Controllo Metabolico e Rischio Cardiovascolare Maria Rosaria Rizzo

Simposio
IL DIABETE NEL PAZIENTE
ANZIANO
Controllo Metabolico e
Rischio Cardiovascolare
Maria Rosaria Rizzo
Dipartimento di Scienze Mediche, Chirurgiche,
Neurologiche, Metaboliche e dell’invecchiamento
Seconda Università Napoli
Piette JD et al, Diabetes Care 2006; Struijs JN et al, BMC Health Serv Res 2006
A retrospective case notes review of 75 people with diabetes in 11 nursing homes in the UK visited February-April 2010.
Gadsby R et al Diabet Med 2011
Adapted from IDF. Time to Act: Type 2 diabetes, the metabolic syndrome and cardiovascular disease in Europe, 2006;
IDF. Time to Act 2001; Seaguist ER, Diabetes 2010
Hyperglycaemia, insulin resistance, and cardiovascular disease
The Risk Factors Continuum
Myocardial
Infarction
Atherosclerosis
and LVH
Hypertension
at high risk
Hypertension
Dyslipidaemia
Diabetes
Remodeling
Congestive
Heart Failure
End-Stage
Heart Disease
and Death
An observational cross-sectional study based on review of medical records and interviews of 123 Type 2 Diabetes in
Geenland. Mean duration of diabetes 6 years.
Pedersen ML et al, Circum. Health 2010
*Adjusted for age, smoking status, BMI, systolic blood pressure, and where appropriate stratified by sex and trial armŦ
Includes both fatal and non-fatal events.
Emerging Risk Factors Collaboration Lancet 2010
Diabetes Care 28:2901–2907, 2005
Incidence per 1,000 person-years and Cox model hazard ratio for CHD death (adjusted for age, area of residence, and sex) during the
18-year follow-up according to the presence of diabetes and prior evidence of MI in 1,373 nondiabetic and 1,059 diabetic subjects
ACCORD –ADVANCE - VADT
Stralton IM et al; BMJ 2000
N Eng J Med 2012
ORIGIN-Outcome Reduction with an Initial Glargine Intervention Trial
This study randomized 12 537 people (mean age, 63.5 years) at high CVD risk plus IFG, IGT or T2DMto receive
insulin glargine (with a target fasting blood glucose level of 5.3 mmol/L (≤95 mg/dL) or to standard care.
After a median follow-up of 6.2 years, the rates of incident CV outcomes were similar in the insulin glargine and
standard care groups.
N Engl J med 2007
Rates of Myocardial Infarction and Death fromCardiovascular Disease
Cardiovascular safety of glucose-lowering agents
Metformin, Sulfonylureas, Pioglitazone
UKPDS follow-up-Myocardial Infarction Hazard Ratio
Cardiovascular safety of sulfonylureas:
a meta-analysis of randomized clinical trials
N Eng J Med 2008
Diabetes, Obesity and Metabolism 2013
PROACTIVE study-Pioglitazone and macrovascular events
Lancet 2005
Monami M et al Curr Med Res 2011
(MACE)
…………..The present meta-analysis suggest a possible direct effect protective from cardiovascular events…………..
Monami M et al Curr Med Res 2011
53 trials
trial duration was 24-104 wks
(MACE)
20.312 patients
13.569 patients
….This result should be interpreted with caution, as those events were not the principal endpoint, the trial duration was short and the
characteristics of patients included could be different from routine clinical practice. DPP4 I were associated with a significantly lower risk
of MACE irrespective of trial duraion, type of DPP4I or comparator…….
The difference in the incidence of MACE between GLP-1 RA and comparators did not
reach statistical significance
A total of 37 trials fulfilling the inclusion
criteria were identified.
Retrieved trials included 8619 and 6779
patients in GLP-1 RA and comparator
groups, respectively; mean trial duration
was 42 weeks.
Of those, 33, 29, 29, 33 and 31 reported
information on MACE,MI, stroke, allcause and cardiovascular mortality,
respectively.
The mean age, duration of diabetes,
baseline HbA1c and body mass index
(BMI) of enrolled patients were 56.0
years, 6.7 years, 8.4% and 31.6 kg/m2,
respectively.
70
42.959 patients
trial duration was 24-104 wks
AMI
Stroke
Mortality
CV Mortality
Global cardiovascular risk
Global cardiometabolic risk
Gelfand EV et al, 2006; Vasudevan AR et al, 2005
Effects of GLP-1 receptor agonists and DPP4 inhibitors on
cardiovascular risk factors
Parks M. Clinical perspectives on FDA guidance for industry: Diabetes mellitus –evaluating CV risk in new anti-diabetic
therapies to treat T2DM. Available at: http//www.fda.gov/downloads/Drugs/NewsEvents/UCM209087.pdf
•
Evaluate CV end points in Phase II and III studies.
• Establish independent CV end point adjudication committees for each
Phase II or III study.
• Perform a meta-analysis of CV end points across all Phase II and III trials .
• Demonstrate that the upper bound of the two-sided 95 percent confidence
interval for the estimated increase in CV risk across all Phase II and III
studies has a hazard ratio (HR) less than 1.8. If the HR upper bound is less
than 1.3, a post-marketing trial of CV risk may not be necessary.
For completed studies, before submission of the new drug application (NDA)/biologics
license application (BLA):
……….a postmarketing trial generally will be necessary to definitively show that the upper
bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less than
1.3. This can be achieved by conducting a single trial that is adequately powered or by combining
the results from a premarketing safety trial with a similarly designed postmarketing safety trial.
This clinical trial will be a required postmarketing safety trial
Scirica BM, et al. N Engl J Med. 2013; White WB, et al. N Engl J Med. 2013 .
SAVOR
Saxagliptin Assessment of Vascular Outcomes recorded in Patients with diabetes mellitus
International, Multi-Center, Phase 4 Study, Randomized, Double blindRANDOMIZE
1:1 DOUBLE BLINDOMIZE 1:1 DOUBLE BLIND
1. Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684; 2. Mosenzon O, et al. Diabetes Metab Res Rev. 2013;29:417-426.
N Engl J Med 2013
Study Design
Superiority
N≈16,500
patients
Documented T2DM and established CVD (secondary prevention)
or multiple CV risk factors (primary prevention)
SAXAGLIPTIN
5 mg/d
(2.5 mg for eGFR ≤50 ml/min)
RANDOMIZE 1:1 DOUBLE BLIND
Dosing based on eGFR
All other diabetes therapy per
treating doctors
Follow-up visits
Q6 months
Final Visit
PLACEBO
All other therapy for the management of the
patient’s diabetes and cardiovascular
disease — including adding, discontinuing,
or changing the dose of concomitant
antihyperglycemic drugs — was at the
discretion of the responsible physician.
CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate
Scirica BM, et al. Am Heart J. 2011;162:818-825. (Permission requested)
29
N Engl J Med 2013
Key Inclusion and Exclusion Criteria
Inclusion Criteria1
Documented T2DM and HbA1c 6.5% and <12.0%; AND
History of Established CVD
• 40 yrs
• Documented atherosclerosis
(coronary, cerebrovascular, PV)
Multiple risk factors:
OR • 55 yrs (male) or 60 yrs (female)
• 1 additional risk factor
(dyslipidemia, HTN, smoking)
Exclusion Criteria
1,2
•Current or previous (within 6 months) incretin-based therapy†
•Acute vascular (cardiac or stroke) event <2 months before randomization
†Includes other DPP-4 inhibitors and GLP-1 agonists
GLP-1: glucagon-like peptide 1; PV: peripheral vascular ; HTN = hypertension
1. Scirica BM, et al. N Engl J Med. 2013.10.1056/NEJMoa1307684; 2. Scirica BM, et al. Am Heart J. 2011;162:818-825.
30
N Engl J Med 2013
Study Design
Documented T2DM and established CVD (secondary prevention)
or multiple CV risk factors (primary prevention)
N≈16,500
patients
SAXAGLIPTIN
5 mg/d
(2.5 mg for eGFR ≤50 ml/min)
RANDOMIZE 1:1 DOUBLE BLIND
Dosing based on eGFR
All other diabetes therapy per
treating doctors
Follow-up visits
Q6 months
Final Visit
CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate
Scirica BM, et al. Am Heart J. 2011;162:818-825. (Permission requested)
PLACEBO
Primary endpoint
CV death, non-fatal MI,
non-fatal ischemic
stroke
Secondar endpoint
Primary composite +
Hospidalization for HF
and coronary
revascularization or
unstable angina
31
N Engl J Med 2013
Prespecified Clinical End Points
N Engl J Med 2013
In this randomized, placebo-controlled trial, the DPP-4 inhibitor saxagliptin neither reduced nor increased the risk
of the primary composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, when added
to the standard of care in patients at high risk for cardiovascular events, thus meeting the criterion for non
inferiority to placebo but not providing any cardioprotective benefit.
Saxagliptin CV Safety
Pooled Analysis (8 trials ) From Phase 2/3 Development Program (N = 4607)
•
Saxagliptin-treated patients vs control patients had a lower rate of CEC-adjudicated MACE
Percent With First Event
Time to onset of first MACE*
5
HR = 0.42; 95% CI (0.23–0.80)
4
3
Control
2
All Saxa
1
0
Baseline
Patients at Risk
Control
1251
All Saxa
3356
24
37
50
63
76
89
102 115 128
144
498
123
436
Time (weeks)
935
2651
860 774 545
2419 2209 1638
288
994
102
373
57
19
Conclusion: No increased risk of CV death/MI/stroke
*Includes CV death, MI, and stroke ; CEC, clinical events committee; MACE, major adverse CV event
Frederich R, et al. Postgrad Med. 2010;122:16-27.
N Engl J Med 2013
Study Design
Documented T2DM and established CVD (secondary prevention)
or multiple CV risk factors (primary prevention)
N≈16,500
patients
SAXAGLIPTIN
5 mg/d
RANDOMIZE 1:1 DOUBLE BLIND
(2.5 mg for eGFR ≤50 ml/min)
Dosing based on eGFR
All other diabetes therapy per
treating doctors
Follow-up visits
Q6 months
Duration
Event driven;
≈1040 events required
Final Visit
CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate
Scirica BM, et al. Am Heart J. 2011;162:818-825. (Permission requested)
PLACEBO
Primary endpoint
CV death, non-fatal MI,
non-fatal ischemic
stroke
Secondar endpoint
Primary composite +
Hospidalization for HF
and coronary
revascularization or
unstable angina
35
N Engl J Med 2013
Prespecified Clinical End Points
EXAMINE
Examination Outcomes with Alogliptin versus Standard of Care
Multi-Center, Phase 4 Study, Randomized, Double blind
N Engl J Med 2013
Study Design
Non inferiority
N≈5,380
patients
Documented T2DM and acute coronary syndrome within 15-90
days before randomization (secondary prevention)
RANDOMIZE 1:1 DOUBLE BLIND
ALOGLIPTIN
25 mg/d
Dosing based on eGFR
PLACEBO
12.5 mg for eGFR 60 -30 ml/min
6.5 mg for eGFR < 30 ml/min
Primary endpoint
CV death, non-fatal MI,
non-fatal ischemic
stroke
Follow-up visits
1, 3, 6, 9, 12
months after
randomization
Final Visit
Secondar endpoint
Primary composite +
urgent revascularization
due to unstable angina
within 24 hours after
hospital admission
38
N Engl J Med 2013
MAJOR SAFETY END POIN
N Engl J Med 2013
N Engl J Med 2013
Numerous Studies Assessing CV Outcomes in T2DM Drugs
Are Either Recently Completed or Ongoing
Drug
Target
Enrollment
Timing*
Saxagliptin
Alogliptin
Sitagliptin
Linagliptin
Linagliptin
N=16,492
N=5384
N=14,000
N=6000
N=8300
Began 2010; Complete
Began 2009; Complete
Began 2008; Ending 2014
Began 2010; Ending 2018
Began 2013; Ending 2018
Lixisenatide
Exenatide
Liraglutide
Dulaglutide
Semaglutide
N=6000
N=9500
N=9340
N=9622
N=3260
Began
Began
Began
Began
Began
CANVAS
Canagliflozin
N=4410
Began 2009; Ending 2018
C-SCADE 8
Empagliflozin
N=7000
Began 2010; Ending 2018
DECLARE
Dapagliflozin
N=17,150
Began 2013; Ending 2019
Trial Name
DPP-4 Inhibitors
SAVOR
EXAMINE
TECOS
CAROLINA
CARMELINA
GLP-1 Agonists
ELIXA
EXSCEL
LEADER
REWIND
SUSTAIN 6
SGLT-2 Inhibitors
2010; Ending
2010; Ending
2010; Ending
2011; Ending
2013; Ending
2014
2017
2016
2019
2016
*Trial ending dates are anticipated based on publicly available information.
Clinicaltrials.gov; Accessed on Aug 12, 2013.