Pathogenesis of Type 2 Diabetes Ominous Octet T2D treatment

27/05/2015
Ominous Octet
RCGP ONE-DAY ESSENTIALS
DIABETES
Thursday 21 May 2015 London
Decreased
Incretin Effect
Decreased Insulin
Secretion
Increased
Lipolysis
Islet– cell
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HYPERGLYCEMIA
The appropriate use of oral blood glucose
lowering agents in a confusing landscape
Increased
Glucagon
Secretion
Increased
Hepatic Glucose
Production
Decreased Glucose
Uptake
Neurotransmitter
Dysfunction
Jane Diggle BSc (Hons) RGN
Practice Nurse, South Kirkby, West Yorkshire
Adapted from DeFronzo R et al. Diabetes. 2009;58:773-795.
T2D treatment options and their primary mode of action
Overview of session
• Recap on the complex pathophysiology of type 2 diabetes
Pancreas
• The pros and cons of different drug classes
•
Increased
Glucose
Reabsorption
Impaired beta-cell
dysfunction
Liver
Making sense of the guidelines
• Adopting an individualised approach – making the right
prescribing decision for each patient.
Muscle & Fat
Gut
Diminished
Incretin effect
Metformin
Pioglitazone
(Insulin)
Oral Glucose-Lowering Agents: An Overview
Increased Glucose
Production
Liver
MuscleLiver
Adapted from DeFronzo RA. Diabetes. 1988;37:667-687.
Effect on insulin secretion3,5
GI disorders
↓
↔
x
Nasopharyngitis
↔
↑*

Hypoglycaemia,
Weight gain
↔
↑
Risk of hypos1,5
Common adverse events1,2,5
Metformin
↔
x
DPP‐4 inhibitors
↔
Sulphonylureas
Decreased
Glucose Uptake
Effect on insulin resistance2,3,4,5
Effect on weight1,5
Impaired Insulin
Secretion
Hyperglycemia
SGLT-2 inhibitors
Insulin
resistance &
reduced
glucose uptake
DPP-4 inhibitors
GLP-1 RA
Pancreas
Glucose
reabsorption
↓Glucose level
Increased hepatic
glucose output
Metformin
Pioglitazone
DPP-4 inhibitors
GLP-1 RA
Insulin
Pathogenesis of Type 2 Diabetes
Kidney
Sulphonylureas
Glinides
DPP-4 inhibitors
GLP-1 RA
Insulin
↑
SGLT2 inhibitors
↓
x
Urinary/genital infection
↓
↔
Glinides
↑

Hypoglycaemia,
Weight gain
↔
↑
↓
↔
↔
↑
Thiazolidinediones
↑
x
Weight gain,
Fluid retention
GLP‐1 RA
↓
x
Nausea
1. AACE/ACE Endocrine Practice 2009:15(6); 540-559
2. Aschner P, et al. Diabetes Care.2006;29(12):2632-7
3. Matthaei S, et al. Endocrine Reviews. 2000;21:585–618
4. Raptis SA & Dimitriadis GD. J Exp Clin Endocrinol. 2001;109:S265–S287.
5. Kim Y & Babu A. Diabetes Metab Syndr Obes. 2012;5:313-27
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27/05/2015
Meglitinides or Prandial Glucose Regulators
Name
Trade Name
Initial daily dose
Repaglinide
Prandin
0.5 mg
Min/max daily dose
0.5 mg - 16 mg
Nateglinide
Starlix
60 mg
120 mg
180 mg
60 mg - 540 mg
•
Stimulate insulin release from the pancreas.
•
Rapid onset of action and short duration of activity.
•
Must be taken at the meal times and omitted if a meal is missed.
•
Particularly effective at lowering post-meal BG levels.
•
Associated with weight gain and hypoglycaemia.
•
Contraindicated in patients with severe liver or renal disease.
Thiazolidenediones (Glitazones)
Metformin
Name
Trade Name
Initial daily dose
Min/Max daily dose
Metformin
(immediate release)
Glucophage
500 mg
500-2000 mg with
food
Metformin
(prolonged release)
Glucophage SR
500 mg
500 mg - 2000 mg
Name
Trade Name
Initial daily dose
Min/max daily dose
Pioglitazone
Actos
15 mg
15 - 45 mg
•
Increase body’s sensitivity to insulin in muscle, liver & adipose tissue.
•
Possible 6-8 week delay before full therapeutic effect is seen.
•
•
Reduces hepatic glucose production, improves insulin sensitivity and increases
peripheral glucose uptake.
Associated with weight gain and in some patients fluid retention (may exacerbate or
precipitate heart failure and contraindicated in those with history of heart failure).
•
Low risk of hypos.
•
Not associated with weight gain, rarely causes hypoglycaemia.
•
Increased risk of fracture in women (possibly men).
•
GI side-effects are common at initiation, but usually resolve. Increase dose
gradually over several weeks and consider trial of extended-absorption metformin
where GI tolerability prevents continuation of the therapy.
•
Possible increased risk of bladder cancer (avoid in patients with active or history of
bladder cancer, or with uninvestigated macroscopic haematuria).
•
•
Temporarily discontinue before elective surgery and administration of iodinated
contrast agents due to risk of renal failure.
Contra-indicated in patients with heart failure or active liver disease, and women of
child-bearing age considering pregnancy.
•
Rarely can provoke lactic acidosis. Avoid in patients at risk e.g. advanced renal
insufficiency.
•
Check liver function prior to commencing therapy, and periodically thereafter. Stop if
ALT rises to more than three times upper limit of normal.
•
•
Review dose if serum creatinine >130µmol/l or eGFR <45ml/min/1.73m². Stop if
serum creatinine >150µmol/l or eGFR <30ml/min/1.73m².
Only continue therapy where there is a reduction in HbA1c of ≥0.5% in 6 months.
Sulphonylureas
Name
Trade Name
Glibenclamide
Gliclazide
•
•
•
•
•
Min/Max daily dose
5 mg
5 - 15 mg
40 - 80 mg
30 mg
40 - 320 mg
30 - 120 mg
Glipizide
Minodiab
2.5 – 5 mg
2.5 - 20 mg
Glimepiride
Amaryl
1 mg
1 - 6 mg
500 mg
500 - 2000 mg
Tolbutamide
•
Diamicron
Diamicron MR
Initial daily dose
Stimulate pancreas to secrete insulin in non-glucose dependent way. Only effective
when residual pancreatic ß-cell activity is present.
Lower BG levels quickly so useful where BG particularly high & patient symptomatic.
Associated with modest weight gain and a risk of hypoglycaemia (greater risk in
elderly and those with renal impairment, if meals are missed or delayed or after
prolonged or vigorous activity, alcohol).
May be loss of efficacy with time as ß-cell function declines.
Use with caution in moderate renal impairment.
Consider offering self-monitoring equipment for those at particular risk of hypos (e.g.
drivers)
DPP-4 Inhibitor Mode of Action
Insulin increased:
Glucose-dependent
GLP-1/GIP stimulation
of β-cells
Gliptins
inhibits DPP-4
action 
GLP-1 action
prolonged
•
•
•
•
•
Food ingested
Incretins released in gut (GLP-1 & GIP)
Incretins promote insulin secretion
GLP-1 inhibits glucagon secretion
Increased
glucose uptake

Glucagon
decreased:
Glucose-dependent
GLP-1 inhibition of
α-cells

Glucose
homestasis
Decreased
hepatic
glucose
production
DPP-4 rapidly degrades GLP-1 & GIP
GLP-1: glucagon-like peptide-1; GIP: gastric-inhibitory polypeptide; DPP-4: dipeptidyl peptidase-4
Adapted from: Drucker DJ, J Clin Invest 2007;117:24–32.
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Sodium glucose co-transporter-2
(SGLT-2) inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Name
Trade Name
Initial daily dose
Min/Max daily dose
Sitagliptin
Januvia
100 mg once daily*
100mg*
Name
Trade Name
Initial daily dose
Min/Max daily dose
Vildagliptin
Galvus
50 mg twice daily*
100mg (50mg if also
taking SU)*
Dapagliflozin
Forxiga
10 mg once daily*
5 - 10 mg
Saxagliptin
Onglyza
5 mg once daily*
5mg*
Canagliflozin
Invokana
100 mg once daily
100 – 300 mg
Linagliptin
Trajenta
5 mg once daily
5mg
Empagliflozin
Jardiance
10 mg once daily
10 – 25 mg
Alogliptin
Vipidia
25 mg once daily*
25 mg*
•
Inhibit DPP-4 activity, increasing postprandial active incretin (GLP-1 and GIP)
concentrations to increase insulin secretion and reduce glucagon secretion, both in
a glucose-dependent manner.
•
Generally weight-neutral and low risk of hypoglycaemia.
•
Rare cases of acute pancreatitis (inform patients of typical signs: persistent severe
abdominal pain).
•
NICE recommended only continue therapy if HbA1c reduced by at least 0.5% within
6 months of starting treatment.
•
*Refer to SPC for dose adjustments in renal impairment.
•
Inhibit SGLT-2 in the kidney to reduce glucose absorption and increase urinary
glucose excretion.
•
Can cause weight loss and associated with low risk of hypoglycaemia.
•
Associated with increased diuresis and modest reduction in blood pressure.
•
Should not be initiated when eGFR is <60 ml/min/1.73m2. Lower doses of
Empagliflozin and Canagliflozin may be continued if eGFR falls to 45-60
ml/min/1.73m2.
•
May be associated with an increased risk of vulvovaginitis, balanitis and related
genitals infections and urinary tract infections (mostly mild to moderate and respond
well to standard treatment).
*Reduce dose to 5mg in severe hepatic impairment.
In normal glucose homeostasis, the kidneys filter and
reabsorb ~180 g of glucose per day1,2
GLP-1 Mechanism of Action
Net balance ~0 g/day
Glucose input ~250 g/day:
Glucose uptake ~250 g/day:
• Dietary intake ~180 g/day
• Glucose production ~70 g/day
Gluconeogenesis
Glycogenolysis
+
The kidney reabsorbs
and recirculates
glucose
The kidney filters
circulating glucose
Glucose filtered
~180 g/day
Glucose reabsorbed
~180 g/day
(Renal threshold for glucose
reabsorption is ~200 mg/dL)
1. Gerich JE. Diabet Med 2010;27:136–42.
2. Marsenic O. Am J Kidney Dis 2009;53:875–83
SGLT-2 inhibitors inhibit SGLT-2 and remove excess
glucose via the urine (independently of insulin)
90% of glucose is reabsorbed
in proximal tubule by SGLT2.
SGLT-2
inhibitorsglucose
reduce this
Reduced
absorption.
reabsorption
Proximal
tubule
Proximal
tubule
SGLT-2
Glucose
SGLT-2 inhibitor
Glucose
filtration
GLP-1 secreted upon
the ingestion of food
• Brain ~125 g/day
• Rest of the body ~125 g/day
10% of glucose is
reabsorbed in distal
segment of tubule by
SGLT-1.
*Increases urinary volume by only ~1 additional void/day (~375 mL/day)
−
2.α-cell:
Suppresses
postprandial
glucagon secretion
3.Liver:
reduces hepatic
glucose output
1.-cell:
Enhances glucosedependent insulin
secretion in the pancreas
In healthy subjects, the incretin
effect accounts for up to 70% of
the total amount of insulin
released in response to an oral
glucose load (Elrick et al, 1964)6.
4.Stomach:
slows the rate of
gastric emptying
Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3Nauck
MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.
6Elrick H, Stimmler L, Hlad CJJr, Rai Y (1964) Plasma insulin responses to oral and intravenous glucose administration. J Clin
Endocrinol Metab 24: 1076-1082
GLP-1 Agonists
Name
Trade Name
Initial daily dose
Min/Max daily dose
Dulaglutide
Trulicity
0.75 – 1.5 mg in
prefilled pen
0.75 – 1.5 mg once weekly
Exenatide BID
Byetta
5mcg in prefilled
pen
5mcg twice daily – 10 mg twice
daily (doses >6 hrs apart & 60 mins
Exenatide QW
Bydureon
2mg powder &
solvent in prefilled
pen
2 mg once weekly
Liraglutide
Victoza
0.6 mg
0.6 mg – 1.8 mg once daily (NICE
does not recommend the 1.8 mg
dose)
Lixisenatide
Lyxumia
10 mcg prefilled
pen
10mcg increasing to 20mcg once
daily (60 mins before main meal).
•
Increased urinary
excretion of excess
glucose (~70 g/day,
corresponding to
280 kcal/day*)
5.Brain:
Promotes satiety and
reduces appetite
before meal).
Stimulate insulin secretion, decrease glucagon secretion in glucose-dependent
manner and slow gastric emptying.
•
Can cause weight loss and low risk of hypoglycaemia.
•
Rare cases of pancreatitis.
•
Most frequent adverse reactions are GI-related especially nausea but usually
transient.
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27/05/2015
…in a nutshell
What about the guidelines?
• Metformin (Standard release only) or Repaglinide
• THEN
(stop Repaglinide → Pio + SU )
• Metformin + Pioglitazone or Met + Sulfonylurea or Met + DPP4-I
• THEN
• Metformin + Pio + SU or Met + SU + DPP4-I
• THEN
• Metformin (or Pio) + SU + NPH Insulin or (Met + SU + GLP-1)
NICE CG 87 (2009)
Confused?
NICE Draft for Consultation
January 2015
The American Diabetes Association and European Association for the Study of Diabetes joint position statement
on the management of hyperglycaemia in type 2 diabetes can be found at
http://care.diabetesjournals.org/content/35/6/1364.long
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A stepwise approach to treatment intensification is
advocated as glycaemic control deteriorates but ……..
One size does not fit all!
Individualisation is key
Factors to consider:
Other factors to consider
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2
diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD). Diabetes Care; 2015;38:140-149
Involve patients
Need to consider renal function
Involving patients in prescribing decisions and supporting
them in taking their medicines is key to improving patient
safety, heath outcomes and satisfaction with clinical care.
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27/05/2015
Hypoglycaemia Risk & Consequences
Brain
Blackouts,
seizures, coma
Cognitive
dysfunction
Psychological
effects
Cardiovascular
Myocardial
ischaemia
(angina and
infarction)
Cardiac
arrhythmia
Financial Costs
(but also value for money!)
Musculoskeletal
Falls, accidents
(driving)
Fractures,
dislocations
• Around 80 per cent is spent on complications.
• Acquisition costs versus long-term outcomes.
Wright RJ, Frier B (2008) Diabetes Metab Res Rev 24: 353–63; Malabu UH et al (2014) Clin Epidemiol 6: 287–94
Don’t forget guidelines are NOT absolutes!
According to NICE (2009) and subsequent Technology
Appraisals, pioglitazone,1 DPP-4 inhibitors1 and SGLT-2
inhibitors2,3 may be considered second-line (after
metformin) when, “…the person is at significant risk of
hypoglycaemia or its consequences (for example, older
people and people in certain jobs [e.g. those working at
heights or with heavy machinery] or people in certain social
circumstances [for example, those living alone])”
“Clinical guidelines are recommendations on the appropriate
treatment and care of people with specific conditions that are
based on the best available evidence. They are designed to
help healthcare professionals in their work, but do not
replace their knowledge and skills.”
NICE (2014) Clinical guidelines. NICE, London.
Available at: www.nice.org.uk/CG (accessed: 23.05.2014)
DPP-4=dipeptidyl peptidase-4; SGLT-2=sodium–glucose cotransporter-2.
1. NICE (2009) Available at: www.nice.org.uk/cg87 (accessed 20.10.2014)
2. NICE (2014) Available at: https://www.nice.org.uk/guidance/ta315 (accessed 30.10.2014)
3. NICE (2013) Available at: https://www.nice.org.uk/guidance/TA288 (accessed 30.10.2014)
Weight Gain
“This guidance represents the view of NICE […] Healthcare
professionals are expected to take it fully into account when
exercising their clinical judgement. However, the guidance does not
override the individual responsibility of healthcare professionals to
make decisions appropriate to the circumstances of the individual,
in consultation with the patient and/or guardian or carer, and
informed by the summary of product characteristics of any drugs
they are considering.”
90% of adults with type 2 diabetes aged 16-54 years in England are
overweight or obese.
National Diabetes Audit Report (2014)
The worst thing that can happen to a person with T2D who is
overweight or obese is to be prescribed a therapy that causes weight
gain and increases their insulin resistance.
NICE (2009) Type 2 Diabetes – newer agents (partial update of CG66)
(CG87). NICE, London. Available at: www.nice.org.uk/cg87 (accessed
23.05.2014)
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