Cardiovascular Outcomes Trials  in Diabetes

M. Angelyn Bethel, MDDeputy Director

University of Oxford Diabetes Trials UnitOxford, UK

How did we get here & where are we going?

Cardiovascular risk in diabetes

Emerging Risk Factors Collaboration. Lancet 2010; 375: 2215-22

Analyses based on 530,083 participants from 102 prospective studies.HRs adjusted for age, smoking status, body-mass index and systolic blood pressure, and, where appropriate, stratified by sex and trial arm.

Reducing risk for complications

•

Microvascular–

Glucose

–

Blood pressure (esp retinopathy, nephropathy)–

Lipids

–

Smoking cessation•

Macrovascular–

Blood pressure

–

Lipids–

Antiplatelet agents

–

Smoking cessation –

Glucose?

THE ROLE OF GLUCOSE CONTROL IN

MACROVASCULAR DISEASE

UKPDS-PTM: Myocardial Infarction Hazard Ratio

(fatal or non-fatal myocardial infarction or sudden death)

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI)

UKPDS 80.  NEJM (2008); 359:1577‐1589

Diabetologia (2009); 52:2288‐2298

Meta-analysis: glucose control and macrovascular disease

Major CV events↓9%

MI↓15%

WHAT IS THE THRESHOLD FOR  HARM?

Meta-analysis: Intensive glucose control & mortality

Diabetologia (2009); 52:2288-98

•

Hypoglycemia–

? Adrenergic overdrive

–

? Causal pathway for mortality or macrovascular events

•

Off-target effects of therapeutic choices–

Cardiovascular morbidity?

–

Fractures?–

Cancer?

–

Pancreatitis?

Defining the risks of overtreatment

(unproven)

(unproven)

Real uncertainty about off-target effects

Can a dirt-cheap diabetes drug fight cancer?

Judge sets first hearing for diabetes drug lawsuits

More Evidence Links Fractures to Diabetes 

DrugsAvandia, Actos Boost Fracture Risk in Older 

Women, Study Finds

Diabetes drug tied to pancreatitis, deaths

Study: Sanofi’s Lantus Insulin Has Possible 

Cancer Link

•

Standardize phase 2 & 3 programs to permit meta-analysis–

Prespecify subgroup analyses and statistical methods

–

Include patient groups representative of the target population (e.g. elderly, high CV risk)

–

Standardize event collection & independent adjudication

•

CV mortality, MI, stroke (±

ACS hospitalization, urgent revascularizations)

•

Use meta-analysis to assess CV risk

2007 FDA guidelines for diabetes drug approval—more than HbA1c

FDA guidance: confidence intervals for meta-analysis

Upper bound of a 2‐sided 95% confidence interval  for estimated CV risk

>1.8 The data are inadequate to support approval.  A large safety trial should be conducted

1.3 – 1.8 The potential for CV harm may still exist.  An adequately powered and designed post‐

marketing trial is necessary to show an upper  bound < 1.3*

<1.3 A post‐marketing trial is generally not needed**with a reassuring point estimate for overall CV risk

FDA Guidance for Industry: Diabetes Mellitus –

Evaluating CV risk in new antidiabetic therapies to treat type 2 diabetes.  

www.fda.gov

FDA Guidelines impact trial design in  diabetes research

•

Search clintrials.gov database for registered trials–

Interventional phase 2 or higher–

Keywords: type 2 diabetes, impaired glucose tolerance, metabolic

syndrome

•

Trial characteristics•

Outcomes measured

March 2008March 2005 March 2011

FDA guidance issued

Curr Card Rep. 2012;14:59‐69

Trials are growing in number, size &  complexity

Pre‐FDA guidance(n=8)

Post‐FDA guidance(n=16)

Size, median (IQR) 1116 (300‐4447) 6000 (4082‐9313)

<1000, n(%) 3 2

1000 ‐

5000, n(%) 3 3

>5000, n(%) 1 11

Countries participating, median (IQR) 17 (1‐20) 27 (6‐35)

Sites participating, median IQR 160 (3‐332)  501 (183‐635)

Global distribution of participantsStudy US/Canada WE EE Middle East Africa Australasia LatinAmerica

Pre‐FDA GuidanceADVANCE X X XProactive X XHEART2D X X X X XSPREADDIMCAD XAleglitazar(term.)Acarbose XPhantom XRECORD X X X

Post‐FDA GuidanceTOSCA‐IT XTECOS X X X X X X XACE XEXAMINE X X X X X X XTIDE X X X X X X XSAVOR‐TIMI53 X X X X X X XEXSCEL X X X X X XELIXA X X X X X X XLEADER X X X X X X XCAROLINA X X X X X X XTaspog X X X X X X XCANVAS X X X X X XBI10773 X X X X X X XAAA XRASCIN XALECARDIO X X X X X X

Alignment of CV composites

Incretins•(GIP)•GLP‐1

Stimulate insulinrelease

Inhibit glucagonrelease

Reduceblood glucose

DPP4

Breakdownproducts DPP4 inhibitors

(“gliptins”)

GLP‐1 agonists/analoguese.g. exenatide

Inhibit renalre‐absorption

(SGLT2 inhibitors)

Inhibit gastro‐intestinal absorption(α‐glucosidase inhib’s)

New approaches to reducing blood glucose

Cardiovascular effects of incretin  therapies

GLP‐1 analogues•

SBP reduced 2‐4 mmHg

•

Weight loss•

~5% total cholesterol, LDL 

reduction•

Reductions in CRP, BNP

DPP‐4 Inhibitors•

SBP reduced 2‐3 mmHg

•

Weight neutral•

Small reductions in LDL 

(inconsistent finding)

Data from meta‐analyses

•

Included all available ≥

12 week trials•

Small number of CV events

GLP-1 Trial type Odds Ratio vs. comparator P Value

Placebo-controlled (n=3)

0.46 (0.18, 1.20) 0.11

Active comparator 0.99 (0.52, 1.91) 0.98

DPP-4 Trial type Odds Ratio vs. comparator

P Value

Placebo-controlled 0.86 (0.47, 1.59) 0.63Active comparator 0.76 (0.46, 1.28) 0.30

Monami et al, European J Endocrinol 2009;160:909-917Monami et al, European J Endocrinol 2009;160:909-917

Monami et al, J Nutr Metab Cardiovasc Dis 2010;20:224-235Monami et al, J Nutr Metab Cardiovasc Dis 2010;20:224-235

24 patients with 

MACE events

41 patients with  

MACE events

CV outcome trials in type‐2 diabetes mellitus:  GLP‐1 analogues

Trial Treatment Inclusion criteria Primary 

endpoint

Number of 

patients

ELIXA   PlaceboLixisenatide 

T2DMHbA1c 6.0% ‐

10.0% ACS

CV death, MI, 

UA or stroke

6000 

EXSCEL  PlaceboExenatide 

T2DMHbA1c 7.0% ‐

10.0%CVD in 60%

CV death, MI 

or stroke

9500 

LEADER  PlaceboLiraglutide 

T2DMHbA1c 

7.0% ≥50 years + CVD≥60 years + CV risk factors 

CV death, MI 

or stroke 

8754 

REWIND  PlaceboDulaglutide Add‐on: 2 oral 

agents +/‐

GLP‐1 

analogue/insulin

T2DM≥50 years + CVD≥55 years + subclinical CVD≥60 years + CV risk factorsHbA1c ≤9.5% 

CV death, MI 

or stroke

9600 

CV Outcome Trials in type‐2 diabetes mellitus:  DPP4 Inhibitors (“Gliptins”)

Trial Treatment Inclusion criteria Primary endpoint Number 

of 

patients

EXAMINE  PlaceboAlogliptin

T2DM HbA1c 6.5 –

11.0%

18 yearsACS

CV death, MI or stroke  5400 

TECOS  PlaceboSitagliptin

T2DM HbA1c 6.5 – 8.0%

50 yearsCVD

CV death, MI, UA or 

stroke

14000 

SAVOR(TIMI‐53) 

PlaceboSaxagliptin 

T2DM HbA1c 

6.5%

40 yearsCVD/CV risk factors 

CV death, MI or stroke 12000

CAROLINA GlimepirideLinagliptin

T2DM HbA1c 6.5‐8.5%40‐85 yearsCVD/CV risk factors/diabetes end organ damage 

CV death, MI, UA or 

stroke

6000

CV outcome trials in type‐2 diabetes mellitus:  SGLT2 inhibitors

Trial Treatment Inclusion criteria Primary 

endpoint

Number of 

patients

BI 10773 PlaceboBI 10773 (low)BI 10773 (high)

T2DM

18 yearsHbA1c 7.0 –

10.0%(7.0 – 8.0% drug naïve)CVD (CHD, stroke, PAD)

CV death, MI or 

stroke

4000

CANVAS PlaceboCanagliflozin 100mgCanagliflozin 300mg

T2DM

30 yearsHbA1c 7.0 –

10.5%History of/high risk of CVD

CV death, MI, 

UA or stroke

4500

CV outcome trials in type‐2 diabetes mellitus:  Glitazones and glitazars

Trial Treatment Inclusion criteria Primary 

endpoint

Number of 

patients

TOSCA IT Add‐on:PioglitazoneSulfonylurea

T2DM inadequately controlled on 

metformin50‐75 years BMI 20‐45 Kg/m2

HbA1c >7.0% <9.0%

Any death, 

MI, stroke, 

unplanned 

coronary 

revasc. 

5172

ALECARDIO  PlaceboAleglitazarPPARα

& PPARγ

T2DM

18 years HbA1c 6.0% ‐

10.0%ACS 

CV death, MI 

or stroke 

7000  

TIDE   FactorialPlaceboPioglitazoneRosiglitazoneVitamin D

T2DMHbA1c 6.5 – 9.5% 

50 years + CVD

55 years + subclinical CVD

60 years + 2 CV risk factors 

CV death, MI 

or stroke 

(TZD 

question) 

16000  

•

Hypoglycemia–

? Adrenergic overdrive

–

? Causal pathway for mortality or macrovascular events

•

Off-target effects of therapeutic choices–

Cardiovascular morbidity?

–

Fractures?–

Cancer?

–

Pancreatitis? Pancreatic cancer?

Defining the risks of overtreatment

(unproven)

(unproven)

•

Generally unexpected, sometimes rare events

•

Gold standard for evaluation remains RCT, but not always feasible

•

Other methodologies –

Epidemiology

–

Post-marketing surveillance–

Registries/Electronic Medical Record

Understanding off-target effects

But there are inherent biases

Biases in existing data collection methods

•

Incomplete Data•

Total number exposed is unknown

•

Reporting bias–

Affected by emerging therapies

–

Affected by media attention

•

Little information to assess–

Exposure time

–

Relatedness

Future of outcomes trials in diabetes

•

More complex trials require efficiencies of design &  conduct

•

Quantifying off‐target effects is the next challenge–

Common outcomes are easy to study (cardiovascular 

disease)–

Rare outcomes will require innovative approaches

THANK YOU

BACKUP SLIDES

Drug class Existing evidence Outcomes trials Number of patients

Metformin UKPDS, meta‐analysis 

suggests benefit

? ?

Glitazones/Glitazars Meta‐analysis suggests 

increased risk of CV 

morbidity for some

TOSCA‐ITALECARDIO

>11,000

DPP‐4 inhibitor Favorable

effects on CV 

risk factors

EXAMINETECOSSAVORCAROLINA

>35,000

GLP‐1 analogue Favorable effects on CV 

risk factors

ELIXAEXSCELLEADERREWIND

>33,000

SGLT‐2 inhibitor Favorable effects on CV 

surrogate markers

BI 10773CANVAS

>8500

Overview of ongoing CV outcomes trials in diabetes