3
ng/ml and SC 1.9 ± 0.3 ng/ml p > 0.05) after
10 min. the glucagon concentrations was
significantly lower in the IN treated children
(p < 0.05). The peak glucagon concentration
1.6 ± 0.4 ng/ml was observed after 10min. in
the IN treated children and after 15 min,
2.6 ± 0.3 ng/ml, in the SC treated children.
For the remainder of the study the glucagon
concentration was twice as high in the S.C
treated children compared with the IN
treated children
2) 10/11 children given SC treatment had
severe nausea 90 min after treatment. After
IN treatment 1/11 child complained of
nausea. Mild nasal irritation was reported by
4 children. Minimal nasal irritation was
observed when the nasal mucosa was
inspected
Evidence tables
197
Study
Population
Intervention
Outcomes
Slama, 1990491
6 adult patients with Adults were randomised to 1 Plasma glucose levels
type 1 diabetes
of 2 treatments after induced
severe hypoglycaemia (blood
Aged 29.6 ± 7.7
glucose < 2.5 mmol/l)
years (mean ± SEM)
A: intranasal glucagon
France
powder pellet (1 mg IN)
Results
Comments
Design
No statistical difference in the plasma
glucose profile between the two treatment
groups (graph for initial 30 min shown, no
numerical data given)
RCT
EL
Ib
the study
Does induced
hypoglycaemia?
B: subcutaneous glucagon
(1 mg SC)
Intranasal glucagon compared with intramuscular glucagon
Study
Population
Intervention
Outcomes
Results
Comments
Pontiroli and
Calderara,
1989492
30 adult patients
with type 1
diabetes, admitted
as inpatients owing
to metabolic
decomposition
Adults were randomised to 1
of 2 treatments.
Blood glucose levels
The mean rise of blood glucose levels was
greater with IM than IN glucagon There was
1 non-responder (increase of blood glucose
levels < 10 mg/dl) with IN and 1 with IM
glucagon. It was not necessary to adopt
additional measures for at least 3 hours after
IN or IM glucagon, indicating their effect
was not transient
RCT
Italy
A: intranasal glucagon (1 mg
IN) and 15 mg sodium
glycocolate (a surfactant as a
spray solution)
B: intramuscular glucagon
(1 mg IM)
the study
Design
EL
Ib
Type 1 diabetes
198
Intranasal glucagon compared with subcutaneous glucagon (continued)
Combined treatment of intravenous glucose and intramuscular glucagon compared with intravenous glucose alone
Study
Population
Hvidberg et al, 18 adult patients
with type 1
1998493
diabetes, admitted
to accident and
emergency
department with
hypoglycaemia
Intervention
Outcomes
Results
Comments
Adults were randomised to 1
of 2 treatments
Blood glucose profile
Did not differ significantly between the 2
treatment groups
RCT
A: combined treatment of
intravenous glucose and
intramuscular glucagon
Design
EL
Ib
the study
B: intravenous glucose
Denmark
Intramuscular epinephrine compared with intramuscular glucagon
Study
Population
Monsod et al,
2001494
10 children with
type 1 diabetes
Intervention
After a night of fasting blood
glucose was allowed to drop
to 2.8 mmol/l then treatment
Mean age 11.7 ± 2.4 was administered in thigh.
years
The children were
randomised to a treatment
USA
group. After an interval of at
least 4 weeks the
investigation was repeated
with the other treatment
B: intramuscular epinephrine
0.3 mg
Results
Comments
1) Plasma glucose levels
1) Administration of glucagon rapidly
reversed the decrease in plasma glucose
(increase of 1.7 ± 0.2 mmol/l by 10 min and
2.6 ± 0.2 mmol/l by 15 min, and to
8.5 ± 1.1 mmol/l by the end of the study). In
comparison, the response to epinephrine
was significantly worse (increase of
0.4 ± 0.3 mmol/l by 10 min and
0.5 ± 0.3 mmol/l by 15 min, p < 0.01
comparison between groups). The plasma
glucose levels began to decline after 30 min
in the epinephrine group
RCT crossover Ib
2) Hypoglycaemia score by child
at 15-min intervals (0–36 point
system, 0 = no symptoms)
3) Adverse effects
2) Peak hypoglycaemia score: glucagon
6 ± 3,vs. epinephrine 10 ± 5 p < 0.01
199
3) 9/10 children complained of severe
nausea 2–6 hours after taking glucagon. The
mean heart rate increased only transiently
after receiving epinephrine
Design
EL
the study
Does induced
hypoglycaemia?
Evidence tables
A: intramuscular 1.0 mg
glucagon
Outcomes
Study
Population
Intervention
Wiethop and
Cryer, 1993482
6 adults with type 1 After a night of fasting blood
diabetes
glucose was allowed to drop
Mean age 29.1 ± 5.7 The adults were randomised
years
to a treatment group
USA
Part 1:
A: 10 g oral glucose
B: 20 g oral glucose
C: 1.0 mg subcutaneous
glucagon
D: placebo
Part 2:
Outcomes
Results
Comments
Plasma glucose levels
Part 1:
RCT crossover Ib
Compared with placebo, 10 g oral glucose,
20 g oral glucose and 1.0 mg subcutaneous
glucagon produced significant but transient
increments in plasma glucose levels, all
p < 0.05
After 10 g oral glucose, plasma glucose
increased to a peak of 5.4 ± 0.4 mM 30 min
later, glucose levels fell after 60 min
After 20 g oral glucose, plasma glucose
increased to a peak of 6.8 ± 0.7 mM 45 min
later, glucose levels fell after 60 min
(significantly different from 10 g oral glucose)
C: 40 g oral Ala
After 1.0 mg subcutaneous glucagon, plasma
glucose increased to a peak of 11.8 ± 0.8 mM
60 min later, glucose levels fell after 90 min
(significantly different from 10 g oral glucose
and 20 g oral glucose)
D: placebo
Part 2:
A: 5.0 mg oral terbutaline
B: 0.25 mg subcutaneous
terbutaline
Compared with placebo, 5.0 mg oral
terbutaline, 0.25 mg subcutaneous
terbutaline and 40 g oral Ala produced
significant sustained increments in plasma
glucose levels, all p < 0.05
After oral terbutaline, plasma glucose
increased to 4.3 ± 0.3 mM 30 min later and
then increased progressively
After subcutaneous terbutaline, plasma
glucose increased to 3.7 ± 0.1 mM 15 min
later then continued to rise (significantly
different from oral terbutaline)
After oral Ala, plasma glucose increased to
4.0 ± 0.4 mM 30 min later then rose
gradually thereafter
the study
Does induced
hypoglycaemia?
Design
EL
Type 1 diabetes
200
What is the optimum treatment of mild to moderate hypoglycaemia in children with type 1 diabetes?
What is the optimum treatment of mild to moderate hypoglycaemia in children with type 1 diabetes?
Study
Population
Intervention
Slama et al,
1990483
41 adults with type
1 diabetes
Mean age 28 ± 2
years
USA
Results
Comments
One-off trial, 12-hour
1) Plasma glucose after 10 min
overnight fast, soluble insulin (mean ± SE)
given to induce
2) Plasma glucose after 20 min
hypoglycaemia
(mean ± SE)
Participants were randomised
to receive 1 of the following: 3) Clinical relief at ≤ 10 min
4) Clinical relief at ≤ 20 min
glucose solution
1) glucose solution 3.4 ± 0.4 mmol/l
glucose tablets 3.6 ± 0.4 mmol/l
glucose gel 2.7 ± 0.4 mmol/l
sucrose solution 3.4 ± 0.2 mmol/l
sucrose tablets 3.9 ± 0.3 mmol/l
hydrolysed polysaccharide solution
3.8 ± 0.7 mmol/l
orange juice 3.2 ± 0.3 mmol/l
RCT crossover Ib
glucose tablets
2) glucose solution 3.9 ± 0.4 mmol/l
glucose tablets 4.6 ± 0.5
glucose gel 3.4 ± 0.4 mmol/l mmol/l
sucrose solution 3.7 ± 0.4 mmol/l
sucrose tablets 5.2 ± 0.6 mmol/l
hydrolysed polysaccharide solution
4.4 ± 0.7 mmol/l
orange juice 4.2 ± 0.5 mmol/l
glucose gel
sucrose solution
sucrose tablets
hydrolysed polysaccharide
solution
orange juice
Outcomes
Design
EL
the study
Does induced
hypoglycaemia?
3) glucose solution 3/6
glucose tablets 0/6
glucose gel 1/6
sucrose solution 2/6
sucrose tablets 0/5
hydrolysed polysaccharide solution 3/5
orange juice 0/6
4) glucose solution 6/6
glucose tablets 5/6
glucose gel 2/6
sucrose solution 6/6
sucrose tablets 6/6
hydrolysed polysaccharide solution 4/5
orange juice 3/6
Evidence tables
201
What is the definition of diabetic ketoacidosis in children with type 1 diabetes?
Incidence of diabetic ketoacidosis
Study
Population
Smith, 20011
10 029 children and
young people with
diabetes (previously
diagnosed)
Intervention
Outcomes
Results
Overnight admission for diabetic
ketoacidosis
4.5% recorded 1 or more admission
53.2% no admission
Comments
Design
EL
Crosssectional
(audit)
III
Crosssectional
III
Crosssectional
(audit)
III
42.3% no record either way
Aged 0 to 16 years
from 1 January to
31 December 2001
The % of children admitted for diabetic
ketoacidosis within a centre had a wide
variation, from 0% to 32%
111 sites in the UK
Edge et al,
1999496
Deaths caused by
diabetes in patients
under the age of 20
years between 1990
and 1996 in the
UK, from Office of
National Statistics
(England and Wales)
Death
116 deaths notified and 83 were caused by
diabetes. The standardised mortality ratio
was 2.3 (95% CI 1.9 to 2.9), highest for the
age group 1–4 years at 9.2 (95% CI 5.4 to
14.7)
Diabetic ketoacidosis or hyperglycaemia was
implicated in 83% (69/83) of deaths in
patients under the age of 20 years between
1990 and 1996 in the UK
Cerebral oedema caused 69% (25/36) of
deaths in children with diabetes under the
age of 12
Edge et al,
2001499
Cases of cerebral
oedema in the UK,
reported through
the British
Paediatric
Surveillance Unit
between October
1995 and
September 1998
Episodes of diabetic
ketoacidosis
reported by 225
paediatricians
identified as caring
for children with
diabetes, between
March 1996 and
February 1998
Case of cerebral oedema and
diabetic ketoacidosis
The risk of developing cerebral oedema was
6.8 per 1000 episodes of diabetic
ketoacidosis in all patients with diabetes. (34
cases of cerebral oedema and 2940 cases of
diabetic ketoacidosis)
The risk is higher in newly diagnosed
patients (11.9 per 1000 episodes) as opposed
to patients with established diabetes (3.8 per
1000)
Of the 34 cases of cerebral oedema, 8
resulted in death (24%)
Type 1 diabetes
202
5.2
Cause of diabetic ketoacidosis
Study
Population
Thompson et
al, 1995500
Morris et al,
1997501
Intervention
Outcomes
Results
28 patients 14–25
years old with 48
episodes of diabetic
ketoacidosis
Insulin error or manipulation
89 patients mean
age 16 ± 7 years
Adherence
Comments
Design
EL
Insulin error or manipulation identified in
42% (20/48 episodes) of the patients
Case series
III
Patients who obtained less insulin than their
prescribed insulin: 25/89 (28%)
Case series
III
Inverse relationship between HbA1c and the
adherence index (R2=0.39; p < 0.001)
Adherence index was inversely related to
hospital admissions for diabetic ketoacidosis
(p < 0.001)
Evidence tables
203
Treatment with continuous versus intermittent insulin
Study
Population
Intervention
Outcomes
Results
Comments
Piters et al,
1977508
26 adult
ketoacidosis
or type 2 diabetes
Patients were all treated with
intravenous insulin and were
then randomly assigned to
one of the following
regimens:
Normalisation of:
Blood glucose: no difference between groups
A and B at 6 hours, 284 ± 36 vs.
297 ± 34 mg/dl. Significantly slower changes
in blood glucose with treatment C compared
with A and B, at 6 hours C 392 ± 84 mg/dl
(p < 0.05)
RCT
Aged 35 ± 3 (SEM),
range 17–79 years
India
Inclusion criteria:
plasma glucose
> 350 mg/dl, plasma
bicarbonate
< 9 mmol/l, serum
ketone bodies
detectable by
nitroprusside test at
8-fold or greater
dilution and arterial
pH < 7.3
A: 50 units of IV insulin
initially and at 2-hour
intervals
B: continuous infusion of
10 units/hour
C: loading dose of 3 units
then 2 units/hour
The dosages were reduced
when serum glucose declined
to 300 mg/dl
Blood glucose
Bicarbonate
Ketone bodies
pH
Bicarbonate: no difference between groups A
and B at 12 hours, 17.0 ± 2.0 vs.
18.4 ± 1.7 mmol/l
Ketone bodies: no difference between groups
A and B at 12 hours, 7.3 ± 1.5 vs.
5.5 ± 0.7 mmol/l. Significantly slower
changes in ketone bodies with treatment C
compared with A and B, at 12 hours C
10.8 ± 2.9 (p < 0.05)
pH: no difference between groups A and B
at 12 hours, 7.36 ± 0.03 vs. 7.37 ± 0.02.
Significantly slower changes in pH with
treatment C compared with A and B, at 12
hours C 7 28 ± 0.04 (p < 0.05)
Treatment C had a worsening effect on the
biochemical parameters of 2 patients during
the first 6 hours; they were then swapped to
treatment A and successfully treated
No description of
selection of patients
Design
EL
Ib
Type 1 diabetes
204
What is the ideal technique for treating diabetic ketoacidosis in children with type 1 diabetes?
Treatment with IV versus IM versus SC
Study
Population
Intervention
Outcomes
Results
Comments
Fisher et al,
1977512
45 patients treated
for diabetic
ketoacidosis from
October 1975 to
September 1976
A: IV insulin administered
first as 0.33 units/kg body
weight as bolus in a
peripheral vein and then
7 units/hour insulin as a
continuous infusion in 0.9%
NaCl solution containing
2.5% human albumin. Once
plasma glucose reached
250 mg/dl, glucose in water
or in saline was substituted
for the NaCl
1) Number of hours taken to
achieve metabolic control
Clinical and biochemical profiles were
similar in all three groups at admission
Unknown how
RCT
2) Time taken to plasma glucose
< 250 mg/dl
1) No differences were seen in the number
of hours taken to achieve metabolic control
of ketoacidosis, for any of the parameters
studied
Ages: IV 37.2 years
(range 21–75), IM
40.7 (19–64), SC
44.3 (28–75)
USA
Inclusion criteria:
plasma glucose
> 300 mg/dl, blood
acetone positive at
> 1:2 dilution,
blood pH < 7.3,
serum bicarbonate
< 15 mEq/l,
glycosuria ≥ 3+
B: IM insulin administration
initiated with a loading dose
injections of 0.33 units/kg
body weight in the deltoid
with a 3.8 cm needle,
followed by 7 units soluble
insulin hourly
C: SC insulin administration
initiated with a loading dose
injections of 0.33 units/kg
body weight in the deltoid
with a 1.3 cm needle,
followed by 7 units soluble
insulin hourly
3) Total amount of fluid
replacement
4) Total amount of insulin therapy
5) Rate of fall of glucose and
ketone bodies
6) Number of patients failing to
achieving a 10% drop in plasma
glucose in the first hour
Design
EL
Ib
2) Time taken to plasma glucose < 250 mg/dl
(hours): IV 6.0 ± 1.4, IM 4.9 ± 1.1, SC
5.6 ± 0.9. Time taken to serum bicarbonate
> 15 mEq/l: IV 13.0 ± 2.2, IM 12.2 ± 1.4, SC
10.8 ± 1.1
3) No significant difference was seen for the
total amount of fluid replacement and
insulin therapy required in each group. Total
fluid (ml):
First 8 hours: IV 4976 ± 351, IM 4899 ± 274,
SC 4622 ± 334
In 24 hours: IV 8109 ± 587, IM 7874 ± 526,
SC 7249 ± 564
4) No significant difference was seen in the
total insulin to achieve glucose 250 mg/dl
(units and (units/kg)): IV 58 ± 11 (0.90 ± 0.2),
IM 57 ± 10 (0.84 ± 0.2), SC 57 ± 7
(0.87 ± 0.1), or the total insulin for total
control: IV 100 ± 11 (1.6 ± 0.2), IM 94 ± 15
(1.4 ± 0.2), SC 85 ± 8 (1.4 ± 0.18)
5) There was a significant increase in the
rate of fall of glucose and ketone bodies in
the 2 hours following IV administration
compared with SC and IM therapy. However,
these differences were not maintained after
the second hour.
205
Evidence tables
6) 9/45 patients failed to achieve a 10%
drop in plasma glucose in the first hour and
required a second loading dose of insulin: IV
2/15 (13%), IM 6/15 (40%), SC 3/15 (20%).
2 patients in the IM group required a third
loading dose to achieve an adequate initial
response (13%)
Study
Population
Intervention
Outcomes
Sacks et al,
1979513
30 patients treated
from October 1976
to September 1977
A: (IV group) porcine insulin
loading dose 0.44 units/kg
body weight injected IV
followed immediately by a
constant infusion of insulin at
7 units/hour
Time of metabolic control of
ketoacidosis
Results
Mean time from admission to emergency
room and initiation of insulin therapy: 5.9
hours (range 2.5–10) in IV group and 3.7
Endpoints decided for biochemical hours (range 1.8–8.5) in IM group.
Mean age:
variables: glucose ≤ 250 mg/dl, pH Differences in time to treatment were mainly
40.6 ± 3.9 and
≥ 7.30, bicarbonate ≥ 15 mEq/l,
due to delays in the emergency room
35.2 ± 3.4 years in
plasma acetone negative at 1:2
the IV and IM
Infusion mix was achieved by dilution
Time to endpoint for biochemical variables
groups, respectively adding 35 units of insulin to
showed considerable individual variation,
100 ml of 0.9% (wt/vol) NaCl
but did not significantly differ between the
USA
solution without albumin and
two groups. Ketoacidosis was controlled
delivered at 20 ml/hour by
after a mean of 16.6 hours in the IM group
Inclusion criteria:
infusion pump. Loading dose
and 20.6 hours in the IV group (p > 0.2)
plasma glucose
> 300 mg/dl, serum was also repeated hourly if
Insulin dose to achieve glucose < 250 mg/dl
plasma glucose failed to fall
bicarbonate
was not significantly different in the two
< 15 mEq/l, arterial by 10% or more of the initial
groups: 65 ± 13 (SEM) in the IV group and
value
pH < 7.30, serum
57 ± 7 in the IM group (corresponding to
acetone positive at B: (IM group) porcine insulin
0.99 ± 0.16 and 0.92 ± 0.13 units/kg body
> 1:2 dilution,
loading dose 0.44 units/kg
weight respectively)
glycosuria ≥ 3+
body weight, half IM and half
Insulin dose to achieve total control was not
rapid IV push. The same dose
significantly different in the two groups:
was repeated hourly if the
118 ± 14 in IV and 87 ± 9 units in IM group
plasma glucose failed to fall
(corresponding to 1.9 ± 0.20 and
by 10% or more of the initial
1.4 ± 0.15 units/kg body weight respectively)
value
1 patient in the IV group and 2 in the IM
Following a fall of 10%
group required additional loading doses of
plasma glucose of initial
insulin. No incidents of hypoglycaemia or
value, 7 units/hour was
mortality were seen in either group. Mild
injected IM.
hypokalaemia (serum potassium 3.0–3.4
Patients were followed up for
mEq/l) occurred in 5 patients in each group
24 hours. When plasma
glucose reached ≤ 250 mg/dl,
saline rehydration solutions
were switched to 5% glucose
in 0.45% or 0.9% saline. If
ketoacidosis was still
uncontrolled (pH ≥ 7.30,
bicarbonate < 15 mEq/l,
plasma acetone negative at
1:2 dilution) soluble insulin
was given every 2 hours by
the same previous route on a
sliding scale based on the
degree of hypoglycaemia
Comments
Design
EL
3 patients had not
previously been treated
with insulin
RCT
Ib
Unknown how
Type 1 diabetes
206
Treatment with low-dose insulin by IM + IV versus IV + saline
Treatment with low-dose IM versus SC + IV insulin
Study
Population
Intervention
Outcomes
Results
Onur et al,
1979511
10 children with a
history of diabetic
ketoacidosis who
had signs of
ketoacidosis (pH
< 7.35 or
bicarbonate < 15
mEq/l)
A: IM 0.1 units/kg soluble
insulin every 2 hours
Time to achieve serum glucose
< 250 mg/dl
Time to achieve serum glucose < 250 mg/dl Not randomised
was 5.3 ± 0.7 hours in the conventionally
treated group and 7.1 ± 0.6 hours in the lowdose IM group. This is approximately 50%
longer in the low-dose IM group to reach the
same control, but this was not statistically
significantly different
Aged 4–15 years
USA
B: 0.1 units/kg soluble insulin, Immunoreactive glucagon
half give SC and half IV every concentration
4 hours
Comments
Design
EL
Controlled
IIa
trial (alternate
allocation)
To achieve serum glucose < 250 mg/dl, total
insulin required was 1.2 ± 0.2 units/kg in the
conventionally treated group and
0.4 ± 0.1 units/kg in the low-dose IM group.
This was statistically significantly different,
p < 0.001. No significant difference in IV
fluids given during this time
No difference in the immunoreactive
glucagon concentration between the two
groups when serum glucose was 250 mg/dl
Evidence tables
207
Study
Population
Intervention
Outcomes
Results
Comments
Wiggam et al,
1997509
22 adults with
diabetic
ketoacidosis (pH
< 7.25, and/or
bicarbonate
< 16 mmol/l)
Extended insulin regimen (as
conventional treatment until
near-normoglycaemia when
insulin is continued at
5 units/hour until resolution of
hyperketonaemia (3hydroxybutyrate
< 0.5 mmol/l))
3-hydroxybutyrate and bicarbonate
levels during 24 hours after
attainment of nearnormoglycaemia (correction of
hyperglycaemia)
Near-normoglycaemia was achieved slightly
later with the extended insulin regimen
(5.1 ± 1.0 vs. 3.4 ± 0.4 hours, p = 0.3) and 3hydroxybutyrate was lower at this point
Unknown how
RCT
Aged 22.4 ± 2.7 for
conventional insulin
regimen, 37.1 ± 6.2 versus
years for extended
conventional insulin regimen
insulin regimen
(rehydration, electrolyte
Belfast
replacement and insulin at
5 units/hour to nearnormoglycaemia (blood
glucose ≤ 10 mmol/l) and then
at a reduced rate until clinical
recovery)
Elevation of blood 3-hydroxybutyrate
(> 0.5 mmol/l) persisted for time after
correction of hyperglycaemia: 5.9 ± 0.8 vs.
21.8 ± 3.4 hours, RR 0.30, 95% CI 0.16 to
0.54, p = 0.0004 (adjusted for serum 3hydroxybutyrate level at baseline and age:
0.42 95% CI 0.24 to 0.76, p = 0.006)
Exposure to 3-hydroxybutyrate over the 24
hours following near-normoglycaemia (ratio
extended/conventional regimens): nonadjusted: 0.43, 95% CI 0.27 to 0.69,
adjusted for serum 3-hydrobutyrate level at
baseline and age 0.58, 95% CI 0.25 to 0.94,
p = 0.03
Resolution of acidosis after nearnormoglycaemia: bicarbonate levels after
baseline (mmol/l): 6h: 16.0 ± 1.3 vs.
18.6 ± 0.6, p = 0.09; 12 hours: 16.5 ± 1.2 vs.
19.0 ± 0.7, p = 0.08. Bicarbonate levels
tended to be higher with the extended
insulin regimen, but this did not reach
statistical significance
Electrolyte concentration over the24 hours
after achievement of near-normoglycaemia:
plasma glucose was adequately controlled in
both groups, and there was no difference in
potassium levels between the two
treatments. Serum phosphate concentrations
at 2 and 6 hours after achieving
normoglycaemia (baseline) were significantly
lower in patients receiving treatment with
extended vs. conventional insulin regimens
(p = 0.003, 0.03 and 0.04 respectively)
Patients allocated to the
extended insulin regimen
were slightly older
(p = 0.07) with a longer
duration of diabetes and
slightly higher plasma
glucose and serum urea
concentrations, but these
differences were not
Design
EL
Ib
Type 1 diabetes
208
Treatment with conventional versus extended insulin regimen
Insulin bolus in low-dose insulin infusion
Study
Population
Intervention
Outcomes
Results
Lindsay and
Bolte, 1989507
38 children with
type 1 diabetes with
59 episodes of
diabetic
ketoacidosis
Bolus (0.1 units/kg of insulin,
and continuous insulin
infusion 0.1 units/kg/hour)
Serum glucose (after 1 hour of
treatment)
Severely acidotic group (pH < 7.10) (bolus
n = 14, non-bolus n = 20): mean ± SD
102 ± 54 vs. 106 ± 124 mg/dl, p > 0.1
Aged 2–17 years
non-bolus (just continuous
insulin infusion
0.1 units/kg/hour)
USA
versus
Comments
Design
Randomisation took place RCT
by children presenting on
even days of the month
receiving bolus and
Mild to moderate acidotic group (pH ≥ 7.10) children presenting on
(bolus n = 10, non-bolus n = 12): 199 ± 98 vs. odd days of the month
101 ± 130 mg/dl, p > 0.1
receiving non-bolus
treatment
EL
Ib
Evidence tables
209
Study
Population
Intervention
Outcomes
Results
Felner and
White, 2001506
90 children treated
for diabetic
ketoacidosis
(1a) Patients treated after July
1997 with new protocol, with
fluid replacement rate not
accounting for dehydration
rate (total fluids 4.35 l/m2/24
hours), and 0.675% NaCl. If
glucose was needed it was
given by disconnecting the
initial 0.45% NaCl solution
and replacing it with identical
solution with appropriate
amount of glucose to provide
4:1 glucose to insulin (n = 30)
Time acidosis resolved
Time acidosis resolved: (1a) 16.7 ± 8.4 hours
vs. (1b) 16.7 ± 8.3 hours vs. (2) 12.6 ± 4.1
hours, p = 0.01
USA
versus
(1b) Patients treated after July
1997 with new protocol, with
fluid replacement rate not
accounting for dehydration
rate (total fluids 4.35 l/m2/24
hours), and 0.675% NaCl. If
glucose was needed a
separate solution with 10g/dl
of glucose that was otherwise
identical to the initial fluid
was added and the infusion
rate of the two solutions was
varied as necessary to control
the level and rate of decrease
of serum glucose, with both
the insulin and total fluid rate
delivery remaining constant
(n = 30)
versus
(2) patients treated before July
1997 with old protocol, with
fluid replacement adjusted for
initial dehydration rate (total
fluids 5.1 l/m2/24 hours) and
0.45% NaCl (n = 30)
Incidence of cerebral oedema for
all treated in hospital (not just 60
in retrospective study)
Incidence: time period (1a) + (1b) 0.5% (1
out of an estimated 220 patients) vs. time
period (2) 0.3% (1 out of an estimated 300
patients)
Comments
Design
EL
Retrospective III
case series
Type 1 diabetes
210
Fluid replacement treatment
Fluid replacement treatment (continued)
Study
Population
Intervention
Outcomes
Mel and
Werther,
1995497
12 chidrlen and
young people with
type 1 diabetes and
diabetic
ketoacidosis
Rapid correction of
Cerebral oedema
dehydration (over 6 hours)
with fluid isotonic for sodium
from 1972 to 1992
dehydration over 24 hours
using half normal saline
Results
Comments
Incidence: 0.19% (6/3134) vs. 0.18%
(6/3373)
Design
EL
Retrospective III
case series
versus
Australia
Treatment with human versus porcine insulin
Study
Population
Intervention
Outcomes
Results
Comments
Storms et al,
1987510
21 patients with
type 1 diabetes with
confirmed diagnosis
of diabetic
ketoacidosis
Human (HI) or porcine insulin
(PI) (8 units/hour IV) in 1 ml
(40 u) Actrapid insulin, 10 ml
pasteurised human plasma
protein solution and 29 ml
0.9% NaCl by continuous
infusion
Plasma glucose levels
No significant difference in plasma glucose,
potassium and sodium levels or other
parameters of diabetic ketoacidosis were
seen between the two groups at the start of
treatment
Unknown how
RCT double
Netherlands
Potassium levels
Sodium levels
Time to reach glucose level of
12.0 mM
Time to reach pH 7.30
Time to reach glucose level of 12.0 mM was
not significantly different between the two
groups: 5.5 ± 4.0 vs. 4.7 ± 3.5 hours
211
No significant differences were seen in the
time to reach pH 7.30 between the two
groups: 7.5 ± 2.0 vs. 8.3 ± 2.0 hours
EL
Ib
Evidence tables
Individual glucose concentrations varied
considerably. A slightly slower decline in
average glucose levels during the first 7
hours of treatment in the PI group was
noted, but this difference was not statistically
significant. Interpatient variations did not
differ significantly between the groups
Design
Study
Population
Intervention
Outcomes
Results
Comments
Morris et al,
1986515
21 adults with
severe diabetic
ketoacidosis (pH
6.9–7.14)
Intravenous bicarbonate
infused over 30 min
(133.8 mEq for arterial pH of
6.9–6.99, or 89.2 mEq for
arterial pH 7.1–7.14),
repeated every 2 hours until
pH was 7.15 or more
Primary outcome: overall
rate of recovery from
diabetic ketoacidosis
Comparison of patients before and after
bicarbonate therapy: At randomisation there was
no difference in the biochemical profile between
the two groups. No significant differences were
seen in the rate of change of pH, ketone bodies,
bicarbonate levels or plasma lactate levels
RCT
Mean age
bicarbonate group
34 ± 5, control
group 28 ± 4 years
versus
USA
no bicarbonate therapy
Inclusion criteria:
plasma glucose
level ≥ 250 mg/dl,
serum testing
acetone positive at
> 1:2 dilution,
serum bicarbonate
level ≤ 15 mEq/l,
arterial pH
6.9–7.14, age ≥ 15
years
Treatment regimen for all
patients to treat diabetic
ketoacidosis (irrespective of
adjunct bicarbonate therapy):
Insulin 0.30 units/kg body
weight, half IV bolus,
1.2 units IM injection, then
hourly injections of 7 units IM
Intravenous fluid as 0.9%
saline or 0.45% saline at
250–1000 ml/hour depending
on patient’s state of hydration
Secondary outcome: number
of concomitant
complications during
treatment
No significant differences were noted in the
recovery time between the 2 groups in terms of
the number of hours required for glucose levels to
reach 250 mg/dl (13.9 mmol/l) (4.9 ± 1.3 vs.
4.2 ± 1.0 hours) or for bicarbonate to reach 15
mEq/l (21 ± 4.3 vs. 21 ± 4.0 hours)
Various chemical components of cerebrospinal
fluid also showed no statistically significant
differences in glucose, bicarbonate, pH, lactate
and ketones at three time points (0, 6–8, 10–12
hours)
There was no effect on mental status. Initially
there appeared to be a greater decline in blood
glucose levels in the control group compared with
the bicarbonate group, although this was not
Frequency of hypokalaemia (potassium
< 3.3 mEq/l) measured by decline in serum
potassium over time showed no significant
difference with or without bicarbonate
Episodes of hypoglycaemia: (0 vs. 1 episode) and
total insulin administered for complete control
(124 ± 22 vs. 92 ± 11 u) did not significantly differ
between the two groups
Intravenous fluid therapy over 8 hours did not
significantly differ in the amount of sodium
(33 ± 31 vs. 451 ± 74 mEq), chloride (333 ± 31 vs.
451 ± 74 mEq), potassium (67 ± 21 vs.
70 ± 17 mEq) or glucose (36 ± 11 vs. 40 ± 8 g)
administered in the bicarbonate or no bicarbonate
groups
Similarly, no differences were seen in electrolyte
supplementation over 24 hours of therapy, or the
amount of intravenous fluid administered in the
bicarbonate or no bicarbonate groups either at 8
hours (7.2 ± 0.96 vs. 9.4 ± 1.3 ml/kg/hour) or 24
hours (4.8 ± 0.5 vs. 5.9 ± 0.6 ml/kg/hour)
No description of
selection of patients
Design
EL
Ib
Type 1 diabetes
212
Treatment with sodium bicarbonate
Treatment with sodium bicarbonate (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Gamba et al,
1991514
20 adult patients
with severe diabetic
ketoacidosis
admitted to an
emergency room
Randomisation of patients in
groups of 4, stratified
according to arterial pH, into
2 intervention groups:
Recovery rate of
arterial pH
No significant differences were seen between groups in
patient age, weight, duration of diabetes and clinical
parameters
RCT double
Mean age
bicarbonate group
29 ± 2.0, placebo
group 28 ± 5.6 years
Mexico
Diabetic
ketoacidosis: arterial
pH < 7.15, arterial
bicarbonate
< 15 mEq/l, positive
urine ketone test
>++
A: sodium bicarbonate
(44.8 mEq in 50 ml for arterial
pH 7.10–7.14, 89 mEq in
100 ml for arterial pH
7.00–7.09, 133.5 mEq in
150 ml for arterial pH
6.90–6.99)
B: 0.9% saline solution
Dose was given over 30 min
and repeated after 2 hours if
the increment in pH was
< 0.05
Additional therapy in all
patients: IV bolus of 5 units
insulin/hour until blood
glucose < 250 mg/dl and
ketone urine <++ or negative.
On admission all patients
received 1000 ml of 0.9%
saline solution with 20 mEq
potassium chloride for 1 hour.
Further treatment was given
as necessary over the next 24
hours. 5% glucose was
instigated when blood
glucose < 250 mg/dl
Design
EL
Ib
No value given for blood
At 2 hours, arterial pH was significantly higher in the
glucose inclusion
bicarbonate-treated group, compared with the noncriterion
bicarbonate-treated group (7.24 ± 0.04 vs. 7.11 ± 0.09,
p < 0.02 95% CI 0.06 to 0.19). At 2 hours, arterial
bicarbonate was also higher in the bicarbonate than the
non-bicarbonate-treated group (6.1 ± 1.56 vs.
3.6 ± 2.0 mEq/l, difference between means 95% CI 0.8 to
4.2, p < 0.01). Changes in arterial pH and bicarbonate
were also higher in the treatment group compared with the
non-bicarbonate-treated group over the first 2 hours
(0.17 ± 0.09 vs. 0.07 ± 0.05, difference betweens means
95% CI 0.03 to 0.16, p < 0.01, and 3.2 ± 1.2 vs.
1.1 ± 1.7 mEq/l, difference between means 95% CI 0.7 to
3.5, p < 0.01, respectively)
No significant differences were seen in pCO2 or blood
glucose levels between the groups at any point throughout
the study. pO2 fell equally in both groups with no
significant difference at 2 hours (–5.2 ± 12.2 vs.
–7.2 ± 18.7, p < 0.05, 95% CI –13 to 17) or at 24 hours
(–9.9 ± 12.4 vs. –10.3 ± 15.2, p > 0.05, 95% CI –12.9 to
13.7)
Heart rates, respiratory rates, mental status, plasma
sodium, urea and mean arterial pressure did not differ
between the groups
Significantly higher levels of serum potassium were seen in
the non-bicarbonate-treated group at 24 hours (3.64 ± 0.62
vs. 2.92 ± 0.45 mEq/l, p < 0.05, 95% CI 0.16 to 1.31), but
at no other time points throughout the study
There were no deaths in either group throughout the study
213
All patients in the bicarbonate group developed
hypokalaemia, possibly due to the differences in potassium
administration. Mean sodium bicarbonate received by the
bicarbonate group was 84 ± 34 mEq
Evidence tables
There were no differences in the amount of insulin solution
or potassium received by each group in the first 2 hours.
The amount of insulin required to decrease blood glucose
to < 250 mg/dl and reduce ketosis did not differ between
the two groups. More potassium was given in the nonbicarbonate-treated group than the bicarbonate group, but
this was not significant (p > 0.10)
Study
Population
Intervention
Outcomes
Results
Fisher and
Kitabchi,
1983516
30 diabetic
ketoacidosis
patients admitted to
a clinical research
centre
8.5 mmol/hour phosphate as a
buffered potassium phosphate
salt solution providing 6 mg
inorganic phosphate over 24
hours, plus potassium (at a
rate of 12.5 mEq/hour)
Patients were followed up for 96
hours
No significant differences were seen for any No description of how
RCT
of the biochemical parameters between the randomisation took place
groups at admission, with the exception of
inorganic phosphate and lactate levels which
were elevated in the phosphate group
(p < 0.05)
Aged 32.4 ± 5.0 for
phosphate salt
group, 30.3 ± 3.5
years for nonphosphate salt
group
USA
Treatment: once
plasma glucose had
decreased to
250 mg/dl, 5%
glucose in water or
saline was
substituted for
NaCl. 0.44 units/kg
body weight of
soluble insulin was
given, regardless of
initial plasma
glucose levels and
repeated hourly
until a fall of at least
10 mg/dl of the
initial glucose
value, after which it
was substituted for
7 units IM soluble
insulin given hourly
until plasma
glucose ≥ 250 mg/dl.
After this, insulin
therapy was
continued every 2
hours until
correction of
diabetic
ketoacidosis
Time to recovery of erythrocyte
2,3-DPG levels and restoration of
oxyhaemoglobin (p50) to a ‘more
favourable’ position, clinical
versus
responses and calcium metabolism No significant difference was seen in the
time taken to achieve significant
only potassium chloride (at a
biochemical endpoints between the
rate of 12.5 mEq/hour) and no
treatment and control groups (glucose
phosphate salts
≤ 250 mg/dl: 5.4 ± 1.4 vs. 3.6 ± 0.8 hours;
bicarbonate ≥ 15 mEq/l: 12.7 ± 1.8 vs.
10.5 ± 0.8 hours; pH ≥ 7.30: 8.3 ± 1.2 vs.
11.3 ± 1.4 hours)
treatment and control groups was seen for
the average rate of decline of glucose (90.8
vs. 93.4 mg/dl/hour) and ketone bodies (0.80
vs. 0.64 mM/hour) Administration of
phosphate during the first 24 hours
prevented hypophosphataemia in the
experimental group. This advantage was lost
when phosphate therapy was discontinued
on the second day
Both groups became hypocalcaemic during
the course of therapy. Total calcium
measurements were not significantly
different in the two groups
Phosphate-treated patients appeared to have
more rapid restoration of erythrocyte 2,3DPG towards normal, although this
difference was not statistically significant
No significant difference was noted in the
p50 determinations between the two groups
There was no detectable difference in mental
alertness or other clinical signs in the
phosphate treated or control groups
Comments
Design
EL
Ib
Type 1 diabetes
214
Treatment with buffered potassium phosphate versus potassium chloride
Treatment with buffered potassium phosphate versus potassium chloride (continued)
Study
Population
Intervention
Wilson et al,
1982517
44 Patients with
diabetic
ketoacidosis (39/44
with type 1
diabetes, five
patients were newly
diagnosed)
A: no phosphate replacement Length of time in diabetic
ketoacidosis
B: 1 dose of 15 mmol
phosphate replacement
Total insulin dose required to treat
therapy (given as the sodium diabetic ketoacidosis
salt) at 4 hours
Diabetic ketoacidosis was
C: 3 doses of 15 mmol
considered corrected when the pH
phosphate replacement
was greater than 7.3, bicarbonate
therapy (given as the sodium level was above 15 mEq/l and
salt) at 2, 6 and 10 hours
serum ketones were negative
Mean age
26.8 ± 11.6, range
14–58 years
USA
Diagnosis of
diabetic
ketoacidosis: blood
pH < 7.25, plasma
glucose
> 250 mg/dl,
bicarbonate level
< 14 mEq/l, serum
ketones positive at a
dilution > 1:2
Outcomes
Results
Comments
Design
No significant difference is seen between
groups of admission biochemical data
RCT
EL
Ib
Serum phosphate was slightly different at
outset in the patients treated with sodium
phosphate compared with untreated
controls, but this difference was not
significant. At 4 hours there was no
significant difference in the serum phosphate
between the intervention groups. At 8 hours
the serum phosphate level was significantly
higher in group B treated with 1 dose of
15 mmol phosphate replacement therapy at
4 hours, compared with no phosphate
treatment. The serum phosphate level
remained raised in the group but the
increase was not significant for 16 and 24
hours. At 8, 16 and 24 hours the serum
phosphate level was significantly higher in
group C, treated with 3 doses of 15 mmol
phosphate replacement therapy at 2, 6 and
10 hours, compared with no phosphate
treatment
Time course to development of diabetic
ketoacidosis did not correlate with any
admission biochemical data. The rate of
correction of arterial blood pH and the mean
duration of time required to correct the
diabetic ketoacidosis was no different in any
of the three groups
There was no difference among the three
groups in the total amount of insulin
necessary to correct the diabetic ketoacidosis
No clinical benefit of phosphate therapy was
evident
Evidence tables
215
Study
Population
Intervention
Outcomes
Results
Yun et al,
1999518
23 patients with
type 1 diabetes
A: IV infusion of low-dose
insulin and 50 g of SC
octreotide every 6 hours
Time to recovery of clinical and
laboratory signs of ketoacidosis,
hypoglycaemia, acidosis and
ketosis
No statistically significant difference seen in Unknown how allocation Intervention
the time to recovery of hypoglycaemia:
to groups took place
study not
octreotide (n = 7) 8.9 ± 3.21 vs. no octreotide
randomised
Possibly groups were
(n = 8) 18.8 ± 13.2 hours, p = 0.089
biased as 3/7 in the
No statistically significant difference seen in octreotide group had
the time to recovery of acidosis: octreotide
alcohol as a precipitating
24.0 ± 12.6 vs. no octreotide 33.2 ± 13.9
factor whereas this was
hours, p = 0.82
not the case in the no
octreotide group
Difference seen in the time to recovery of
ketonuria: octreotide 38.0 ± 32.0 vs. no
Numbers in study do not
octreotide 68.3 ± 26.0 hours, p = 0.049,
add up: 8 patients in the
borderline statistically significant
no octreotide group were
not included in the results
but it was not explained
why
Aged 36.1 ± 10.73
with octreotide,
33.25 ± 13.4 years
with no octreotide
Korea
Patients with
stuporous or
comatose mental
state were excluded
B: IV infusion of low-dose
insulin, no octreotide
Octreotide is a synthetic longacting somatostatin
Comments
Design
EL
IIa
Type 1 diabetes
216
Treatment with somatostatin
What is the ideal method for measuring ketones in children with type 1 diabetes?
Screening for ketones
Study
Population
Intervention
Hendey et al,
1997525
114 patients with
146 occurrences of
diabetic
ketoacidosis or
ketosis presenting at
the emergency
department, seen
during 1994 and
1995
Urine ketone dip test which
can be used to screen for
ketonuria in ketoacidosis and
ketosis. Screening measured
against diabetic ketoacidosis
or ketosis in medical notes
Outcomes
Results
Design
EL
Test
evaluation
III
Comparison to the laboratory enzymatic
assay shows good correlation (r = 0.97,
p < 0.05)
Test
evaluation
III
The test has been shown to have a sensitivity
to detect ketonaemia in all patients with
diabetic ketoacidosis and diabetic ketosis of
97% (95% CI 94% to 99%), for the subgroup
of diabetic ketoacidosis sensitivity 97% (95%
CI 92% to 99%), in the subgroup of diabetic
ketosis sensitivity 98% (95% CI 89% to 99%)
Comments
99 cases of diabetic ketoacidosis, and 47
cases of diabetic ketosis
USA
96/99 cases of diabetic ketoacidosis positive
with urine ketone dip test, and 46/47 cases
of diabetic ketosis positive with urine ketone
dip test. 142/146 cases of diabetic
ketoacidosis or diabetic ketosis positive with
urine ketone dip test
5 patients with
diabetic
ketoacidosis
managed by an
hourly
intramuscular
insulin regimen
Bedside blood ketone body
Correlation
monitoring during the clinical
management of diabetic
ketoacidosis through
measurement of 3hydroxybutyrate
Byrne et al,
2000523
19 patients admitted Paired capillary and venous
with diabetic
whole blood samples were
ketoacidosis
measured using a hand-held
ketone sensor in 30 seconds
and also using an enzymatic
In all 19 subjects with diabetic ketoacidosis,
the ketone sensor accurately measured hydroxybutyrate concentrations (limits of
agreement –0.9 to 1.0 mmol/l)
Test
evaluation
III
Wallace et al,
2001521
14 patients admitted Paired capillary blood
with diabetic
samples (n = 1099) were
ketoacidosis
measured using a hand-held
ketone sensor in 30 seconds
and also using an enzymatic
The enzymatic laboratory reference method
on admission was 7.4 mmol/l (range
3.9–12.3 mmol/l)
Test
evaluation
III
The median time taken from start of
treatment for -hydroxybutyrate
concentrations to fall to below 1 mmol/l was
8.46 hours (range 5–58 hours)
217
This meter and simple hyperglycaemia data
suggest that -hydroxybutyrate ≥ 1 mmol/l
requires further action and levels >3 mmol/l
necessitate medical review, a fall of hydroxybutyrate in diabetic ketoacidosis can
indicate adequacy of treatment
Evidence tables
McBride et al,
1991522
Study
Population
Schwab et al,
1999526
697 patients
Urine dip test, serum ketone
admitted with
and electrolyte levels were
known diabetes and determined on all subjects
complaint of illness
or patients with
hyperglycaemia and
symptoms of
undiagnosed
diabetes
USA
Including 98
patients with
diabetic
ketoacidosis, and
88 with diabetic
ketosis
Intervention
Outcomes
Results
Comments
Design
EL
The anion gap and serum bicarbonate level were less
sensitive but more specific than the urine ketone dip
test for the detection of diabetic ketoacidosis and
diabetic ketosis
The anion gap was
calculated by subtracting
the chloride and
bicarbonate
concentrations from the
serum sodium
concentration with a
normal value range from
8 to 16 mEq/l
Test
evaluation
III
For the urine ketone dip test for the detection of
diabetic ketoacidosis:
Sensitivity 99% (95% CI 97% to 100%)
Specificity 69% (95% CI 66% to 73%)
Positive predictive value 35% (95% CI 29% to 41%)
Negative predictive value 100% (95% CI 99% to
100%)
For the urine ketone dip test for the detection of
diabetic ketoacidosis and ketosis:
Negative predictive value 98% (95% CI 96% to 99%)
For the anion gap test for the detection of diabetic
ketoacidosis:
For the anion gap test for the detection of diabetic
ketoacidosis and ketosis:
For the serum bicarbonate level test for the detection
of diabetic ketoacidosis:
For the serum bicarbonate level test for the detection
of diabetic ketoacidosis and ketosis:
The urine dip test and
serum ketone were tested
by laboratory personnel
Type 1 diabetes
218
Screening for ketones (continued)
Screening for ketones (continued)
Study
Population
Intervention
Outcomes
Samuelsson
and
Ludvigsson,
2002524
45 children and
young people with
type 1 diabetes
8 blood glucose
measurements a day for 2
weeks with blood glucose
and -hydroxybutyrate. Total
11189 blood glucose and
7057 -hydroxybutyrate
measures
Frequency and degree of
0.3% of the -hydroxybutyrate
ketonaemia in daily life of children measurements were ≥ 1.0 mmol/l
with diabetes
6.0% of the -hydroxybutyrate
measurements were ≥ 0.2 mmol/l (considered
as positive ketonaemia)
Mean age
11.6 ± 3.5, range
4–19 years
Results
Comments
Design
EL
Test
evaluation
III
Comments
Design
EL
Small number of cases
Case–control III
Sweden
What are the factors associated with cerebral oedema in children with type 1 diabetes?
What are the factors associated with cerebral oedema?
Study
Population
Intervention
Outcomes
Hale et al,
1997520
4 children with type
1 diabetes under 5
years old with
diabetic
ketoacidosis leading
to cerebral oedema
compared with 10
age-matched
controls with DKS
but no cerebral
oedema
Children with cerebral oedema vs. Weight: 13.0 ± 3.7 vs. 9.1 ± 2.2 kg (p < 0.05)
children with no cerebral oedema
Serum glucose: 26.3 ± 3.3 vs.
Weight
43.1 ± 19.7 mmol/l (p < 0.05)
USA
Initial serum sodium
Serum glucose
Minimum serum osmolality
Age
Body surface area
219
Initial serum bicarbonate values
Minimum serum sodium: 128.8 ± 4.4 vs.
142.2 ± 8.9 mmol/l (p < 0.02)
Minimum serum osmolality: 265.5 ± 10 vs.
296.7 ± 15.3 osm.kg (p < 0.01)
No differences in initial age, body surface
area, serum sodium or serum bicarbonate
values
Evidence tables
Minimum serum sodium
Results
Study
Population
Marcin et al,
2002519
61 children with
diabetic
ketoacidosis and
cerebral oedema
Under the age of 18
Intervention
Outcomes
Results
Logistic analysis to identify factors
associated with outcome of
cerebral oedema: children who
died or persistent vegetative state
vs. mild to moderate neurological
disability vs. normal following
cerebral oedema
Neurological depression at time of diagnosis
of cerebral oedema: coefficient 2.2 (95% CI
1.06– to 3.37), p < 0.001
Comments
Design
EL
Retrospective III
case series
High initial serum urea nitrogen
concentration: coefficient 0.086 (95% CI
0.01– to 0.16), p = 0.02
Intubation with hyperventilation to a PCO2
< 22 mmHg: 11/17 (65%) vs. 2/8 (25%) vs.
4/36 (11%), coefficient 2.1 (95% CI 0.29– to
3.84), p = 0.02
Glaser et al,
2001498
61 children with
diabetic
ketoacidosis and
cerebral oedema,
compared with
children with
diabetic
ketoacidosis and no
cerebral oedema,
181 randomly
selected and 174
children matched to
the cerebral
oedema children
Aged under 18
years
USA
Logistic analysis for the factors
associated with cerebral oedema
Occurrence of cerebral oedema: 61/6977
(0.9%) hospitalisation for diabetic
ketoacidosis
Cerebral oedema significantly associated
with (compared with randomly selected
group):
Lower initial partial pressure of arterial
carbon dioxide: RR for each decrease of
7.8 mmHg 3.4, 95% CI 1.9 to 6.3 (p < 0.001)
Higher initial serum nitrogen concentration:
RR for each increase of 9 mg/dl 1.7, 95% CI
12 to 2.5 (p = 0.003)
(these were also both significant when
compared with the control group who were
matched to the cerebral oedema patients)
Treatment with bicarbonate was associated
with cerebral oedema: RR 4.2, 95% CI 1.5
to 12.1 (p = 0.008)
Same children as in
Marcin et al 519
7.8 mmHg = 1.0 kPa
9 mg/dl nitrogen
= 25 mmol/l
Retrospective III
case series
Type 1 diabetes
220
What are the factors associated with cerebral oedema? (continued)
5.3
Surgery
No studies identified, discussion articles evaluated in text
5.4
Intercurrent illness
No studies identified, discussion articles evaluated in text
5.5
Screening for complications and associated conditions
Screening for coeliac disease and thyroid disease
Study
Population
Dretzke et al,
2002532
Symptomatic patient
populations, or
populations at a
higher risk of
developing coeliac
disease (for example
diabetes or first
degree relatives of
individuals with
coeliac disease)
Intervention
Outcomes
Results
Area under curve
Area under curve > 0.9 for all tests (all
showed reasonably good diagnosis accuracy)
Sensitivity
Specificity
Children and young
people with type 1
diabetes
Design
EL
Systematic
review of
cohorts or
controlled
trials of
screening
IIb
Guidelines
based on
systematic
review and
consensus
IV
IgA EMA tests have the highest pooled
positive likelihood ratio and lowest negative
likelihood ratio and IgA tTG tests have high
positive likelihood ratio compared with AGA
tests
76 studies
SIGN, 2001419
IgA EMA (endomysial antibodies), IgA ARA
and IgA tTG (tissue transglutaminase) stood
out as particularly good tests, followed by
IgA AGA (antigliadin antibodies) and then
IgG AGA
Comments
Screening for thyroid and coeliac
disease
Screened at onset of diabetes and ‘at
intervals’
Evidence tables
221
Study
Population
ISPAD, 200015
Screening for
complications in
children and young
people
Intervention
Outcomes
Results
Screening for:
hypothyroidism/thyrotoxicosis
Thyroid function tests at diagnosis and
annual review
Coeliac disease
Be aware with any child with GI symptoms,
unexplained poor growth or anaemia
Comments
Design
EL
Guidelines
based on
consensus/
study review
IV
Summary of
existing
guidelines
IV
Consider immunological screening close to
diagnosis and as needed thereafter
EMA (endomysial antibodies) is the most
specific test (combine it with total IgA level
to exclude false-negative)
Diagnosis by jejunal biopsy
Treatment: gluten-free diet
Badman and
Chowdhury,
2002534
Adults and young
people with type 1
diabetes and type 2
diabetes
Thyroid function tests screening
Blair and
Allgrove,
2003533
247 children and
young people with
type 1 diabetes
Thyroid function tests screening
Annual screening ‘likely’ to be beneficial to
UK
Barera et al,
2002529
274 consecutive
diabetes referred to
a Milan paediatric
clinic
159 males, mean
age 8.3 ± 4.7 years
Offered to newly diagnosed patients and to
those with symptoms suggestive of disease
Not specifically directed
towards children/young
people
Thyroid disease identified in 11/247 children Abstract only
(4.5%). All patients were asymptomatic at
time of thyroid disease diagnosis. 4 patients Children’s age not given
were diagnosed at or before diagnosis of
type 1 diabetes and in the other 7 thyroid
disease was identified 2.0 to 10.7 years after
diagnosis of type 1 diabetes
Screening for coeliac disease:
At entry: 5.5% tested positive (95% CI 3.1% On average the study lost
to 8.9%)
42 patients with each
EMA (endomysial antibodies) assay
year of follow-up
3.3% (95% CI 1.5% to 6.2%) of EMA
Intestinal biopsy
positives had hyperplastic/destructive lesions Total serum IgA levels
also measured
Overall prevalence: 3.6% (95% CI 1.7% to
6.6%) in patients with new-onset type 1
diabetes
Survival curves estimate for at least 1
positive EMA from diabetes onset and 6
years follow-up: 13.8% and biopsy
confirmed disease: 8.3%
Observational III
study
Initial
screening
with 6-year
longitudinal
follow-up,
screening
once a year
Entry between
1993 and
1997
IIb
Type 1 diabetes
222
Screening for coeliac disease and thyroid disease (continued)
Screening for coeliac disease and thyroid disease (continued)
Study
Population
Calero et al,
1996530
141 children with
type 1 diabetes
attending endocrine
clinic between
1989 and 1991
Intervention
Outcomes
Results
Screened for serum IgA antigliadin 12 patients had positive IgA AGA on ≥ 2
antibodies (AGA)
consecutive measurements and had jejunal
biopsy
Comments
Design
ELISA method used,
absorbance > 0.3 was
positive
Longitudinal IIb
observational
4/12 were diagnosed with coeliac disease
68 males, mean age
at study entry
10.5 ± 3.1 years
EL
IgA AGA
levels
measured 3–6
months later
Valencia, Spain
Barera et al,
1991531
498 patients with
type 1 diabetes and
no history of
intestinal
malabsorption from
6 paediatric centres
Screening for coeliac disease: IgA
and IgG antigliadin antibodies
(AGA)
5% had abnormal concentrations of IgA
AGA: of those, 80% had a biopsy and 3.2%
were diagnosed with coeliac disease
Observational III
IgG AGA levels were abnormal in 3% of
total sample: 2 out of 5 patients with
abnormal IgA and IgG AGA had biopsy and
both had normal histology
271 males, mean
age 12.7 years
Italy
Saukkonen et
al, 2002528
Coeliac disease
cases among 776
diabetes, from 14
hospitals in Finland
Mean age at type 1
diabetes onset
8.0 ± 4.5 years
157 patients with
type 1 diabetes
83 males, mean age
14.8, range 4–21
years
Austria
Growth
Glycaemic control (HbA1c)
Gluten-free diet
Screening for coeliac disease with
EMA (endomysial antibodies)
18 cases diagnosed
Weight-for-height increased significantly
after diagnosis and introduction of glutenfree diet (4.3 ±18.1% to 8.2 ± 15.4%,
p = 0.02)
Increase in weight-for-height inversely
correlated with changes in glycaemic
control (r = –0.57, p = 0.02)
10.2% prevalence of positive EMA (n = 16), 5
diagnosed at onset of type 1 diabetes, 11
during a mean duration of 33.6 months
Biopsy-proven coeliac disease is 5.1%; 8 of
those patients were ‘silent’ cases but were
put on a gluten-free diet
A few patients already
had jejunal biopsy before
study samples were
taken, 9/18 cases had
positive antibody test at
diabetes diagnosis
Retrospective IIb
detection of
cases already
enrolled in a
national type
1 diabetes
study, followup of 1 year
coeliac
disease
detected and
questionnaire
s sent to
families of
cases
Cohort,
followed for
at least 3
years
IIb
223
Evidence tables
Crone, 2003527
Coeliac disease (positive
gliadin/reticulin antibodies and
jejunal biopsy)
Study
Population
Sochett and
Daneman,
1999539
Screening for
diabetic
complications in
children and young
people
Intervention
Outcomes
Results
1) HbA1c
1) Every 3–4 months
2) Retinopathy
2) Annual exam (dilated pupils) starting after
age 15 or 5 years diabetes duration. Increase
frequency with positive findings
3) Blood pressure
4) Nephropathy
5) Blood lipid profile
6) Neuropathy
3) Every 3–6 months, no data to determine
when to start
4) Annual timed urine for AER (albumin
excretion rate) commencing at puberty or
3–5 years diabetes duration
Comments
Design
EL
Review article III/IV
based on
American and
Canadian
clinical
practice
recommendations
5) HDL, LDL, total cholesterol and
triglycerides within 6 months of diagnosis; if
normal repeat at mid-puberty, otherwise
screen for familial hyperlipidaemia
6) No routine screening required
Cameron,
2002540
Screening for
complications
among patients with
diabetes
1) HbA1c
Range (goal) and intervals:
2) Blood pressure
1) < 7%, perform 2–4 times/year
3) Lipid profile
2) < 130/80 mmHg, perform annually, per
visit
4) Urine microalbumin: random
spot check, 24-hour collection
5) Dilated eye exam and vision
testing
6) Foot exam: ability to sense
touch, monofilament or vibration,
structure and movement, blood
supply and skin integrity
3) Every 1–2 years:
Total cholesterol: < 200 mg/dl
HDL: > 45 mg/dl (men) and > 55 mg/dl
(women)
LDL: < 100 mg/dl
Triglycerides: < 200 mg/dl
4) Spot check: < 30 g/mg creatinine,
perform annually
24-hour: < 30 mg/24 hours
5) Negative, perform annually
6) No noted abnormalities, perform annually
Review article III/IV
based on
DCCT and
UKPDS
studies and
ADA recommendations
Type 1 diabetes
224
Screening for microvascular and other complications
Screening for microvascular and other complications (continued)
Study
Population
Intervention
Outcomes
Donaghue et
al, 1999536
937 children and
young people with
type 1 diabetes
years recruited from
a hospital-based
clinic in New South
Wales
Risk factors for 1) retinopathy and 1) Retinopathy significant risk factors:
2) nephropathy (albumin excretion
Increased duration of diabetes: OR 1.22
rate AER ≥ 20 g/min) from the
(95% CI 1.16 to 1.29)
following factors:
Older age: OR 1.13 (95% CI 1.06 to 1.21)
Duration of diabetes
Aged 6–20 years
Blood pressure
Mean diabetes
duration 5.5 years
Age
HbA1c (median over 36 months)
Cholesterol
Puberty stage
ISPAD, 200015
Screening for
complications in
children and young
people
1) Retinopathy
2) Nephropathy
3) Neuropathy
4) Growth/development
5) Foot disease
6) Dental
Results
Elevated HbA1c: OR 1.26 (95% CI 1.11 to
1.43)
2) Nephropathy significant risk factors:
Comments
Design
EL
Only significant results
reported
Study
duration:
1990–1997
IIb
Significance of elevated
blood pressure and
2 blood
cholesterol levels negated pressure
in multivariate analysis
readings
taken 5 min
apart
Retinopathy
defined as at
least 21/10
and judged
by blinded
graders
Longer diabetes duration: OR
1.19 (95% CI 1.06 to 1.33)
Older age: OR 1.37 (95% CI 1.16 to 1.62)
1) Prepubertal onset: 5 years after onset or at Other complications
age 11, then annually
included: thyroid disease,
autoimmune diseases
Postpubertal onset: 2 years after onset, then (coeliac), skin conditions,
annually
joint mobility
2) Prepubertal onset: 5 years after onset or at
age 11 or at puberty, then annually
Guidelines
based on
consensus/
study review
IV
Pubertal onset: 2 years after onset, then
annually
3) Rare among children/young people with
good glycaemic control
4) Regular monitoring and assessment
5) Rare among younger people; discuss
potential problems
6) Dental checks are part of routine health
care
SIGN, 2001419
1) Retinopathy
2) Blood pressure
3) Glycaemic control
4) Nephropathy
1) Annual retinal examinations from age 12
years
2) Annual measurements from age 12 years
3) Optimise glycaemic control towards
normal level
4) Annual 24-hour AER (albumin excretion
rate) or morning ACR (albumin-to-creatinine
ratio) testing from age 12 years
Neuropathy not
addressed
Guidelines
IIb
based on
systematic
review of
literature and
consensus
225
Evidence tables
Children and young
people with type 1
diabetes
Study
Population
Intervention
Outcomes
Newman et al, Non-systematic
review of global
1990552
childhood
cholesterol
screening
Results
Comments
Authors argue against screening cholesterol
among children; reasons based on studies
and opinion include: management by diet
carries implications for the family (e.g.
conflict), adherence, increase in noncardiovascular related events, possible
adverse outcome of labelling, screening in
adulthood just as effective in preventing
cardiovascular events
Design
EL
Nonsystematic
review
III/IV
Design
EL
Survey
III
Survey
III
Blood pressure
Study
Population
Intervention
Drummond
and Mauer,
2002551
243 children and
adults with type 1
diabetes
Investigation into the
determinants of early
structural abnormalities
Aged 10–40 years
2 renal biopsies obtained at
5-year intervals, with baseline
and follow-up measures of
renal function, blood
pressure, HbA1c plasma lipids
and albumin excretion rates
USA, Canada,
France
Roy, 2000549
725 patients with
Investigation into the risk
type 1 diabetes, 463 factors of retinopathy
with retinopathy
Aged 3–80 years
USA
Outcomes
Results
Frequency of abnormalities increased with
increasing duration of diabetes
Comments
HbA1c was not shown to be associated with
morphometric kidney abnormalities
Diastolic blood pressure was shown to be
associated with morphometric kidney
abnormalities
34% of patients with retinopathy had
systemic hypertension
Type 1 diabetes
226
Lipids – no studies examine lipid screening and potential complications among children/young people
Retinopathy
Study
Population
AAP, 1998541
Guidelines from
American Academy
of Pediatrics for
retinopathy
screening among
asymptomatic
diabetes
Intervention
Outcomes
Results
1) Initial diabetes diagnosis
1) Within the first year after diagnosis,
referral to paediatrician/paediatric
endocrinologist for counselling about early
ophthalmic check-ups
2) Initial examination
3) Follow-up examination
Recommendations
for early retinopathy
detection – The
Australian Diabetes
Society
Design
EL
Consensus
guideline
IV
Consensus
guideline
IV
2) Refer to ophthalmologist within 3–5 years
after diabetes diagnosed, if child > 9 years.
3) Annually (abnormal results warrant more
frequent visits)
Aged 0–20 years
Harper et al,
1995544
Comments
1) Initial examination
2) Follow-up
1) Diabetes onset < 30 years: examine 5
years after diagnosis; diabetes onset > 30
years: examine at diagnosis
2) Check-ups at least every 2 years, or more
in the presence of: visual symptoms,
pregnancy, or other risk factors (e.g.
hypertension)
Guidelines from
American College
of Physicians,
American Diabetes
Associations,
American Academy
of Ophthalmology
for retinopathy
screening among
asymptomatic
diabetes (aged 0–20
years)
Patients with type 1 diabetes screened
annually beginning 5 years after the onset of
diabetes, generally not indicated before the
start of puberty
Consensus
guideline
IV
Cooney and
Schachat,
1998542
Chapter review of
epidemiological,
therapeutic studies
that have
contributed to
guideline screening
Annual screening for patients with type 1
diabetes to commence 5 years after onset,
screening is not indicated prior to puberty
Review
IV
People with diabetes with persistently
elevated glucose levels or proteinuria should
have annual examinations
227
Evidence tables
ACP, 1992545
Study
Population
UKNSC,
2003543
Advisory Panel
Final Report to the
UK National
Screening
Committee
Owen et al,
1994537
Intervention
Outcomes
UK
Design
EL
Review
IV
Frequency: all patients with diabetes should
have annual examinations of the retina
(possible to reduce visits for those at lower
risk for sight-threatening retinopathy)
Preferred modality is digital imaging
90 patients with
type 1 diabetes of
an outpatient clinic,
University of Wales
Hospital, Cardiff,
diagnosed with
1 year
1998 survey of 302
paediatricians
identified as
providing care for
children with
diabetes aged under
16 years; 244
returned
questionnaire
Comments
Eligible population: all patients with either
type 1 diabetes or type 2 diabetes, aged over
12 years or post-puberty
Retinopathy (4 retinal
photographs, examined by a
diabetologist and an
ophthalmologist)
45 males, mean age
14.7 years
Jefferson et al,
200318
Results
14% developed retinopathy
When compared with those without
retinopathy, those with retinopathy: were
older (mean age 16.9 vs. 14.7 years), had
longer mean diabetes duration (10.7 vs. 6.6
years), had poorer levels of glycaemic
control (HbA1 15.1% vs. 12.6%) and
attended clinic less frequently (1.7 vs. 2.9
visits/year)
Retrospective data for
HbA1c collected from
medical records
Cohort seen 4 IIb
times a year
from 1990 to
1993;
ophthalmosco
py and fundus
photography
performed
annually
All variables achieved statistical significance
p < 0.05
paediatricians
and physicians who provide
care for children with
diabetes
1) % paediatricians
1) 87% of paediatrician respondents
Children and young
indicated that retinopathy screening was
people cared for
who provide care for children with performed on an annual basis
n = 17 192
diabetes who work in clinics
where there was retinopathy
2) 31% of consultant paediatricians reported
screening
screening all children, 59% reported
screening if the patient was over the age of
2) Was there any limit to who was 12 years and 40% reported screening if the
screened?
child was over the age of 12 years and/or
had a duration of diabetes of more than five
years
Survey
III
Type 1 diabetes
228
Retinopathy (continued)
Retinopathy (continued)
Study
Population
Intervention
Outcomes
Results
Klein et al,
1998550
634 people taking
insulin diagnosed
with diabetes before
the age of 30 years
Retinopathy:
Retinopathy:
1) 14-year rate of progression of retinopathy
1) 86%
2) Sex (male baseline) RR (95% CI)
2) Female: 0.83 (0.73 to 0.93)
USA
3) Glycated haemoglobin (5.6–9.4% baseline)
RR (95% CI)
3) 9.5–10.5%:1.37 (1.12 to 1.68)
10.6–12.0%: 1.99 (1.67 to 2.38)
12.1–19.5%: 2.64 (2.18 to 3.20)
4) Systolic blood pressure (78–110 mmHg
baseline) RR (95% CI)
5) Diastolic blood pressure (42–71 mmHg
6) Hypertension (baseline absent) RR (95% CI)
Proliferative retinopathy:
7) 37%
9) Glycated haemoglobin (5.6–9.4% baseline)
RR (95% CI)
8) Female: 0.96 (0.76 to 1.22)
9) 9.5–10.5%: 2.81 (1.77 to 4.47)
10.6–12.0%: 4.42 (2.90 to 6.72)
12.1–19.5%: 6.23 (4.21 to 9.22)
Macular oedema:
13) 14-year rate of incidence of macular
oedema
III
10) 111–120 mmHg: 1.12 (0.80 to 1.57)
121–134 mmHg: 1.56 (1.14. to 215)
135–221 mmHg: 1.06 (1.43 to 2.96)
11) 72–78 mmHg: 1.46 (1.03 to 2.06)
79–85 mmHg: 1.69 (1.20 to 2.39)
86–117 mmHg: 2.56 (1.82 to 3.58)
12) Present: 1.91 (1.41 to 2.59)
Macular oedema:
15) Glycated haemoglobin (5.6–9.4%
13) 26%
15) 9.5–10.5%: 1.90 (1.12 to 3.25)
10.6–12.0%: 3.11 (1.95 to 4.95)
12.1–19.5%: 3.37 (2.12 to 5.34)
14) Female: 0.77 (0.57 to 1.03)
16) 111–120 mmHg: 0.94 (0.64 to 1.39)
121–134 mmHg: 0.86 (0.56 to 1.30)
135–221 mmHg: 1.58 (1.04 to 2.40)
229
17) 72–78 mmHg: 1.30 (0.86 to 1.93)
79–85 mmHg: 1.16 (0.75 to 1.80)
86–117 mmHg: 1.76 (1.16 to 2.67)
18) Present: 1.40 (0.93 to 2.12)
Evidence tables
18) Hypertension (baseline absent) RR (95%
CI)
Survey
Proliferative retinopathy:
EL
5) 72–78 mmHg: 1.13 (0.96 to 1.32)
79–85 mmHg: 1.17 (0.99 to 1.38)
86–117 mmHg: 1.20 (1.00 to 1.43)
6) Present: 1.04 (0.87 to 1.26)
12) Hypertension (baseline absent) RR (95%
CI)
Design
4) 111–120 mmHg: 1.01 (0.86 to 1.17)
121–134 mmHg: 1.04 (0.89 to 1.22)
135–221 mmHg: 0.98 (0.80 to 1.20)
7) 14-year rate of progress to proliferative
retinopathy
Comments
Study
Population
Dahlquist et al, 60 children with
type 1 diabetes of
2001547
over 8 years
duration recruited
from a Stockholm
Children’s Hospital
Intervention
Outcomes
Results
Comments
Predictors of nephropathy:
1) OR of developing persistent macro- or
microalbuminuria: 45.5 (95% CI 7.8 to
264.8), PPV 93%, NPV 78%
Microalbuminuria defined Prospective
III
as AER in range
cohort
15–200 mg/min
followed for a
mean of
Endpoint measurements
29 ± 3 year;
of AER were mailed
GFR, AER,
(43/60) and the rest were blood
taken from medical
pressure and
records and estimated
HbA1c
with radioimmunoassay
measured at
(RIA) or immunobaseline and
turbidimetric methods
every second
year
1) 24-hour albumin excretion rate
AER > 15 mg/min
2) Glomerular filtration rate
GFR≥ 125 ml/min/1.73 m2
2) Crude OR: 3.8 (95% CI 0.90 to 16.1),
adjusted for duration of diabetes: 5.4 (95%
CI 1.0 to 28.6)
41 children with
type 1 diabetes
recruited from The
Hospital for Sick
Children, Toronto
Screening tests for
microalbuminuria:
Sensitivity, specificity, PPV and NPV,
respectively:
Albumin excretion rate AER (1hour)
Albumin excretion rate AER (1-hour): 87%,
81%, 53, 96
Mean age 13.5 ± 2.7
years
Albumin-to-creatinine ratio
Albumin-to-creatinine ratio: 75%, 77%, 46,
92
37 males, mean age
at onset 5.7 ± 3.0
years
Sochett and
Daneman,
1988546
Albumin concentration
Albumin concentration: 50%, 67%, 28, 84
24-hour AER correlation with 1-hour AER:
r = 0.68, p < 0.001
24-hour AER correlation with albumin-tocreatinine ratio: r = 0.41, p < 0.01
24-hour AER correlation with albumin
concentration: r = 0.36, p < 0.05
Design
Random urine samples at Crossthe clinic and home 24- sectional
hour samples were
collected
EL
III
Type 1 diabetes
230
Nephropathy
Nephropathy (continued)
Study
Population
Schultz et al,
1999548
465 children
recruited from the
Oxford Regional
Prospective Study
Intervention
Outcomes
Results
Microalbuminuria (defined by
albumin-to-creatinine ratio)
12.8% developed microalbuminuria, median Age 11 years was proxy
duration 5 years
for onset of puberty
Diabetes duration, age, sex, onset
of puberty
Children over 11 years at diagnosis had
greater mean HbA1c (mean difference:
0.5 ± 0.2%, p = 0.0005)
Aged under 16
years and diagnosed
between 1986 and
1996
Comments
Design
EL
Cohort
IIb
Survey
III
More girls developed microalbuminuria:
17% vs. 9%, p = 0.014
Cumulative probability of developing
microalbuminuria: 40% after 11 years
HbA1c worse in those who developed
microalbuminuria (mean difference:
1.1 ± 0.2%, p < 0.001)
Jefferson et al,
200318
1998 survey of 302
paediatricians
identified as
providing care for
children with
diabetes aged under
16 years; 244
returned
questionnaire
with diabetes
1) % paediatricians who provide
care for children with diabetes
who work in clinics where there
was urinary microalbumin
screening
1) 66% of paediatrician respondents
indicated that urinary microalbumin is
regularly measured at clinic
2) 26% reported that this was limited to
certain ages and/or durations of diabetes
n = 163 respondents
Children and young
people cared for
n = 17 192
2) Was there any limit to who was
screened?
UK
Evidence tables
231
Study
Population
Bodimeade,
2002554
30 parents of
diabetes from
outpatient clinic at
a London hospital
Mean age of person
with diabetes:11
years, 50% male,
majority diagnosed
with diabetes for
4–6 years
Intervention
Outcomes
Results
Comments
Parents’ knowledge and education 37% had received no foot care advice
about foot care
Paediatric diabetes nurse specialist gave
Practice guidance
advice to 10/19 parents who received
education
Design
EL
Crosssectional
survey
III
60% of the children had never had their feet
examined since diagnosis
Foot care advice given within first year of
diagnosis and then ‘reinforced’
Examinations should be performed annually
Establish a written foot care protocol to
ensure understanding
Davis et al,
1997553
307 children with
type 1 diabetes from
a diabetes clinic in
Perth, Australia
Mean age:
13.3 ± 4.6 years,
144 males, mean
duration of
diabetes: 5.1 ± 4.9
years
Controls: 232
children from local
schools, mean age
12.9 ± 4.2 years,
106 males
Reference ranges for vibration
VPT reference ranges for non-diabetic
perception threshold (VPT) using a children and young people (expressed as
biothesiometer
centiles) for the medial malleolus and great
toe; height was used as the anthropometric
variable
Children/young people with type 1 diabetes
had significantly higher VPTs than nondiabetics at both anatomical sites (p < 0.05)
9% of the group with diabetes had mean
VPT > 97th centile (developed from nondiabetic range)
Sensitivity 82%, specificity 75% when
compared with nerve conduction studies
Assume abnormal VPTs
Observational III
serve as a marker for subclinical neuropathy
Subjects included in the
analyses were older than
7 years
Type 1 diabetes
232
Neuropathy
Dental care
Study
Population
De Pommereau 85 patients with
et al, 1992556
outpatient clinics in
Paris and summer
camps
Intervention
Outcomes
Results
Comments
Gingivitis
Patients with diabetes had a higher
percentage of sites with inflammation than
non-diabetics (48% vs. 26%, p < 0.001)
Demographics of controls Case–control III
were not given
study
Authors recommend an increased
periodontal follow-up for children/young
people with type 1 diabetes
Mean age 15.1 ± 1.6
years, 42 males,
60% had diabetes
for ≥ 6 years
Design
EL
Gingivitis: scores 2 and 3
according to Loe and
Silness criteria
Controls: 38 healthy
schoolchildren, no
history of type 1
diabetes in the
family
Iughetti et al,
1999559
Children and young
people with type 1
diabetes
Recommendations for prevention
of periodontal disease
Maintain good metabolic control, diet, and
oral hygiene
Based on education (child and parent) and
regular plaque removal by a dentist twice a
year
A review of
studies
combined
with clinical
experience
IV
Brush teeth correctly, twice a day
Twetman et al, 28 children and
1992557
young people with
onset for 2 years
1) Development of dental caries
2) HbA1c
1) 46% developed caries in the follow-up
period
Observational III
study
2) HbA1c: caries inactive 6.5 ± 0.8% and
caries active 7.8 ± 0.9%, p < 0.001
Sweden
Twetman et al, 64 children and
2002558
young people with
onset for 3 years
Aged 8–15 years
Sweden
Development of dental caries
HbA1c
Patients with less good metabolic control
(> 8.0% HbA1c) exhibited higher glucose
levels in resting saliva (p < 0.05) and a
significantly higher caries incidence
(p < 0.05) compared with those with good
metabolic control
233
Evidence tables
Less good metabolic control: New cavities
41% vs. no new caries 11%, OR < 5.7
p< 0.05
Observational III
study
Study
Population
Wise et al,
1992563
Intervention
Outcomes
Results
122 children from a
diabetes clinic in
Illinois
Height
GHb < 8% associated with growth
acceleration (<capitaldelta>Z = +0.10 ± 0.03)
60 boys, mean age
at diagnosis
7.4 ± 3.4 years
GHb
Pubertal stage (Tanner)
Comments
Design
EL
5 year follow- IIb
up study;
examined
every 4
months
GHb > 16% associated with growth
deceleration (<capitaldelta>Z = –0.07 ± 0.03)
Level of growth suppression dependent on
pubertal status:
1 ≥ 10%
2 or 3 ≥ 8%
4 or 5 ≥ 16%
Du Caju et al,
1995561
46 children,
paediatric clinic,
Antwerp, Belgium
1) Height (SDS)
1) Final height in girls lower than target
height (163.7 ± 5.9 cm and 167.1 ± 5.0 cm,
2) BMI in relation to pubertal stage p < 0.05)
24 boys, aged < 10
years at diabetes
onset
Mortensen and 2873 children and
Hougaard,
young people
1997562
22 paediatric
departments from
18 countries in
Europe, Japan,
North America
Scottish Study 1609 patients from
Group, 2001560 18 centres caring
for children < 15
years in Scotland
53% male, mean
age 10.2 years,
mean duration of
type 1 diabetes 3.7
years
2) Girls tended to become obese during their
pubertal height spurt
Measured
every 6
months,
duration of
follow-up
unclear
III
Crosssectional
survey
III
BMI SDS increased from an average of
0.26 ± 0.98 to 0.69 ± 0.97
1443 boys, median age 13
years
Height (SDS)
GHb
Girls on ≥ 4 injections/day had significantly
higher BMI than those on twice-daily insulin
(0.84 ± 0.26 kg/m2, p < 0.01)
BMI
High levels of GHb (≥ 9.5%) associated with
impaired growth (SDS height), regardless of
diabetes duration, more so in boys
Glycaemic control in relation to:
Boys and girls had a significant excess in
height relative to national standards
(p < 0.001); mean height SDS 0.18 (95% CI
0.11 to 0.25) for boys and 0.12 (0.04 to
0.20) for girls
BMI
Age
BMI was also greater than that of the normal
population: boys 0.61 (0.55–0.67, girls 0.57
(0.50–0.64
After adjusting for age group, sex, duration,
broken home, family history and centre, a
negative relationship between BMI per SDS
and GHb level: –0.12 (–0.19 to –0.04),
p = 0.005
Glycaemic control significantly worse in
older children: age range 10–15 years 9.5%
vs. all other ages 8.6%; p < 0.001
Duplicate blood samples
taken at clinic visit
Significant differences
found in HbA1c levels
between centres
Observational III
study,
completed
over 3 years
Type 1 diabetes
234
Growth
Growth (continued)
Study
Population
Jacobson et al, 57 children with
type 1 diabetes
1997568
(aged 9–16 years)
recruited within 1
year of diagnosis
from 1982 to 1984
Boston, USA
Controls: acute
illness group
(n = 54) recruited
from a local HMO
(no longer ill when
studied)
Intervention
Outcomes
Results
Comments
At follow-up mean age for
both groups: 22.9 ± 2.0 years
Psychological adjustment:
Self-esteem
11% of children with type 1 diabetes had
Acute illnesses included:
symptoms suggestive of a current psychiatric fractures, infection,
illness
injuries
General (SCL-90R)
No between-group differences found
Diabetes Adjustment Scale (DAS)
Differences found with lower scores among
children with type 1 diabetes for: global selfworth and sociability (mean score 2.9 ± 0.6
vs. 3.3± 0.6, p ≤ 0.006); and physical
appearance, humour and adequate provider
(p ≤ 0.03)
2 deaths occurred in the
initial type 1 diabetes
group (n = 61)
Design
EL
10-year
follow-up
after initial
evaluation;
cohort/case–
control
IIb–III
Rate of change in total DAS score (mean:
–2.0, SD 3.6, p < 0.0001) differed
significantly from zero
Evidence tables
235
6.1
Emotional and behavioural problems
Study
Population
Jacobson et al, 61 patients enrolled
1994566
within 12 months of
diagnosis
Intervention
Outcomes
Results
Family Environment Scale (FES)
Children with the least open, expressive
Frequency of visits varied 4-year study IIb
families had greater deterioration in
period;
glycaemic control (maternal report
routine visits
<capitaldelta>R2 = 0.12, p ≤ 0.01; child report
every 2–4
<capitaldelta>R2 = 0.15, p ≤ 0.006)
months in first
2 years and
Boys from less cohesive and more conflicted
then 1 every
families showed deterioration in glycaemic
4–6 months
control (p ≤ 0.01)
HbA1c
Aged 9–16 years
Boston, USA
Mothers also
interviewed
Comments
Design
EL
Worsened over the 4-years (mean 11.1% to
12%)
Close et al,
1986567
Landolt et al,
2002569
60 children and
young people (aged
9–18 years),
Manchester
Children’s Hospital
Rutter Parental Screening
Questionnaire
28% of children had ‘appreciable
emotional/behavioural difficulties’
Birleson Depression Inventory
12% reported possible depression; all had
values of HbA1c below 10% (p < 0.01)
30 boys, mean age
14.1 ± 2.3 years
Locus control scale
Parents (37 mothers
and 36 fathers) of
38 children with
type 1 diabetes in 4
hospitals of
German-speaking
cantons in
Switzerland, within
the first 6 weeks of
diagnosis
Post-traumatic stress disorder
(PTSD)
14 girls, mean age
10.5 ± 2.5 years
Lipsitt Self-Esteem Scale
Crosssectional
III
Crosssectional
survey
III
No significant relation of HbA1c with other
psychosocial measures
Mean HbA1c
24% of mothers and 22% of fathers met full
DSM-IV PTSD criteria, only 2 families
showed full PTSD at the same time
Type 1 diabetes
236
Chapter 6 Psychological and social issues
Emotional and behavioural problems (continued)
Study
Population
Hatton et al,
1995571
82 parent families
with an infant or
toddler with
diabetes (minimum
duration 2 months)
from the provincial
clinic register of
British Columbia
Intervention
Outcomes
Results
Comments
Design
Parents’ perceptions of caring
No numbers were given; descriptive and
verbatim passages
Data subjected to
‘phenomenological’
analytical procedures
Qualitative
III
study
consisting of
a series of 14
audio-taped
interviews
Family support significantly related to %
approach coping, and % approach coping
significantly associated with depressive
symptom (p < 0.05 level)
Tested predictive
Crossframework using a LISREL sectional
model
Stress
Diagnosis, hospitalisation
Emotion
EL
Coping strategies
Age range of
children at diabetes
diagnosis: 5 weeks
to 29 months
Blankfeld et al, 52 mothers of
Family support showed an
Family Support (FES)
1996570
children with type 1 indirect relationship to
diabetes
mothers’ depressive symptoms Maternal % approach coping
(Coping Responses Inventory)
participating in a
paediatric diabetes
Depressive symptoms (Health and
management
Daily Living Form)
programme
III
Mean age of
children 11.3 ± 3.2
years, 24 boys,
mean duration of
diabetes 2.65 years
Evidence tables
237
Anxiety and depression
What is the optimum method of identifying depression in children with type 1 diabetes?
Study
Population
Lernmark et al, 62/114 eligible
children from the
1999574
diabetes clinic at
Children’s Hospital,
Stockholm
Inclusion criteria:
aged 9–18 years
with at least a 2year history of type
1 diabetes
Exclusion criteria:
mental retardation,
non-Swedish
speaking families
Median age 14
years, 25 males
Intervention
Outcomes
Results
Psychological function:
Prevalence of depression: 14.5%
Depression (The Children’s
Depressive Inventory)
Self-esteem (‘I think I am’ test),
abilities/talents, psychological
wellbeing, relations to
others/family
Fear (The Fear Survey Schedule for
children)
Adaptation to diabetes (Adaptation
to Diabetes Scale, FIAD),
monitoring, impact on daily life,
attitude to diabetes, emotional
difficulties, feelings toward
diabetes
Metabolic control (average of all
HbA1c during the previous year)
Comments
Depressive symptoms
defined as CDI cut-off
Patients with more depressive symptoms had score of ≥ 15
poor adaptation, poor self-esteem, poor
metabolic control (p < 0.01)
Regression analysis showed adaptation to
diabetes was significantly related to
metabolic control and depression
(p < 0.0001 and p = 0.002)
Design
EL
Crosssectional
survey
III
Type 1 diabetes
238
6.2
What is the optimum method of identifying depression in children with type 1 diabetes? (continued)
Study
Population
Whittemore et
al, 2002575
97 young people
attending Yale
Children’s Diabetes
Program; November
1995 to November
2000
Inclusion criteria:
aged 12–20 years,
no other illness
except treated
hypothyroidism, on
insulin for at least 1
year, recent HbA1c
in range 7.2–14%,
no severe
hypoglycaemic
events within
previous 6 months
Intervention
Outcomes
Results
Relationship between depressive
symptoms (The Children’s
Depression Inventory) and:
Prevalence of depressive symptoms at
entry:15.4%; 2-year follow-up: 10%
Age, duration of illness
Comments
Depressive symptoms
defined as CDI score
≥ 13; analysis at entry
Depressive symptoms more prevalent among n = 97 and at 2-year
14–16 year olds (25%) and those with
follow-up n = 57
diabetes ≥ 10 years (23%)
Family factors (Family Adaptability
and Cohesion Scale)
At entry general and diabetes-specific family
function was significantly associated with
Family behaviour (Diabetes Family depressive symptoms (p = 0.03); upon
Behaviour Scale)
multivariate analysis only diabetes-specific
factors (less warm and caring behaviour) at
Metabolic control (HbA1c)
2-year follow-up (p = 0.08)
Design
EL
Longitudinal IIb
cohort with
assessments at
study entry
and 2-year
follow-up
At 2-year follow-up those with depressive
symptoms had significantly higher HbA1c:
9.0 ± 0.85% vs. 8.3 ± 1.4% (p = 0.03)
Exclusion criteria:
type 2 diabetes, comorbid chronic
illness, inability to
comply with
protocol
Mean age 14.3 ± 2.0
years, 38% male
Kovacs et al,
1997579
92 sequential
inpatient admissions
at Children’s
Hospital, Pittsburgh,
recruited between
1978 to 1985, 85
were prospectively
followed up for 5
years
43 boys, mean age
11 years
16% had a psychiatric disorder predating
type 1 diabetes onset (none had depression)
Interview Schedule for Children
and Adolescents (ISCA)
42% developed at least 1 episode of a
psychiatric disorder during follow-up
BDI and Hamilton Depression
Rating Scales (HAM-D) used to
assess maternal psychopathology
26% had major depressive/dysthymic
disorder
Cumulative probability of any depression
during 10 years after type 1 diabetes onset:
0.27 (significantly higher than all other
disorders)
Maternal depression was a significant risk
factor for depression among patients with
type 1 diabetes (p = 0.02); regression
coefficient: 0.97
Time intervals between
Longitudinal IIb
assessments varied across cohort
cases
Initial
evaluation
2–3 weeks
post-diagnosis
then 1–3
visits every
year
Subjects and
parents
interviewed
239
Evidence tables
Inclusion criteria:
type 1 diabetes,
aged 8–13 years
Prevalence of Psychiatric
Disorders:
Study
Population
Goldston et al, 95 consecutive
children admitted to
1994580
inpatient unit,
Children’s Hospital,
Pittsburgh between
1978 and 1985, 5year follow-up
period
Inclusion criteria:
type 1 diabetes, no
other systemic
illness, aged 8–13
years, within
commuting distance
Intervention
Outcomes
Results
1) Suicide Ideation Predictor
variables: female gender, low
socio-economic status, pre-existing
psychiatric disorder, age,
depressive, anxiety, and severity of
illness at diagnosis symptoms
cluster
1) Within 1 year before intake: 21.1%
(retrospective)
2) Suicide Attempt
(The Interview Schedule for
Children and Adolescents was
used for both outcome measures)
Comments
Time intervals between
assessments varied across
cases, parents and
At study intake: 29.5%
children interviewed,
Severity of depression significantly related to pervasive noncompliance not defined
history of suicide ideation (p < 0.004)
During follow-up (n = 85): 46%
Those with suicide ideation were more likely
be non-compliant compared with those
without suicide ideation (p < 0.003)
Design
EL
5-year follow- IIb
up cohort (3
visits per year
and then 1
assessment
every 8–12
months), first
research
assessment
2–3 weeks
after diagnosis
2) Suicide attempt during follow-up (n = 6)
6.4%, 3 had a history of earlier suicide
ideation
Exclusion criteria:
mental retardation
Median age 11
years, 44 males
Lawler, 1990578 16 young people
recruited from
physicians and
newspaper
advertisements in
Oklahoma
Aged 15–18 years,
> 1 year, two nondiabetic parental
figures present, 10
males
Thernlund et
al, 1996581
HbA1c
FACES III
Family Emotional Health
Observational III
Depression was positively correlated with
diabetic control (r = 0.51, p < 0.05)
Beck Depression Inventory
2 subjects scored mild and severe depression
Family Inventory of Life Events and 10/16 experienced moderate to high stress
Changes
Social support
76 children from 5 Reactions assessed during first Family crisis
paediatric clinics in 3 weeks
Psychological adjustment
Sweden
Mean age 8.6 ± 3.9
years, 38 boys
Social support positively correlated with
Family Emotional Health (r = 0.46, p < 0.05)
Grief and anxiety of children were less
marked than that of parents (0.05)
Among children age ≥ 6 years: distress
increased the odds of poor metabolic control
(OR 1.3, p < 0.01)
Related to maternal stress and reaction
Factor
analysis,
follow-up at
10 months
IIb
Type 1 diabetes
240
Study
Population
Viner et al,
1996582
Intervention
Outcomes
Results
Comments
Design
EL
43 children and
young people and
their mothers,
outpatient clinic,
Brisbane, Australia
Increased HbA1c at the time of FILE
questionnaire associated with increased
stress (rs = 0.554, p < 0.001)
No significant evidence
of association between
admission rate or
glycated Hb measures of
control with family stress
Crosssectional
III
Mean age
10.2 ± 3.16 years,
42% male
Social support (perceived by
mother)
Family Inventory of Life Events
(FILE) (measure of stress as
perceived by mother)
Mean HbA1c associated with FILE (rs = 0.563,
p < 0.001)
Family social support not directly related to
HbA1c, but high support buffered the effects
of family life stress. The means of the two
mean HbA1c groups stratified by support
level were not statistically significant at the
at 1% level (p ≥ 0.01)
Evidence tables
241
Study
Population
Intervention
Hazell et al,
2002586
Children and young Tricyclic antidepressants
people without type
versus
1 diabetes treated
for depression
placebo
Outcomes
Results
Comments
1) Failure to recover
1) Overall improvement OR 0.84, 95% CI
0.56 to 1.25
Patterns of co-morbidities Systematic
likely to have differed
review
across studies
2) Change in depression checklist
scores
Adolescent OR 0.85, 95% CI 0.54 to 1.34
Child OR 0.69, 95% CI 0.25 to 1.89
Aged 6–18 years
2) Overall change in depression checklist
scores –0.312 (95% CI 0.62 to –0.01)
Design
EL
Ia
13 trials found, n = 506
Intention to treat analysis
Adolescent –0.469 (–0.922 to –0.016)
Child 0.147 (–0.343 to 0.638)
Harrington et
al, 1998588
Harrington et
al, 1998587
Review article of
CBT
studies addressing 3
domains of
cognitive behaviour
therapy (CBT)
Improvement in:
6 RCTs, children
aged 8–19 years
with depressive
disorder of
moderate severity
Remission rates
Cognitive behaviour therapy
(CBT)
versus
inactive interventions (waiting
list, relaxing training, art
exercises)
Depressive symptoms
Depressive disorder
As a Family intervention
9 controlled studies in children recruited
from school, 6 trials provided quantitative
evidence and 4 of those showed CBT
significantly superior to no treatment
Limitations of existing
research: poor quality
trials, depression is main
focus of outcome
assessment (co-morbid
6 RCTs with a variety of sample populations, conditions?), follow-up
a meta-analysis showed significant
intervals rarely exceed a
improvement in CBT group
year
Review of the IV
literature
–RCTs
Higher in the CBT group (129/208, 62%) vs. Most studies based on
comparison (61/168, 36%)
mild cases of depression
Systematic
Ia
review/
meta-analysis
Pooled OR 3.2 (95% CI 1.9 to 5.2)
Type 1 diabetes
242
What is the optimum method of managing depression in children with type 1 diabetes?
6.3
Eating disorders
Study
Population
Nielsen,
2002590
Females with type 1 Anorexia nervosa in female
diabetes
Adults and young
people
Nielsen,
2002590
Outcomes
Results
Prevalence of anorexia nervosa
Prevalence of anorexia nervosa: 5/727 vs.
1/1499, OR 1.99, 95% CI 0.95 to 4.17,
p = 0.14
versus
anorexia nervosa in female
patients without type 1
diabetes
Females with type 1 Bulimia nervosa in female
diabetes
Adults and young
people
Nielsen,
2002590
Intervention
Prevalence of bulimia nervosa
versus
bulimia nervosa in female
diabetes
Females with type 1 Eating disorders – not
diabetes
otherwise specified in female
Adults and young
people
versus
Prevalence of eating disorders –
not otherwise specified
eating disorders – not
otherwise specified in female
diabetes
Nielsen,
2002590
Females with type 1 Sub-threshold eating disorders
diabetes
in female patients with type 1
diabetes
Adults and young
people
versus
Comments
Systematic
III
review of
observational
studies
Prevalence of bulimia nervosa: 13/727 vs.
8/1499, OR 3.12, 95% CI 1.24 to 7.9,
p = 0.024
8 studies: Rosmark 1986,
Robertson 1990, Fairburn
1991, Striegel-Moore
1992, Peveler 1992, Vila
With the 1986 Rosmark study excluded from 1995, Engström 1999,
the meta-analysis due to self-rating
Jones 2000
instruments, the OR for prevalence of
bulimia nervosa decreased to 2.89, 95% CI
1.13 to 7.4, p = 0.04
Systematic
III
review of
observational
studies
Prevalence eating disorders – not otherwise 7 studies: Robertson
specified: 79/686 vs. 80/1457, OR 1.8, 95% 1990, Fairburn 1991,
CI 1.3 to 2.7, p = 0.0009
Striegel-Moore 1992,
Peveler 1992, Vila 1995,
Engström 1999, Jones
2000
Systematic
III
review of
observational
studies
Prevalence of sub-threshold eating Prevalence of sub-threshold eating disorders:
disorders in female patients with
79/542 vs. 105/1307, OR 1.88, 95% CI 1.3
type 1 diabetes compared with
to 2.6, p = 0.0002
without type 1 diabetes
Robertson 1990,
Engström 1999, Jones
2000
243
retinopathy in female patients
with type 1 diabetes, without
eating disorders
Search
Medline up to
an unknown
date
Search
Medline up to
an unknown
date
Search
Medline up to
an unknown
date
Systematic
III
review of
observational
studies
Search
Medline up to
an unknown
date
Prevalence of retinopathy in
female patients with type 1
diabetes with eating disorders
compared with without eating
disorders
Prevalence of retinopathy and eating
6 studies: Steel 1987
disorders: 74/106 vs. 58/317, OR 4.84, 95% (1993), Colas 1991,
CI 3.0 to 7.8, p < 0.00001
Cantwell 1996, Rydall
1997, Affentio (personal
Unweighted mean of risk difference: 0.33,
communication), Takii
95% CI 0.25 to 0.42, p < 0.00001
1999
Systematic
III
review of
observational
studies
Search
Medline up to
an unknown
date
Evidence tables
Females with type 1 Retinopathy in female
diabetes
patients with type 1 diabetes,
with eating disorders
Adults and young
people
versus
EL
Robertson 1990, Fairburn
1991, Striegel-Moore
1992, Peveler 1992, Vila
With the 1986 Rosmark study excluded from 1995, Engström 1999,
the meta-analysis due to self-rating
Jones 2000, Nielsen 1998
instruments, the OR for prevalence of
(follow-up study)
anorexia nervosa decreased to 1.53, 95% CI
0.67 to 3.47, p = 0.42
sub-threshold eating disorders
in female patients without
type 1 diabetes
Nielsen,
2002590
Design
Eating disorders (continued)
Study
Population
Intervention
Nielsen,
2002590
Females with type 1 Insulin misuse in female
diabetes
with eating disorders
Adults and young
people
versus
Outcomes
Results
Prevalence of insulin misuse in
female patients with type 1
diabetes with eating disorders
compared with without eating
disorders
Prevalence of insulin misuse and eating
7 studies: Rodin 1991,
disorders: 83/171 vs. 43/603, OR 12.6, 95% Fairburn 1991, Cantwell
CI 7.8 to 21.1, p < 0.00001
1996, Affentio 1997, Takii
1999, Bryden 1999, Jones
Weighted mean of risk difference: 0.40, 95% 2000
CI 0.29 to 0.50, p < 0.00001
Mortality after 10 years
Type 1 diabetes: 13/510 (2.5%), RR 2.2
mortality per 1000 person years
insulin misuse in female
without eating disorders
Nielsen et al,
2002591
510 females with
10-year follow-up
type 1 diabetes
(mean age
15.8 ± 7.9 years),
658 females with
anorexia nervosa
(mean age
22.2 ± 8.5 years),
and 23 females with
type 1 diabetes and
anorexia nervosa
(mean age
26.1 ± 13.4 years)
Anorexia nervosa: 43/658 (6.5%), RR 7.3
mortality per 1000 person years
152 young people
Self-reported questionnaire
with type 1 diabetes measuring attitudes, feelings
and behaviours characteristic
Aged 11–19 years
of individuals with eating
disorders
USA
Design
EL
Systematic
III
review of
observational
studies
Search
Medline up to
an unknown
date
Populations were found
Observational III
from different sources and study
were of different age
groups so may not be
directly comparable
Type 1 diabetes and anorexia nervosa: 8/23
(34.8%), RR 34.6 mortality per 1000 person
years
Comparing the mortality rate of subjects with
type 1 diabetes and subjects with type 1
diabetes and anorexia nervosa: OR for
premature death 20.39, 95% CI 6.6 to 38.3,
p < 0.001
Denmark
Meltzer et al,
2001592
Comments
Association between bulimia and Association between bulimia score ≥ 5 and
HbA1c, thought multiple regression HbA1c, regression coefficient = 0.19, t = 1.70,
model
p = 0.09
Comparison between young men
and young women in eating
disorders
Observational III
study
Body dissatisfaction: male mean 4.0, SD 4.8,
n = 64; female mean 8.6, SD 7.1, n = 75
(p < 0.0001)
Bulimia: male mean 0.7, SD 1.8, n = 65;
female mean 1.8, SD 3.3, n = 79 (p < 0.0173)
Drive for thinness: male mean 2.3, SD 2.6,
n = 68; female mean 6.6, SD 7.1, n = 75
(p < 0.0001)
Herpertz et al,
1998593
341 adults with type Questionnaire and interview.
1 diabetes
Aged 18–65 years
Germany
Glycaemic control when relative
HbA1 and HbA1c levels for the
patients with type 1 diabetes and
eating disorder compared with
without an eating disorder
Glycaemic control: 1.56 vs. 1.53, p = 0.416
Observational III
study
Type 1 diabetes
244
6.3
6.3
Eating disorders (continued)
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Olmsted et al,
2002595
85 young women in
paediatric diabetes
clinic who had
showed evidence of
disturbed eating
attitudes or
behaviour (130
eligible, 85 agreed
to participate)
Psychoeducation (n = 50)
Eating Disorder Inventory:
Eating Disorder Inventory (mean (SD)):
RCT
Ib
versus
1) Objective binge episodes
1) 1.3 (3.3) vs. 3.1 (7.1)
212 young women in
paediatric diabetes clinic
originally
treat-as-usual (n = 35)
2) Insulin omission days
2) 1.4 (5.6) vs. 1.2 (5.3)
Results after 6-month followup
3) HbA1c levels
3) 9.3% (1.7%) vs. 9.3% (1.5%)
4) Drive of thinness
4) 5.5 (6.4) vs. 5.7 (5.2)
5) Bulimia
5) 0.7 (1.3) vs. 1.6 (3.9)
Aged 12–19 years
6) Body dissatisfaction
6) 11.1 (8.0) vs. 12.1 (6.8)
Canada
Eating Disorder Examination:
Eating Disorder Examination (mean (SD)):
7) Restraint
7) 1.0 (1.1) vs. 1.0 (1.2)
8) Overeating
8) 1.6 (0.4) vs. 1.7 (0.5)
9) Eating concern
9) 0.5 (0.7) vs. 0.7 (0.9)
10) Shape concern
10) 1.6 (1.5) vs. 1.7 (1.3)
11) Weight concern
11) 1.3 (1.4) vs. 1.4 (1.1)
Evidence tables
245
Cognitive disorders
Cognition
Study
Population
16 children from 2
Rovet and
Ehrlich, 1999598 studies in Canada
Mean age at
diagnosis 4.5 ± 3.0
years, 10 males
Intervention
Outcomes
9 children had had
hypoglycaemic seizures
Verbal intelligence quotient
Evaluations at diagnosis, 1, 3
and 7 years
Results
Comments
Design
EL
Those with hypoglycaemic seizures more
Methodology and
likely to decline than without (67% vs. 14%, analyses unclear
Perceptual, fine motor, visuomotor, p < 0.05)
visual memory, attention
Children with diabetes with history of
seizure scored significantly lower (p < 0.01)
Prospective
and
retrospective
data
collection,
nested
case–control
study
IIb–III
Wechsler Intelligence Scale for
Children-Revised (WISC-R)
Severe hypoglycaemia
defined as
unconsciousness/convulsi
ons with blood glucose
concentration < 3 mmol/l
Case–control, III
interviewed
2–3 sessions
within 2
weeks;,
examiner
blinded to
type 1
diabetes
group
Severe hypoglycaemia
defined as blood glucose
concentration
<3.5 mmol/l on 2
2) Higher after a night of hypoglycaemia:
successive 15-min
median score 5 (range 2–8.5) vs. 3 (1.5–6.5) measurements
on control night, p = 0.03
Significant difference
between those with
hypoglycaemia and
without for higher insulin
dose, p < 0.0006
Case–control, III
2 overnight
glucose
measurements
at home with
cognitive and
mood
assessment
the next day
Controls: matched
for socio-economic
status, sex and age
Hannonen et
al, 2003599
21 children with
3 groups:
type 1 diabetes and
10 healthy children Children with type 1 diabetes
with least 1 episode of severe
in Finland
hypoglycaemia (n = 11)
Aged 5–11years,
Children with type 1 diabetes
diabetes duration
and no history of
1–10 years
hypoglycaemia (n = 10)
NEPSY (developmental
neuropsychological assessment)
Phonological processes in type 1 diabetes
with history of severe hypoglycaemia scored Controls were volunteers
lower than controls (p < 0.05)
from a local sports club
or children of hospital
Memory: digit span forward both type 1
staff
diabetes with and without scored lower
compared with controls (p < 0.01)
Significant (p < 0.05)
differences between the
people with diabetes with
and without
hypoglycaemia regarding:
duration of type 1
diabetes, age at diagnosis
and neurological
impairment
Controls (n = 10)
Matyka et al,
1999603
29 prepubertal (over
age 5 years)
recruited from
paediatric clinic in
Oxford
Mean age 9.5 years,
mean diabetes
duration 3.4 years
Controls: 15 healthy
children (siblings or
friends of cases),
mean age 9.5 years
Overall episodes of
hypoglycaemia = 24
Study night 1: n = 13
Study night 2: n = 7
Attention: type 1 diabetes without history of
severe hypoglycaemia had test scores that
were significantly lower than controls
(p < 0.05)
1) Cognitive function tests such as: 1) No significant differences found between
apiral maze, pegboard, immediate 17 children with nocturnal hypoglycaemia
story recall, digit span
compared with a control night
2) Mood: Children’s Depression
Inventory
Type 1 diabetes
246
6.4
Cognition (continued)
Study
Population
Intervention
Outcomes
Results
Austin and
Deary, 1999604
1441 patients with
type 1 diabetes
Patients who had 5 or more
hypoglycaemic incidents
Cognitive score
Aged 13–39 years
versus
General ability (mean ± SEM (n)):
Year 2: –3.32 ± 3.64 (8) vs. –0.04 ± 0.23
DCCT subgroup only
(1121)
Year 5: 1.06 ± 1.51 (50) vs. –0.10 ± 0.28
(943)
Year 7: 4.50 ± 2.41 (30) vs. 0.91 ± 0.56 (371)
Year 9: 1.11 ± 2.16 (18) vs. 1.00 ± 0.90 (139)
patients who had no
hypoglycaemic incidents
Comments
Design
EL
Controlled
study
IIa
Crosssectional
III
No significant difference in the cognitive
scores when split into the topics spatial
ability, processing speed, verbal, memory
and finger tapping
Holmes and
Richman,
1985596
Rovet, 1990609
42 children with
a university
paediatric
department, Iowa
Study population split into
groups (onset/duration):
Aged 6–16 years
late (≥ 7 years)/short n = 9
Inclusion criteria:
IQ = 85–129
early/short (< 5 years) n = 10
63 children with
newly diagnosed
type 1 diabetes at
Hospital for Sick
Children in Toronto
Neurocognitive function
examined at diabetes onset
(n = 63) and 1 year later
(n = 60), cases compared with
controls only at T0
WISC-R
Verbal subtests
early (age < 7 years)/long (≥ 5
years) n = 12
Higher rates of reading and memory
impairment in early onset long duration
group
Cognitive function including
general IQ, verbal and spatial
abilities, memory, academic
achievement
IIb–III
Cognitive function:
WISC-111
8/12 had a decrease in performance IQ
Subjects randomised to a
score when hyperglycaemic (p < 0.05) (as did euglycaemic state on one
the performance centile score)
occasion and a
hyperglycaemic state on
another
Crossover
Ib
RCT, assessed
on 2
occasions, 6
months apart
247
Evidence tables
12 children with
Effects of hyperglycaemia
a paediatric clinic
in Australia
No significant difference in outcomes except Number of subjects
Cohort and
one test (WISC-R vocabulary) differed
differed with almost every nested
between diagnosis and 1-year follow-up in
comparison
case–control
the children with diabetes (p < 0.05)
Number of monthly low blood sugar
readings (< 4.0 mmol/dl) without symptoms,
with symptoms and episodes of
unconsciousness, convulsions correlated
positively with improved outcome over time
Controls: 40 siblings
without diabetes
under age 12 years
6 boys, mean age
12.4 ± 2.6 years
Word recognition ability,
visual-motor skill,
auditory verbal learning
test and digit span were
NS
late/long n = 11
33 boys, mean age
7.32 ± 4.3 years
Davis et al,
1996611
Median performance IQ scores significantly
lower in early onset, longer duration group
(p < 0.05)
Study
Population
Intervention
Sansbury,
1997597
28 children with
Age at diabetes onset
type 1 diabetes > 1
year duration from a Duration of disease
university medical Metabolic control (HbA1c)
centre in Atlanta,
USA
Outcomes
Results
Comments
Cognitive function:
Increase in chronological age associated
with decreased full-scale IQ (p < 0.004),
arithmetic (p < 0.007), verbal fluency
(p < 0.005), and block design (p < 0.01)
Participants were more
Observational III
likely to be from a higher
socio-economic status
than non-participants
WISC-R
Matching Familiar Figures Test
Child Behaviour Checklist
12 boys, mean age
12.6 years
Northam et al,
1998610
116 patients from
children’s hospital
in Melbourne with
newly diagnosed
1990–1992
Aged 3–14 years,
55 boys
Rovet and
Alvarez,
1997600
Poor metabolic control associated with
lower vocabulary subtest scores (p < 0.03)
1) General intelligence: WPPSI-R 1) At baseline no differences between 2
for children under 7 years old and groups
WISC-R for children 7 years old
2) Significant differences between two years
and over
after baseline and baseline:
2) Vocabulary
Vocabulary p < 0.01
Block design p < 0.05
Block design
Learning p < 0.01
Speed of processing p < 0.05
Learning
Speed of processing
103 children with
diabetes from a
clinic in Toronto
Attention (mean composite scores) Compared with controls select attention
scores lower (p = 0.05)
Intelligence (WISC-R and MMFFT)
Poorer performance by patients with early
onset (< 6 years old, n = 51) (p = 0.01)
100 controls
EL
Increased type 1 diabetes duration
associated with lower MFFT scores (p < 0.01)
112 ‘well’ controls
from schools, 54
boys
Aged 9.3–18.3
years, diabetes
duration > 2 years
Design
3) No significant difference found
Analyses performed
ANOVA and
MANCOVA;, smaller
developmental gains in
type 1 diabetes compared
with controls
Case–control, IIb–III
2
assessments:
T1 = 3 months
after type 1
diabetes onset
and T2 = 2
Type 1 diabetes showed a years postless positive change in
baseline
general intelligence
scores
3) Child Behaviour Checklist
Control source: friends,
siblings, cousins of study
group, friends/children of
hospital employees
Retrospective diabetes
Seizure history (S+): S+ had lower verbal IQs history data collection
than controls (p < 0.01), no difference found
compared with children with diabetes and
S-, S+ associated with poorer inhibit and
focus aspects of attention
Observational III
3-year study
period,
subjects
randomly
assigned to 1
or 4 tests
Type 1 diabetes
248
Study
Population
McCarthy et al, Children with type
1 diabetes (n = 244)
2002601 and
2003602
Mean age 14.8 ± 3.2
years
Intervention
Outcomes
Results
Academic performance
The study found that current academic
performance by children and young people
with type 1 diabetes was not lower than the
sibling control group or the matched
classmate control group
Sibling control
group (n = 110) and
matched classmate
control group
(n = 209)
Comments
Design
EL
Case–control III
study
The children and young people with type 1
diabetes performed better than their siblings
on maths (mean stand score 115.0 vs. 111.1,
p < 0.02) and core total (mean stand score
113. vs. 110.5, p < 0.04) and better than their
matched classmates on reading (mean stand
score 108.9. vs. 106.8, p < 0.04)
USA
The study found lower achievement in
children and young people with type 1
diabetes who had poor metabolic control
than those with average control
Socio-economic status and parent ratings of
behaviour problems were significantly
correlated with academic achievement,
medical variables added only slightly to
predictive precision
Wysocki et al,
2003605
142 children and
young people with
type 1 diabetes
No association between occurrence or
frequency of severe hypoglycaemia and
cognitive function (intelligence quotient)
Case–control III
study
Association between
neurocognitive test scores and
hypoglycaemia
No association found
Case–control III
study
Cognitive performance
No difference found
Aged 6 to 15 years
Kaufman et al,
1999606
55 children with
type 1 diabetes
Aged 5 to 10 years
USA
Bjorgaas et al,
1997607
249
Aged 9 to 16 years
Norway
Children/young people with type 1 diabetes
who had experienced an episode of severe
hypoglycaemia: those with onset of diabetes
before the age of 5 years had lower
psychomotor efficiency scores than those
with onset of diabetes after the age of 5
years
Case–control III
study
Evidence tables
15 children and
young people with
type 1 diabetes
compared with
healthy
children/young
people matched for
age, gender and
social background
Subjects with a history of hypoglycaemic
seizures had lower scores on tests assessing
memory skills, including short-term memory
(p < 0.03)
Study
Population
Golden et al,
1989608
23 children with
type 1 diabetes
Intervention
Aged 5.9 ± 1.8 years
Outcomes
Results
Association between
hypoglycaemia and results of the
Stanford–Binet Intelligence Scale
No association found
Outcomes
Results
Comments
Design
Youth Self Report (YSR) for
behaviour problems
Attention problems scale significantly
associated with higher GHb levels: 2.32
times (95% CI 1.2 to 4.34, p = 0.01) more
likely to have GHb > 9%
Externalising behaviour is
defined as a combination
of aggressive and
delinquent behaviour
subscales
CrossIII
sectional
survey, 18
month period
USA
6.5
Comments
Design
EL
Case–control III
study
The relative frequency of asymptomatic
hypoglycaemia correlated with scores on the
abstract/visual reasoning scale
Behavioural and conduct disorders
Severe conduct
Study
Population
Leonard et al,
2002617
231 children with
type 1 diabetes
attending treatment
centres in
Minnesota, USA
Mean age
15.5 ± 2.2, range
11–18 years
More than 50% of
the sample had
GHb > 9%
Intervention
GHb levels
Externalising scale also statistically
significant and remained so when attention
problems were controlled for: exp(B) = 2.41,
95% CI 1.35 to 4.30, p < 0.003
Do higher levels of
attention problems,
aggressive and delinquent
behaviour predict higher
levels of GHb or vice
versa?
EL
Type 1 diabetes
250
Severe conduct (continued)
Study
Population
Liss et al,
1998614
25 children and
young people with
type 1 diabetes, at
least 1 year with
diabetic
ketoacidosis, and
parents
Intervention
Outcomes
Results
Comments
Design
Psychiatric disorders (DISC)
More diagnoses reported by diabetic
ketoacidosis children than controls (mean
1.9, SD1.9 vs. 0.2, SD 0.4; p ≤ 0.001)
Cases and controls
matched on age, sex,
ethnicity
Case–control III
Majority of cases: anxiety, affective and
disruptive behaviour disorders
subjects were in poor
control at study entry and
diagnosis as reported by
mean number of
hospitalisations and
Accident and Emergency
visits compared with
controls (both p ≤ 0.001)
Child Behaviour Checklist
Family Assessment Measure III
Brief Symptom Inventory (parents)
88% of cases met criteria for at least 1
psychiatric disorder vs. 28% of controls
(p ≤ 0.001)
Aged 9–17 years
Dallas clinic, USA
Self-esteem and social competence lower
among cases
Controls: children
(no history of
diabetic
ketoacidosis
hospitalisation) and
parents, n = 25
Court et al,
1988613
127 children with
type 1 diabetes
Families of cases scored lower on problem
solving and diabetes-specific ‘warmth-caring’
Rutter scales (A2 and B3)
Aged 8–16 years
25% of children with type 1 diabetes were
perceived by parents to be disturbed
compared with 14% of controls
EL
Parents’ and teachers’
perception of children’s
behavioural problems
Observational III
Interviews conducted
with family 2 months
after diagnosis
Retrospective III
case–control
No relationship found between extent of
behaviour problems and control of diabetes
51 children without
diabetes
UK
Thernlund et
al, 1995612
Swedish study of 67
diabetes and 61
healthy ‘control’
matched subjects,
diagnosed during
1988 and 89
Mean age 8 ± 4,
range 0–14 years
Child behaviour (interviews with
parents)
More behavioural problems among cases
compared with controls
Mean scores and SD for cases and Inhibition: 6.67 ± 12.94 vs. 3.00 ± 5.82,
controls
p = 0.02
Acting-out: 11.08 ± 13.75 vs. 5.00 ± 8.28,
p = 0.004
OR for acting-out and developing diabetes:
1.05, p = 0.022, no confidence intervals
provided
251
Evidence tables
Negative event in first 2 years OR: 1.94;
family function (hierarchical organisation)
OR: 1.52 (both statistically significant)
Study
Population
Gath et al,
1980616
76 children with
type 1 diabetes
Intervention
Outcomes
Results
Comments
Design
Rutter scale (B2) for teachers
70 forms completed and 70 controls
Case–control III
Backwardness in reading
NS difference between cases and controls
12% reported discordant
family relationships
Parents given a fee to
cover out-of-pocket
expenses
Observational III
43 boys, mean age
10.9 ± 2.8 years,
mean diabetes
duration 3.5 years
EL
28.5% of cases and 19% of controls were at
least 2 years behind chronological age in
reading (p < 0.01)
Oxford
Brown et al,
1991615
28 children and
young people with
university clinic,
Atlanta USA
Children’s Depression Inventory
Mean age 12.5
years, 13 boys
Mothers: Child Behaviour
Checklist
Teachers and
mothers also
surveyed
Teacher Rating Scale
Children’s Manifest Anxiety Scale
Children’s Attributional Style
Questionnaire
Last HbA1c measurement
When controlled for age and sex, children
with better glycaemic control made more
internal, stable, and global attributions for
negative events (p < 0.02)
Teachers rated children with later onset of
type 1 diabetes as having more externalising
behavioural symptoms (p < 0.0005)
Type 1 diabetes
252
Severe conduct (continued)
6.6
Non-adherence
Study
Population
Intervention
Tubiana-Rufi et 150 French children
al, 1998625
and their parents
from 6 university
paediatric clinics
Outcomes
Results
Comments
Family Adaptability and Cohesion
Evaluation Scale
Families of children with diabetes: 33% of
disengaged families with low levels of
cohesion (vs. 21%, p < 0.05); 26% of rigid
families with a low level of adaptability (vs.
13%, p < 0.0001)
Families without children Crosswith diabetes were
sectional
controls, no mention of
survey
origin of comparison
group
Adherence to diabetes regimen
Mean age
10.2 ± 1.9, range
7–13 years, mean
3.1 years
Family adaptability in diabetes children was
significantly and positively correlated with
parent’s educational level (mother: r = 0.37,
p < 0.001; father: r = 0.24,p < 0.01)
Mendez and
Belendez,
1997633
37 young people
Behavioural intervention
with type 1 diabetes programme: 12 sessions over
from hospitals in
4 months (n = 18)
Spain
versus
Aged 11–18 years
standard medical care (n = 19)
Parents also
interviewed
No effect on diet, exercise or glycaemic
control
Morris et al,
1997501
89 patients with
type 1 diabetes
younger than 30
years attending
clinic in Scotland
Adherence index (days insulin per Inverse association between adherence
annum)
index, HbA1c and admissions for diabetic
ketoacidosis (R2 = 0.39, p < 0.001)
Patients aged 10–20 years had higher HbA1c
(p = 0.01 ) and lower adherence index
(p < 0.001) compared with patients < 10 or
> 20 years
Rate of failing to take insulin: 28%
III
Complicane to:
insulin treatment
diet
home monitoring
Co-operation
Shows the best adherence to insulin
treatment, self-care and co-operation
Diet and home monitoring are areas where
there is less compliance
Population had
QuasiIIb
reasonable baseline levels experimental
of HbA1c
study,
baseline and
13-month
measurements
Failure, poor control,
Cohort
acute hospitalisation for
diabetic ketoacidosis, and
related acute
complications were
associated
IIb
Insulin regimens varied
from day-to-day
Crosssectional
survey
III
253
Evidence tables
Finland
EL
Family scores of cohesion correlated to
parents’ adherence to diet (r = 0.19, p < 0.05),
hypoglycaemia (p < 0.01), and insulin
therapy (p < 0.01)
Mean age 16 years,
51% males
Hentinen and 47 children with
Kyngäs, 1992620 diabetes (unknown
type)
Design
Non-adherence (continued)
Study
Population
Johnson et al, 140 children with
1990624, 1992623 type 1 diabetes and
their mothers,
Florida camps
Mean age 11.9
years, 54% male
Jacobson et al, 57 children with
1987622
type 1 diabetes seen
at Joslin clinic,
Boston
Intervention
Outcomes
Results
Effect of age and duration on
metabolic control and adherence
(24-hour recall interviews
conducted 3 times over a 2-week
period)
Psychological predictors of
compliance
Mean age 12.8 ± 2.1
years, mean
5.5 years, 29 males
Frank, 1996626
Design
EL
Older patients were less adherent and worse Assessed at study entry
with HbA1c control
and 1.65 years after,
adherence measures
included aspects of
injection, exercise, diet
type, testing/eating
frequency
Longitudinal
IIb
Young people (13–15 years old) less
compliant than children aged 9–12 years
ANOVA used, no
correlation with duration
of diabetes detected
Longitudinal
over 18
months
IIb
Mean age at discharge
from paediatric clinic
17.7 ± 0.38 years
Retrospective IIb
cohort, using
medical
records,
telephone
interview
Age influenced compliance with diet
(p ≤ 0.04), metabolic monitoring, (p ≤ 0.01)
and composite index (p ≤ 0.01)
Comments
Patients with higher self-esteem (selfreported), perceived competence, diabetes
adjustment and social functioning (parent
reported) adhered more closely
41 participants with
a paediatric clinic
in Ontario, Canada
Comparing compliant patients
(n = 31)
Mean age
21.7 ± 0.55 years at
study entry; 26
males
non-compliant (n = 10)
versus
Significantly more likely to have gone
beyond high school education (82% vs.
30%, p < 0.01)
In the year prior to discharge: non-compliant
group more likely to have been hospitalised
(p < 0.05), have a lower mean HbA1c
(p < 0.05), have attended clinic less often
(p < 0.01)
Following discharge: non-compliant group
also required more hospitalisations (p < 0.01)
Burroughs et
al, 1993621
21 young people
with type 1 diabtes
Predictors of compliance (5
domains)
Dietary compliance best predictor of
metabolic control (p < 0.01)
Questionnaire III
survey
136 children with
type 1 diabetes at
summer camps, and
parents
Self-efficacy
Questionnaire III
survey
Mean age 13.9
years, 44% male
Diabetes Family Behaviour
Checklist
Self-efficacy was shown to be a mediating
variable for the relation between mastery
experience (i.e. assuming personal
responsibility for treatment) and adherence
to treatment
Aged 13–18 years
USA
Ott et al,
2000619
USA
Diabetes Family Responsibility
Questionnaire
Type 1 diabetes
254
6.6
6.7
Psychological support
Behaviour Therapy
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Wysocki et al,
2000644
119 families of
young people with
type 1 diabetes
recruited from
Missouri and
Florida
3 months treatment of:
Composite scores and mean GHb
values
Baseline: 73% of young people exceeded
‘good’ GHb levels
RCT
Ib
Parent–adolescent relationship
(PARQ)
Effect for all groups on mean change in
family composite scores; overt conflict and
skills deficits (p = 0.05) and extreme beliefs
(p = 0.006)
Families were paid $100
upon completing each
evaluation (to improve
adherence)
Inclusion criteria:
young people aged
12–17 years, type 1
1 year
Current therapy (CT), n = 41
RCT
Ib
Behavioural Family Systems
Therapy (BFST), n = 38
Education and support group
(ES), n = 40
Assessments made at
baseline, 3 months
Parent–child conflict (DRC)
Teen Adjustment to Diabetes Scale Composite scores favoured BFST p = 0.05
(TADS)
(decreased type 1 diabetes-specific conflict)
Analysis of change in family composite
scores showed significant age and gender
interactions (p = 0.04 and p = 0.05) for BFST
and ES
119/228 families enrolled
Exclusion criteria:
families with recent
treatment for
psychiatric
diagnoses
Wysocki et al,
2001645
Follow-up 6 and 12 Behavioural Family Systems
months later of
Therapy (BFST), n = 38
above study
Education and support group
(ES), n = 40
Current therapy (CT), n = 41
Parent–adolescent relationship
(PARQ)
Parent–child conflict (DRC)
BFST group had lasting improvement in
extreme beliefs scale (p < 0.01) with different
change scores from CT and ES (p < 0.05);
Overt conflict and skills deficits: BFST
differed from CT at post-treatment (p < 0.03)
and 6 months (p < 0.05)
GHb level of 10%
considered ‘good’
diabetic control
Groups differed at
baseline with respect to:
intact families, singleparent families, divorce
rate
TADS – no significant
differences between
groups or interaction at
any point in the study
BFST differed from CT and ES at posttreatment (p < 0.04) and 6 months
(p < 0.05);at 12 months the difference
remained with the CT group (p < 0.05)
Total GHb values increased throughout the
study (significant main effect for time
p < 0.05)
Evidence tables
255
Study
Population
Hampson et al, Systematic review
of 35 behavioural
2000640
intervention studies
in type 1 diabetes
children and young
people (age 9–21
years) with a control
group
Study description:
74% of studies were
RCTs, mean age
12.4 years, mean
type 1 diabetes
duration 4.7 years
Grey et al,
1998641
65 young people
from the Yale
Clinic
Aged 13–20 years
Grey et al,
1999642
Intervention
Outcomes
Results
Comments
Behavioural intervention
(education or skills training)
1) All outcomes
1) Overall mean effect size across all
outcomes for all studies: 0.33
Overall sample size not
Meta-analysis Ia–IIa
given; unable to conclude of 18 study
which interventions were interventions
most effective for relevant
outcomes
versus
control
2) Psychosocial
3) GHb
4) Other metabolic
5) Self-management
6) Knowledge
2) Mean: 0.37 ± 0.24
3) 0.33 ± 0.67, significant heterogeneity
4) –0.13
5) –0.15
Design
EL
Small-to-moderate
beneficial effect size
6) 0.16
Mean effect size for theoretical interventions
(0.47 ± 0.60) compared with ‘atheoretical’
(0.06 ± 0.16), p < 0.05
Intensive therapy with coping Self-Efficacy for Diabetes scale
skills training (CST) (n = 34)
Children’s Depressive Inventory
versus
Issues in Coping with type 1
intensive therapy alone
diabetes scale
(n = 31)
Diabetes Quality of Life: Youth
Data collected baseline and
(DQOLY)
at 3-month follow-up
Monthly HbA1c
77 young people
from the Yale
Clinic
Intensive therapy with coping Self-Efficacy for Diabetes scale
skills training (CST) (n = 42)
versus
intensive diabetes
diabetes scale
Aged 12.5–20 years management alone (n = 35)
(DQOLY)
Monthly HbA1c
After 3 months: CST group had significantly
better reported self-efficacy (p = 0.05) and
were less upset (p = 0.001), found it less hard
to cope with (p = 0.01) and thought diabetes
had a less negative impact on quality of life
(p = 0.04)
Intensive therapy similar RCT
to that described in
DCCT, CST not effective
in reducing acute
complications of intensive
therapy
After 3 months: HbA1c fell in both groups
compared with baseline (7.9 ± 1.3%,
p < 0.01) but fell faster and to a greater
extent in the CST
Means and SD compared
Same as above but maintained in the CST
group after 6 months
RCT
Ib
Ib
Type 1 diabetes
256
Behaviour Therapy (continued)
Behaviour Therapy (continued)
Study
Population
Intervention
Outcomes
Results
Grey et al,
2000643
75 patients with
type 1 diabetes
Intensive therapy and coping
skills training (n = 41)
Self-Efficacy for Diabetes scale
Mean age
14.2 ± 1.9, range
12–20 years, mean
duration 8.7 ± 3.9
years, 43 females
versus
diabetes scale
intensive therapy alone
(n = 34)
(DQOLY)
Coping skills training with intensive therapy Same as above but 1-year RCT
recipients reported better diabetes selffollow-up
efficacy and medical efficacy after 12
months (p = 0.002 and p = 0.04, respectively) Only F scores, degrees of
freedom and p-values
After 12 months coping skills training with
reported
intensive therapy group also reported less
negative impact on quality of life (p = 0.005),
the greatest improvement occurring during
the first 3 months (p = 0.002)
Data collected at baseline, 3, Monthly HbA1c
6 and 12 months
Comments
Design
EL
Ib
HbA1c:
Baseline and 12 months (p = 0.01)
Between 3 months and 12 months
(p < 0.001)
Between 6 months and 12 months (p = 0.03)
Suggesting that coping skills training with
intensive therapy will improve glycaemic
control more than intensive therapy alone
Evidence tables
257
Study
Population
Intervention
Nicholson,
2001639
13 new families of
diabetes attending
paediatric service at
a hospital in Leeds
Age < 16 years
Jefferson et al,
200318
1998 survey of 302
paediatricians
identified as
providing care for
children with
diabetes aged under
16 years; 244
returned
questionnaire
UK
Outcomes
Results
Comments
Design
EL
Questionnaires and
Psychology service
interviews to compare service
with standards, whether the
service meets demands of
parents and children, and
psychology in diabetes care
2 families indicated a positive need
Views of families
conflicted with those of
healthcare professionals
Crosssectional
survey
III
with diabetes
25% reported that there was some form of
Children and young
‘counsellor’ regularly attending the children’s people cared for
diabetes clinic: psychologists (75.8%),
n = 17 192
psychiatrists (11.3%), nurse therapists (6.5%),
other counsellors (6.5%) such as
psychotherapists
Survey
III
% paediatricians who provide care
for children with diabetes where
there was a form of ‘counsellor’
present
What type of ‘counsellor’
All other responses expressed reluctance in
receiving psychological support
Type 1 diabetes
258
Psychosocial
Family support
Study
Population
Intervention
Outcomes
Results
Comments
Design
Ireys et al,
2001648
136 mothers of
chronically ill
children (aged 7–11
years) including
diabetes
Community-based family
support (n = 86, 73
completed)
Psychiatric Symptom Index
Lower levels of anxiety post-intervention in
experimental group (ANOVA, F = 5.07,
p = 0.03)
Randomisation to clinics
using blocks of 4 cells
RCT, baseline Ib
and 15-month
measurements
At each face-to-face
interview mothers were
paid $20 and children
received a toy
RCT, same as Ib
above
Beck Depression Inventory
versus
Greater effects of intervention found for
mothers with high baseline anxiety
(p < 0.001) and those in poor health
(p < 0.01)
control (n = 75, 66 completed)
39.6% of the total
sample (n = 139)
had diabetes
Chernoff et al,
2002649
136 mothers and
Intervention (Family-to-family
chronically ill
network) (n = 64)
children (aged 7–11
versus
years)
control (n = 72)
Baltimore, USA
No demonstrable effect on depressive
symptoms
Child mental health
Personal Adjustment and Roles
Skills Scale
Children’s Manifest Anxiety Scale
Anderson et al, 85 patients and
Teamwork intervention
1999646
their parents from a (n = 28)
USA clinic
Attention control (n = 30)
Mean age 12.6,
range 10–15 years, Standard care (n = 24)
mean duration type
1 diabetes 5.5 years
EL
Parent involvement in diabetes
management
Diabetes-related family conflict
Glycaemic control
Intervention group had an increased mean
adjustment score (over time) while the
control group’s decreased
Percentage of children in maladjustment
range fell from 19% to 10% in the
experimental group compared with an
increase in the controls (15% to 21%)
No significant differences were found
Combined study groups to make a single
comparison group (n = 57)
No effect of intervention
on measures of children’s
anxiety, depression or
self-esteem
Random assignment
RCT,
Followed for
24 months
Ib
Significantly more parents (16%) in the
intervention group showed a deterioration in
parental involvement in insulin
administration (p < 0.03)
Teamwork families reported a greater
decrease in diabetes-specific conflict at the
end of study (p < 0.02)
OR 2.4 (no CI) improving glycaemic control
if in teamwork group than in comparison
group (p < 0.07)
Evidence tables
259
Study
Population
Intervention
Outcomes
Results
Harris et al,
2001647
119 children with
type 1 diabetes for
at least 1 year
Behavioural Family Systems
Therapy (BFST) (n = 39)
Diabetes-related conflict score
from young people, mothers,
fathers
Post-treatment data:
Aged 12–16.75
years
Education/support (EDSP)
group (n = 40)
Pre-treatment and post-treatment
Controls (n = 40)
USA
18 young people
and their primary
care giver
Aged 13–18 years,
12 males, mean age
at diagnosis
9.7 ± 3.8 years
10 half-hour sessions of
home-based Behavioural
Family Systems Therapy
(BFST)
1) Mean HbA1c = 11.3 ± 1.5% with 2 previous ‘within subjects design’,
readings above 9%
33% of population was
2) Child Behaviour Checklist
African-American
2) Positive changes in young people’s
3) Conflict Behaviour
general psychological functioning based on
Questionnaire
mothers’ pre- and post-treatment scores
4) Diabetes Responsibility Conflict (p = 0.024)
Scale
3) Positive change in family functioning
Aged 11–18 years,
diagnosed prior to
age 10, living with
at least one parent
RCT
Ib
Cohort,
IIb
assessment at
baseline and
6–10 weeks
based on pre- and post-treatment mothers’
scores (p < 0.001)
Inclusion criteria:
chronically poor
metabolic control,
history of 2 or more
missed clinic
appointments
16 young people
and their parents
enrolled from
diabetes specialty
clinics, USA
EL
Changes in mothers’ scores for BFST group
were lower (–1.0 SD) compared with the
controls (–0.33 SD) and those of the EDSP
group (–027 SD), p < 0.05
1) HbA1c
USA
Hanna and
Guthrie,
2001651
Design
Young people’s scores were minimally lower
in all groups (–0.25 SD)
Families with scores
on conflict
questionnaire ≥60th
centile qualified to
participate
Harris and
Mertlich,
2003650
Comments
4) Positive pre- and post-treatment change in
mothers’ score (mean 29.7 ± 15.0 and
23.9 ± 6.9, p < 0.002)
Open-ended questions:
What things did your parent do
that helped?... that did not help?
Parents: 14 responses of ‘helpful’ support
(directive guidance, nondirective support,
positive social interaction and forms of
physical assistance), 13 responses of nonhelpful support
Young people: 19 helpful (related to parents’
giving or not giving tangible assistance), 6
non-helpful, 4 of which were about directive
guidance (behaviours to aid performance)
Sample was a subset of a
larger study
Descriptive
study of
helpful and
non-helpful
support
III
Type 1 diabetes
260
Family support (continued)
Peer support
Study
Population
Intervention
Outcomes
Results
Comments
Pendley et al,
2002655
68 children with
type 1 diabetes for
at least 15 months
recruited from a
children’s hospital
in Delaware
5 sessions, home-based
intervention (n = 21); each
child chose 3 people from
family, peers, neighbourhood
or school to participate
Measured by:
Children with lower HbAc1 (better control)
had more support team peers (r = –0.50,
p < 0.05)
Analyses performed
Cohort with
separately for the
intervention
intervention group but
results unclear (no overall
numbers presented)
Mean age per
group:12.9 and
12.5 years
Greco et al,
2001656
21 young people
with diabetes, their
parents and best
friends (n = 21)
2 paediatric clinics
in Florida and
Delaware
Problem-solving with selfmonitoring blood glucose
(SMBG) integrated into
standard outpatient care
(n = 30)
Young people perceived better diabetesrelated peer support than school-age
children
Diabetes Patient Knowledge Test
Children perceptions of peer support were
not correlated with metabolic control, selfreport of adherence, or the number of
support team peers who participated in the
intervention
Metabolic control (HbA1)
50% of controls > 1% increase in HbA1
compared with 23% of intervention group
(baseline to follow-up)
Mean follow-up HbA1 levels were
significantly lower in the experimental group
vs. control (10.1 ± 2.0% vs. 11.0 ±2.3%,
p = 0.04)
versus
standard outpatient care
(n = 30)
RCT,
evaluated at
baseline and
18 months
attending
clinic every
3–4 months
EL
IIb
Ib
The intervention group reported increased
use of SMBG information when exercising
compared with controls (60% vs. 33.3%,
p = 0.04)
4-week intervention attended Diabetes Social Support Survey
by adolescent–peer pair
Diabetes Education and Support
consisting of four 2-hour
Assessment Tool
sessions
Teen Adjustment to Diabetes Scale
Self-care Inventory
Peer Interaction Record
Adolescent–peer pair reported higher levels Young people and peers
of diabetes knowledge and support
each paid $45 for
(p < 0.0001), and a higher ratio of peer to
participating
family support (p < 0.05) at post-intervention
Peers provided a greater
Friends reported improved self-perception
proportion of support
(p < 0.0001)
relative to family
Cohort study, IIb
pre- and postintervention
measurements
Parents reported decreased diabetes-related
conflict (p < 0.05)
261
Evidence tables
Mean age of
patients and peers:
13.1 ± 2.0 years and
13.6 ± 2.3years, 10
pairs of females
Diabetes responsibility and
conflict scale
Diabetes Social Support Interview
Mean age
12.9 ± 2.7, range
8–17 years, mean
5.5 ± 3.2 years
Anderson et al, 11–14 year-old
1989654
young people seen
at diabetes clinics in
Michigan
Self-care Inventory
Design
Study
Population
Bearman and
La Greca,
2002638
74 young people
from a diabetes care
clinic
Intervention
Outcomes
Results
Comments
Design
Diabetes Social Support
Questionnaire – Friend Version
Girls reported more support for blood
glucose monitoring and emotions compared
with boys (p < 0.01)
Study developed and
evaluated a checklist to
measure peer support of
young people with
diabetes
Observational III
study
Diabetes Social Support Interview
Mean age
14.2 ± 2.3, range
11–18 years, 60%
boys
Perceived Social Support from
Friends and Family
DSSQ correlated well with other measures of
friend support (p < 0.05–0.001)
USA
Daley, 1992653
Skinner and
Hampson,
1998636
54 young people
from a children’s
hospital in Los
Angeles
Skinner et al,
2000637
Teens with sponsorship by
insulin-dependent adults,
bimonthly contact
versus
Childhood Behaviour Checklist
(Youth Self-Report Form)
Diabetes Adjustment Scale
Aged 12–16 years,
control
21 boys, 33%
Hispanic, all but 1
of the sponsors was
Caucasian
Self-perception Profile for
Adolescents
74 young people of
144 eligible; (12–18
years old) from 4
regional hospitals in
Southern England,
diagnosis of type 1
diabetes at least 6
months
Wellbeing questionnaire
Mean age 15.2 ± 2.0
years, 57% boys
52 young people
from outpatient lists
of 4 regional
hospitals in
Southern England,
diagnosis of type 1
diabetes at least 9
months
Aged 12–18 years,
28 boys
Support from friends was related to
adherence for blood glucose monitoring
(controlled for age) (p < 0.001)
EL
Intervention group was significantly less
Sponsors were aged
RCT
likely to agree with the following statements: 25–43 years from a range
‘I wish I could run away, I wish I didn’t have of professions
diabetes’
Number in each group
Significant increases in self-esteem with
not given
respect to social acceptance and romantic
appeal in the intervention compared with
controls (p < 0.05)
Ib
Mean HbA1c declined in intervention group
and increased in control group – no numbers
given
Diabetes Self-Care Schedule
Perceived impact of diabetes and peer
support were significant predictors of
depression (p < 0.002 and p < 0.02)
Family and Friends questionnaire
Family support was significantly associated
with all self-management measures (p < 0.05)
Crosssectional
III
Checklist
Perceived efficacy of control mediated
dietary self-management and its association
Diabetes Inventory of Peer Support with family support (p < 0.001)
Wellbeing questionnaire
Diabetes Self-Care Schedule
Girls reported higher levels of depression
and anxiety (p < 0.02 and p < 0.001) and
overall lower levels of wellbeing (p < 0.004)
Family and Friends questionnaire
Girls also reported more peer support than
boys (p < 0.05)
Checklist
Personal beliefs mediate the positive effect of
family and social support on better dietary
Diabetes Inventory of Peer Support care (p < 0.01)
This study is a follow-up
of the cross-sectional
study above
Followed for III
6 months,
questionnaires
sent by post
Type 1 diabetes
262
Peer support (continued)
Peer support (continued)
Study
Population
Burroughs et
al, 1997652
Review of 32
studies that
examined the
relationship
between social
support and
metabolic control in
young people with
type 1 diabetes
Intervention
Outcomes
Results
1) Qualitative Family support
1) 18 studies
2) Communication
2) 2 studies
3) Sibling and Peer
3) 6 studies
4) Regimen-specific support
4) 11 studies
5) Intervention studies
5) 5 studies
Comments
Design
EL
Review
IV
Evidence tables
263
Adolescence
Study
Population
Bryden et al,
2001659
73 patients from a
paediatric diabetes
clinic interviewed at
baseline
Intervention
Outcomes
Results
Comments
Design
EL
Mean HbA1c
Proportion of patients overweight
(BMI > 25.0 kg/m2) increased over 8-year
period from 21% to 54% in females and
from 2% to 28% in males
Trend also evident
between adolescent
emotional problems and
lower mean HbA1c levels
Longitudinal
cohort study
IIb
Crosssectional;
descriptive
III
BMI
Aged 11–18 years,
43 males
Psychological state – Youth Self
Report and Profile/Brief Symptom
Inventory
Oxford
Childhood Behaviour Checklist
n = 65 reinterviewed as
young adults (20–28
years)
Self-esteem
Baseline: females had more emotional
symptoms than males (difference = 8.0, 95%
CI 3.0 to 13.0, p < 0.001), and lower selfesteem (difference = –8.41, 95% CI –16.0 to
–0.61, p < 0.03)
Follow-up: 27% females and 8% males
suffered from a psychiatric disorder
Behavioural problems in young people were
significantly related to higher mean HbA1c
during the subsequent 8 years: (regression
coefficient = 0.15, p < 0.001, 95% CI 0.07 to
0.24), and borderline related to emotional
state (regression coefficient = 0.06, p < 0.06,
95% CI –0.002 to 0.13)
Recurrent admission for diabetic
ketoacidosis was a significant predictor of
psychological state at follow-up (t = 4.4,
p < 0.001, 95% CI 0.4 to 1.1)
Delamater et
al, 1987663
27 young people
Mean HbA1c:
Good
(8.4%) n = 8
from an outpatient
clinic in St Louis,
Fair (10.9%) n = 9
MO, USA
Poor (13.3%) n = 10
Mean age 15.4 ± 1.6
years, 16 males,
mean duration
7.1 ± 3.6 years
Anxiety
No difference in anxiety or stress measures
Stress
Poor controllers used more wishful thinking
(F = 5.32, p < 0.01) and avoidance/helpseeking than good controllers (F = 3.96,
p < 0.03)
Means of coping
38% of poor controllers rated diabetes as a
stressful event in preceding month compared
with 12.5% of good and none of the fair
controllers (NS)
Type 1 diabetes
264
6.8
6.8
Adolescence (continued)
Study
Population
Intervention
Outcomes
Results
Cook et al,
2002660
53 young people
from 2 large
metropolitan
hospitals, Chicago,
at least 1 year since
diagnosis of type 1
diabetes
6-week problem solving
diabetes education
programme – CHOICES
(n = 26)
Problem solving test scores
(DPSMA)
Significant difference (p < 0.02) in the mean
number of times per day the intervention
group tested blood glucose (3.8) compared
with the controls (3.0)
versus
HbA1c
Diabetes Behaviour Rating Scale
control (n = 27)
Aged 13–17 years
Hains et al,
2000661
14 children with
HbA1c values
>9 .0% during
previous clinic visit
were targeted from
a children’s
hospital, Wisconsin
Stress management training
(n = 8)
versus
control (n = 6)
Perceived use of coping strategies
Anxiety level
Diabetes Stress Questionnaire
Comments
Design
EL
Baseline and 6 months
Random
Ib
data collection; ‘intent-to- assignment,
treat model’ used
repeatedmeasure
Programme did not
control group
No significant differences between groups at include a parental
6 months otherwise
component or integration
with clinical care
Significant within intervention group
comparisons for problem solving score,
responsibility score, decreased mean HbA1c
No significant difference found between the
two groups at post-test or at follow-up
Small sample size
RCT
Ib
Controlled
treatmentoutcome
study
IIa
Descriptive
III
Significant pre-test to post-test improvements
within the experimental group in anxiety,
diabetes-related stress, negative coping, as
well as pre-test to follow-up
Aged 12–15 years
Boardway et al, 19 young people
1993662
diagnosed for at
least 1 year,
children’s hospital,
Michigan
Hanson et al,
1987664
Stress management training
(SMT) (n = 9)
versus
controls (n = 10)
Coping
93 young people
and their parents
Adherence
Family knowledge
Good adherence predicted by high family
knowledge about type 1 diabetes, positive
family relations and young adolescent age
Family relations
Stress
Does pubertal development
have an effect on family
environment and diabetes
adjustment?
Family Environment Scale (FES)
Diabetes Adjustment Scale (DAS)
Pubertal status (pre-adolescent,
post-adolescent)
Family cohesion and organisation related to
multiple aspects of DAS (overall adjustment
correlated with cohesion, r = 0.38, p < 0.01)
Pre-adolescents had significantly higher
correlations for family cohesion on: overall
adjustment (p = 0.02), peer relationships
(p = 0.008), attitude to diabetes (p = 0.03),
body image concerns (p = 0.05), compared
with adolescents
Patients offered free
outpatient care and
routine lab testing during
a 4-year period
Observational IIb–III
4-year study
period
Evidence tables
265
Mean age 12.9 ± 2.1
years, 19 boys,
,mean duration of
diabetes at study
entry 4.7 ± 3.7 years
Small sample size
Life events checklist
HbA1c
42 children with
type 1 diabetes
admitted to a
diabetes centre in
Boston, MA, USA
No significant differences observed between Measured at entry, 3, 6
groups
and 9 months
Self-efficacy
Aged 12–17 years
Mean age
14.4 ± 2.45 years,
51% female
Safyer et al,
1993665
Diabetes Stress Questionnaire
7.1
Communication between organisations
Study
Population
Intervention
Outcomes
Results
Melchionne,
1993670
159 teaching staff
(104 teachers
completed the
follow-up)
Diabetes education module
(n = 48)
1) Diabetes knowledge pre-test
(mean ± SD)
1) 17.33 ± 4.56 vs. 17.56 ± 3.47 vs.
15.57 ± 6.38
versus
2) Diabetes knowledge post-test
2) 21.47 ± 3.62 vs. 20.87 ± 2.26 vs.
17.50 ± 6.14
USA
literature (n = 44)
control (n = 12)
Greenhalgh,
1997666
156 school
personnel
USA
pre-test
versus
Diabetes knowledge pre-and post- 75 ± 11.0 vs. 94 ± 4.1, p < 0.004
test (mean ± SD)
post-test (lecture 1 to 1.5
hours) diabetes knowledge
25 primary school
Diabetes questionnaire
teachers and 60
secondary school
teachers who had
some contact with a
child with type 1
diabetes, and
responded to the
questionnaire
Design
EL
RCT
Ib
Noncontrolled
intervention
study
IIb
Survey
III
Survey
III
Post-test knowledge directional t-test:
diabetes education module vs. control,
p = 0.032; literature vs. control, p = 0.056
versus
Siminerio and
Koerbel,
2000671
Comments
Knowledge
Source of knowledge
38.8% were found to have adequate
knowledge of diabetes
In primary school teachers the main source
of information was parents of a child with
type 1 diabetes, 64% of secondary school
teachers received information from a wider
variety of sources, including radio,
television, other school staff, teaching
literature, newspapers and magazines
Originally 142
questionnaires sent out,
return rate 59.8%
Manchester, UK
Luddvigsson,
1977669
308 staff members Diabetes knowledge
in schools (17
questionnaire
school doctors, 34
school nurses, 83
canteen staff, 70
class teachers, 31
physical education
instructors, 20
vocational guidance
teachers)
255 who had
regular contact with
children with
diabetes
Sweden
Approximate % who have
inadequate or unsatisfactory
knowledge on general facts of
diabetes
School doctor: 35%
School nurse: 55%
Canteen staff: 80%
Class teachers with pupils with diabetes:
85%
Class teacher without pupils with diabetes:
80%
Physical education instructors: 85%
Vocational guidance teachers: 90%
Type 1 diabetes
266
Chapter 7 Continuity of care
Communication between organisations (continued)
Study
Population
Intervention
Bradbury and
Smith, 1983667
97 teachers of
students with
diabetes
Diabetes knowledge
questionnaire
Liverpool, UK
Outcomes
Results
Comments
22/97 admitted anxiety about having a child 132 questionnaires
with diabetes in their class
originally sent out –
73.5% returned
91/97 thought that it would be helpful to
have more information on diabetes and its
treatment and its treatment in relation to the
school child
Design
EL
Survey
III
Survey
III
Mean score out of 18 for all teachers: 10.4
(range 1–17)
Lindsay et al,
1987668
475 teachers
Diabetes knowledge
responded to survey questionnaire
sent to 800 teachers
USA
54% of teachers thought the cause of
diabetes was lack of insulin
23% of teachers thought the treatment of
diabetes was insulin injections
Random selection of
teachers (not just ones
with students who have
type 1 diabetes)
Evidence tables
267
Transition from paediatric to adult care
Study
Population
Intervention
Outcomes
Results
Kipps et al,
2002679
229 subjects with
type 1 diabetes
222 audit of notes
1) Mean age of transfer
1) 17.9 years (range 13.3–22.4 years)
164 interviewed by a single
nurse
2) Rate of clinical attendance (at
least 6-monthly)
> 18 and < 16
between the years
of 1985 and 1995
Oxford, UK
Comments
Design
EL
Survey
III
Survey
III
Survey
III
2) 2 years pre-transfer: 98%
1 year pre-transfer: 87%
2 years post-transfer: 81%
3) Rate of clinical attendance (3–4 2 years post-transfer: 61%
monthly)
p < 0.0005 2 years pre-transfer vs. 2 years
post-transfer
4) Transfer letter identified in
clinical record
3) 2 years pre-transfer: 77%
5) Attendance of first appointment
in new clinic
1 year pre-transfer: 54%
p < 0.0005 2 years pre-transfer vs. 2 years
post-transfer
4) 86%
5) 79%
Kipps et al,
2002679
229 subjects with
type 1 diabetes
> 18 and < 16
between the years
of 1985 and 1995
Glycaemic control
1) Age at transfer
2) Mean HbA1c at 2 years before
transfer comparing patients who
attended clinic 2 years posttransfer or had moved to GP care
1) Unrelated to transfer outcome (attendance
at clinic)
2) 9.9 ± 1.9% vs. 11.4 ± 1.9%, p = 0.0004
Oxford , UK
Kipps et al,
2002679
229 subjects with
type 1 diabetes
> 18 and < 16
between the years
of 1985 and 1995
Oxford, UK
Patients’ perception of transfer 1) Satisfaction with transfer
1) 57% satisfied
20% not satisfied
2) Patients’ perception of the
24% indifferent
importance of meeting adult clinic
staff prior to transfer
2) 10% very important
43% important
46% not important
1% discouraging
Type 1 diabetes
268
7.2
Transition from paediatric to adult care (continued)
Study
Population
Intervention
Datta, 2003680
42 young people
Questionnaire
attending an
adolescent or
transition clinic
Outcomes
Results
1) Do you know when the adult
clinic is held?
1) Definitely 6/42 (14%), have some idea
3/42 (7%), don’t know 33/42 (79%)
2) Do you know where the adult
clinic is held?
3) Do you know how often
appointments will be?
Comments
Design
EL
The data suggest that the Survey
young people have little
knowledge of adult clinic,
2) Definitely 11/42 (26%), have some idea
this may be due to not
7/42 (17%), don’t know 24/42 (57%)
having been prepared yet
3) Definitely 1/42 (2%), have some idea 6/42 as they are not going to
move for a while
(14%), don’t know 35/42 (84%)
III
4) Do you know which doctor you 4) Definitely 3/42 (7%), have some idea 6/42 There are no indications
that any of the outcomes
will see?
(14%), don’t know 33/42 (79%)
asked about lead to an
5) Do you know which nurse you 5) Definitely 0/42 (0%), have some idea 2/42 increase or decrease of
will see?
(5%), don’t know 40/42 (95%)
any clinically related
outcome
6) Have you met any of the
6) Yes, more than once 8/42 (19%), Yes,
doctors at the adult clinic?
once 3/42 (7%), no 23/42 (55%)not sure
8/42 (19%)
7) Have you met any of the nurses
at the adult clinic?
7) Yes, more than once 4/42 (9.5%), Yes,
once 4/42 (9.5%), no 23/42 (55%), not sure
11/42 (26%)
Evidence tables
269
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Datta, 2003680
43 young people
with unknown type
of diabetes
attending adult
clinic
Questionnaire
Preparation for transfer:
Preparation for transfer:
III
1) Did you see a leaflet about the
adult clinic?
1) Yes 4/43 (9%), no 29/43 (91%)
The data suggest that the Survey
young people have little
knowledge of adult clinic,
this may be due to not
having been prepared yet
as they are not going to
move for a while
2) Had you met any of the staff
beforehand?
3) Did you discuss the change
beforehand?
2) Yes 11/43 (26%), no 32/43 (74%)
3) Yes 15/43 (35%), no 28/43 (65%)
4) Yes 7/43 (16%), no 36/43 (84%)
5) Yes 23/43 (53%), no 20/43 (47%)
4) Did you have a choice when to 6) Yes 11/43 (26%), no 32/43 (74%)
move?
Feelings about moving to adult care:
5) Did you know which doctor
7) Yes 36/43 (84%), no 6/43 (14%), not sure
you would see
1/43 (2%)
6) Did you know which nurse you
8) Yes 17/43 (40%), no 25/43 (58%), not
would see?
sure 1/43 (2%)
Feelings about moving to adult
9) Yes 22/43 (51%), no 20/43 (47%), not
care:
sure 1/43 (2%)
7) Were you ready for the move?
10) Yes 4/43 (10%), no 38/43 (88%), not
8) Were you well prepared by the sure 1/43 (2%)
staff?
11) Yes 6/43 (14%), no 34/43 (79%), not sure
9) Were you not sure what to
3/43 (7%)
expect?
10) Were you worried about the
move?
11) Were you pleased to be
moving?
There are no indications
that any of the outcomes
asked about lead to an
increase or decrease of
any clinically related
outcome
Type 1 diabetes
270
Study
Population
Intervention
Outcomes
Results
Pacaud et al,
1996681
212 subjects with
type 1 diabetes
Questionnaire
1) Mean age of transfer
(mean ± SEM)
1) 18.5 ± 0.1 years
Referral to adult
clinic from child
clinic between
October 1990 and
October 1995
Two different
hospitals
Canada
2) Suggested age of transfer
(mean ± SEM)
3) Adult care services used by the
respondents for follow-up of there
diabetes care
4) If they felt they had a problem
with the transition from paediatric
to adult care
5) A delay of more than 6 months
between last visit at paediatric
clinic and first visit at adult clinic
Comments
Design
EL
Survey
III
2) 18.8 ± 0.2 years
5/212 answered age at transfer should
depend on each individual, 5/212 answered
never
21% felt they should have been transferred
earlier
39% felt they had been transfer at the
correct time
65% felt they should have been transferred
at a later age
(Numbers from original paper add up to
greater than 100% even though questions
seem to be mutually exclusive.)
3) 30% diabetes clinic, 54% endocrinologist,
3% family physician, 13% no regular
contact
4) 32.8% responded yes
5) 27.5% (In 17% the delay was more than 1
year)
Salmi et al,
1986682
61 consecutive
HbA1 measured at 3-monthly
cases of adolescent intervals for year before and
diabetes followed 1 year after transfer
year before and 1
year after the
patients were
referred from a
paediatric to adult
clinic
1980–1983
Finland
1) Mean HbA1
1) 1 year before transfer: 11.2 ± 2.2% (n = 49)
2) Mean age at transfer
first visit at the adult clinic: 11.2 ± 2.3%
(n = 49)
NonIII
experimental
descriptive
study
1 year after transfer: 9.9 ± 1.7% (n = 49)
p < 0.001
2) 17.5 ± 0.5 years (range 16.5–18.8 years)
Decision made by paediatrician after
verifying cessation of stature growth, full
pubertal development and some degree of
social maturation
Evidence tables
271
Study
Population
Intervention
Outcomes
Results
Comments
Design
EL
Court, 1993683
105 patients with
type 1 diabetes
Questionnaire
1) Preferred sources of further
adult care (more than one picked
by some patients)
1) 72.3% public hospital (range to chose
from), 42.9% private specialist, 14.3% GP
only, 1.9% don’t know, 1.9% don’t care
152 questionnaires sent
(105 received back)
Survey
III
2) Best age of transfer
2) 5.7% felt before the age of 17 years
Survey
III
Survey
III
Mean age 16.5 ± 0.9
(range 15–18 years)
Australia
48.6% felt between the ages of 17 and 20
years
44.8% felt any age up to 25 years
Eiser et al,
1993684
69 young people
Questionnaire on experiences 1) Mean age on transfer (n = 69)
1) 15.9 years (range 12–20 years)
with type 1 diabetes in transferring from a
2) Patient knowledge of any
2) 27.3% offered some reasons
paediatric clinic
Exeter, UK
special reasons for transfer (n = 69)
3) Patients considered it helpful to visit the
3) Importance of visits before
under-25 clinic before transfer: 3.4
transferring (mean rating, from
Greater coordination between paediatricians
scale 0 = not at all important,
5 = very important indeed) (n = 69) and physicians: 3.4
If a nurse from the under-25 clinic visited the
4) Patients’ perceptions on the
paediatric clinic: 3.3
importance assigned by staff in
paediatric and adult clinic to
Adult physicians visiting the paediatric
aspects of the treatment and social clinic: 2.2
life (n = 41)
4) Diet: 4.2 vs. 4.6, NS
Paediatric vs. adult clinic (mean
Exercise: 3.7 vs. 4.2, p < 0.05
rating, from scale 0 = not at all
important, 5 = very important
School progress: 2.9 vs. 2.4, p < 0.05
indeed)
Family relations: 3.3 vs. 2.7, p < 0.05
Avoidance of complications: 4.5 vs. 4.9,
p < 0.05
Blood glucose level: 4.5 vs. 4.9,
p < 0p < 0.05
Insulin management: 4.1 vs. 4.5, NS
Privacy: 2.7 vs. 2.6, NS
Jefferson et al,
200318
paediatricians
identified as
providing care for
children with
diabetes aged under
16 years; 244
returned
questionnaire
UK
Age of transfer
14% at 14–16 years
31% at 16 years
45% at 16–20 years
2% at patient’s preference
(no information given on the final 8%)
53% transfer young people into a young
adult diabetes clinic
Children and young
people cared for
n = 17 192
Type 1 diabetes
272

Type 1 diabetes: diagnosis and management of type 1 diabetes

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