Jay S. Skyler, MD, MACP Division of Endocrinology, Diabetes, and Metabolism

and Diabetes Research Institute University of Miami Miller School of Medicine

Recent and Ongoing Cardiovascular Outcomes Trials

with Diabetes Drugs

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 Guidance for CVD Risk

SAVOR TIMI-53

Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes

Medications

N Engl J Med 2013; 369:1317-1326

SAVOR TIMI-53 • Population: T2D, age >40, A1c ≥6.5% & ≤12%, previous

CVD diagnosis • 16,492 patients, 532 sites in Australasia, Asia, Europe,

North America, South America, India and South Africa • Design: Saxagliptin vs placebo added to ongoing care

regime • Objective: To compare the impact of adding

saxagliptin or placebo added to usual care, with regard to first occurrence of CVD death, non-fatal myocardial infarction, or non-fatal stroke

• Study Duration: up to 2.9 years, median 2.1 years,

SAVOR: TIMI 53 – Primary End Point Standard MACE

N Engl J Med 2013. 369:1317-1326

SAVOR: TIMI 53 – Secondary End Point MACE + Hospitalization for Unstable Angina, Coronary

Revascularization, or Heart Failure

N Engl J Med 2013. 369:1317-1326

N Engl J Med 2013. 369:1317-1326

Pancreatic Cancer 5 12 0.095

EXAMINE

Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2

Diabetes and Acute Coronary Syndrome

N Engl J Med 2013; 369:1327-1335

EXAMINE • Population: T2D, age >18, A1c ≥6.5% & ≤11%, diagnosis

of acute coronary syndrome 15 to 90 days prior to randomization

• 5,380 patients, 904 sites in Australasia, Asia, Europe, North America, South America, India and South Africa

• Design: Alogliptin vs placebo added to ongoing care regime

• Objective: To compare the impact of adding alogliptin or placebo to usual care, with regard to first occurrence of CVD death, non-fatal myocardial infarction, or non-fatal stroke

• Study Duration: up to 3.3 years, median 1.5 years

Mean Change from Baseline HbA1c over Time According to Study Group.

N Engl J Med 2013. 369:1327-1335

EXAMINE – Primary End Point Standard MACE

N Engl J Med 2013. 369:1327-1335

EXAMINE – Secondary End Point CVD Death

N Engl J Med 2013. 369:1327-1335

EXAMINE – Secondary End Point Death from Any Cause

N Engl J Med 2013. 369:1327-1335

EXAMINE – Non-Inferiority Met for All End Points

N Engl J Med 2013. 369:1327-1335

Conclusion • In patients with type 2 diabetes, major

adverse cardiovascular events were not increased with either of two DPP-4 inhibitors – saxagliptin or alogliptin – versus placebo

Cardiovascular Outcomes Study of Aleglitazar in Subjects With Type 2

Diabetes and Acute Coronary Syndrome

JAMA 2014; xxx:yyyy-zzzz

AleCardio

AleCardio • Population: T2D, age >18, A1c 6.0-10.0%, diagnosis of

acute coronary syndrome within previous 8 weeks • 7,226 patients, 720 sites in, North America, South

America, Europe, and Asia-Pacific • Design: Aleglitazar vs placebo added to ongoing care

regime • Objective: To compare the impact of adding aleglitazar

or placebo to usual care, with regard to first occurrence of CVD death, non-fatal myocardial infarction, or non-fatal stroke

• Study Duration: up to 3.3 years, median 2.0 years

AleCardio - Primary End Point Standard MACE

JAMA. 2014;():. doi:10.1001/jama.2014.3321

Kaplan-Meier Estimates of Time to First Occurrence of Primary Efficacy End Point and Hospitalization for Heart FailureY-axis in blue indicates range from 0% to 10%. The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Figure Legend:

AleCardio – Hospitalization for Heart Failure

JAMA. 2014;():. doi:10.1001/jama.2014.3321

Kaplan-Meier Estimates of Time to First Occurrence of Primary Efficacy End Point and Hospitalization for Heart FailureY-axis in blue indicates range from 0% to 10%. The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Figure Legend:

• A serious adverse event of heart failure was reported in 4.7% of patients in the aleglitazar group and 3.8% of patients in the placebo group (HR, 1.24[95%CI,0.99-1.66],p = .06)

• More patients receiving aleglitazar developed peripheral edema (14.0%for aleglitazar vs 6.6% for placebo, p < .001)

AleCardio –Heart Failure

From: Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial

JAMA. 2014;():. doi:10.1001/jama.2014.3321

Figure Legend:

Mean Change from Baseline HbA1c over Time According to Study Group.

Baseline A1c, 7.8% for both placebo and aleglitazar

p<0.001

From: Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial

JAMA. 2014;():. doi:10.1001/jama.2014.3321

Figure Legend:

Mean Change from Baseline in Triglycerides and HDL-Cholesterol over Time According to Study Group.

p<0.001 p<0.001

From: Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial

JAMA. 2014;():. doi:10.1001/jama.2014.3321

Figure Legend:

Mean Change from Baseline LDL-Cholesterol over Time According to Study Group.

p<0.001

JAMA. 2014;():. doi:10.1001/jama.2014.3321

Mean Change from Baseline in Weight and Serum Creatinine over Time According to Study Group.

p<0.001 p<0.001

AleCardio – Gastrointestinal Hemorrhage

Conclusion • In patients with type 2 diabetes, major

adverse cardiovascular events were not increased with either of aleglitazar versus placebo

• There were more adverse events with aleglitazar than with placebo

Outcome Reduction with an Initial Glargine INtervention

N Engl J Med 2012;367:319-328

Glargine Standard Care

Omega 3 FA* Glargine + Omega 3 Omega 3

Placebo Glargine + Placebo Placebo

Recruitment: Sept ‘03 - Dec’05 Final Visit: Q4 2011 Median (IQR) Follow-up: 6.2 y (5.8-6.6)

Glargine (Lantus): open vs. standard care Omega 3 FA (Omacor): double-blind; 1 cap/day*

*Omacor contains EPA 465 mg & DHA 375 mg People aged ≥50 years with pre-diabetes or early T2DM and high cardiovascular risk

N Engl J Med 2012;367:319-328

ORIGIN factorial design N = 12,537; 573 sites; 40 countries; 2 comparisons

Omega 3 fatty acid results will not be presented here. Insulin glargine is not approved for patients with IFG or IGT

N Engl J Med 2012;367:319-328

Insulin use by allocated Glargine vs. other insulins in standard care

IQR 79 - 104

IQR 103 – 142

N Engl J Med 2012;367:319-328

Median FPG

Secondary endpoint

IQR 5.5 – 6.5

IQR 5.8 – 6.9

N Engl J Med 2012;367:319-328

Median A1C levels

p < 0.001

Secondary endpoint

766 800

3611 3639

5151 5156

5379 5415

5619 5632

5850 5847

6057 6043

6264 6273

0.5

0.4

0.3

0.2

0.1

0.0

Prop

ortio

n w

ith e

vent

7 6 5 4 3 2 1 0 Years of follow-up

Glargine

Standard Care

Nb at risk:

Adj. HR 1.02 (0.94, 1.11) log Rank p = 0.63 (NS)

Glargine Standard Care

N Engl J Med 2012;367:319-328

1st Co-primary endpoint: MI, stroke, or CV death

631 663

3076 3142

4523 4555

4835 4880

5153 5186

5474 5493

5827 5833

6264 6273

0.5

0.4

0.3

0.2

0.1

0.0

Prop

ortio

n w

ith e

vent

7 6 5 4 3 2 1 0 Years of follow-up

Glargine

Standard Care

Nb at risk:

Adj. HR 1.04 (0.97, 1.11) log Rank p = 0.27 (NS)

Glargine Standard Care

N Engl J Med 2012;367:319-328

2nd Co-primary endpoint: MI, stroke, or CV death Revascularization, heart failure

HR (95%CI) p

Glargine Standard N (%) Rate N (%) Rate

Cancer Death 0.94 (0.77, 1.15) 0.52 189 (3.0) 0.51 201 (3.2) 0.54

Any Cancer 1.00 (0.88, 1.13) 0.97 476 (7.6) 1.32 477 (7.6) 1.32

Lung 1.21 (0.87, 1.67) 0.27 80 (1.3) 0.22 66 (1.1) 0.18 Colon 1.09 (0.79, 1.51) 0.61 76 (1.2) 0.21 70 (1.1) 0.19

Breast 1.01 (0.60, 1.71) 0.95 28 (0.4) 0.08 28 (0.4) 0.08

Prostate 0.94 (0.70, 1.26) 0.70 88 (2.1) 0.36 89 (2.2) 0.38

Melanoma 0.88 (0.44, 1.75) 0.71 15 (0.2) 0.04 17 (0.3) 0.05

Other 0.95 (0.80, 1.14) 0.59 233 (3.7) 0.64 245 (3.9) 0.67

Any Skin 1.02 (0.78, 1.33) 0.88 110 (1.8) 0.30 108 (1.7) 0.29 HR

N Engl J Med 2012;367:319-328

Cancers overall & by type (N = 953)

Favors Standard Favors Insulin 0.25 0.5 1 2

OR (95% CI) p Glargine (n = 737)

Standard (n = 719)

New Diabetes* 0.72 (0.58, 0.91) 0.006

After 2nd OGTT 0.80 (0.64, 1.00) 0.050

Adjudicated + Uncertain Cases

0.69 (0.56, 0.86) 0.001

182 (24.7) 225 (31.2)

219 (29.7) 248 (34.5)

254 (34.5) 310 (43.1)

0.5 1 2

Favors Insulin

Favors Standard

Odds Ratio

* Predefined New Diabetes Outcome – results up to & including first OGTT N Engl J Med 2012;367:319-328

New Diabetes

Conclusions • Early use of basal insulin glargine for > 6 years…

– had a neutral effect on CV events – was possible & feasible in a clinical trial setting – reduced progression from pre-diabetes to

diabetes by 28%, p = 0.006 – had a neutral effect on cancers – modestly increased weight & hypoglycemia

incidence

Ongoing Cardiovascular Outcomes Trials • Sitagliptin – TECOS • Linagliptin – CAROLINA and CARMELINA • Liraglutide – LEADER • Exenatide – EXSCEL • Lixisenatide – ELIXIR • Dulaglutide – REWIND • Albiglutide – • Semiglutide - SUSTAIN • Canagliflozin – CANVAS • Dapagliflozin – DECLARE TIMI-58 • Empagliflozin – EMPA-REG OUTCOME • Insulin Degludec – DEVOTE • Inhaled Insulin Afrezza –