Recent and Ongoing Cardiovascular Outcomes Trials with Diabetes Drugs

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1 Recent and Ongoing Cardiovascular Outcomes Trials with Diabetes Drugs Jay S. Skyler, MD, MACP Division of Endocrinology, Diabetes, and Metabolism and Diabetes Research Institute University of Miami Miller School of Medicine

2 FDA Guidance for CVD Risk 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 The potential for CV harm may still exist. An adequately powered and designed postmarketing 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.

3 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:

4 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,

5 SAVOR: TIMI 53 Primary End Point Standard MACE N Engl J Med :

6 SAVOR: TIMI 53 Secondary End Point MACE + Hospitalization for Unstable Angina, Coronary Revascularization, or Heart Failure N Engl J Med :

7 N Engl J Med :

8 Pancreatic Cancer

9 EXAMINE Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coronary Syndrome N Engl J Med 2013; 369:

10 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

11 Mean Change from Baseline HbA1c over Time According to Study Group. N Engl J Med :

12 EXAMINE Primary End Point Standard MACE N Engl J Med :

13 EXAMINE Secondary End Point CVD Death N Engl J Med :

14 EXAMINE Secondary End Point Death from Any Cause N Engl J Med :

15 EXAMINE Non-Inferiority Met for All End Points N Engl J Med :

16 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

17 AleCardio Cardiovascular Outcomes Study of Aleglitazar in Subjects With Type 2 Diabetes and Acute Coronary Syndrome JAMA 2014; xxx:yyyy-zzzz

18 AleCardio Population: T2D, age >18, A1c %, 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 nonfatal stroke Study Duration: up to 3.3 years, median 2.0 years

19 AleCardio - Primary End Point Standard MACE Figure Legend: 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. JAMA. 2014;():. doi: /jama

20 AleCardio Hospitalization for Heart Failure Figure Legend: 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. JAMA. 2014;():. doi: /jama

21 AleCardio Heart Failure 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, ],p =.06) More patients receiving aleglitazar developed peripheral edema (14.0%for aleglitazar vs 6.6% for placebo, p <.001)

22 Mean Change from Baseline HbA1c over Time According to Study Group. 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: /jama p<0.001 Baseline A1c, 7.8% for both placebo and aleglitazar Figure Legend:

23 Mean Change from Baseline in Triglycerides and HDL- Cholesterol over Time According to Study Group. 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: /jama p<0.001 p<0.001 Figure Legend:

24 Mean Change from Baseline LDL-Cholesterol over Time According to Study Group. 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: /jama p<0.001 Figure Legend:

25 Mean Change from Baseline in Weight and Serum Creatinine over Time According to Study Group. JAMA. 2014;():. doi: /jama p<0.001 p<0.001

26 AleCardio Gastrointestinal Hemorrhage

27 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

28 Outcome Reduction with an Initial Glargine INtervention N Engl J Med 2012;367:

29 ORIGIN factorial design N = 12,537; 573 sites; 40 countries; 2 comparisons Glargine Standard Care Omega 3 FA* Glargine + Omega 3 Omega 3 Placebo Glargine + Placebo Placebo Glargine (Lantus): Omega 3 FA (Omacor): open vs. standard care double-blind; 1 cap/day* Recruitment: Sept 03 - Dec 05 Final Visit: Q Median (IQR) Follow-up: 6.2 y ( ) *Omacor contains EPA 465 mg & DHA 375 mg People aged 50 years with pre-diabetes or early T2DM and high cardiovascular risk 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:

30 Insulin use by allocated Glargine vs. other insulins in standard care N Engl J Med 2012;367:

31 Median FPG IQR IQR Secondary endpoint N Engl J Med 2012;367:

32 Median A1C levels IQR p < IQR Secondary endpoint N Engl J Med 2012;367:

33 1st Co-primary endpoint: MI, stroke, or CV death 0.5 Nb at risk: Proportion with event Glargine Standard Care Adj. HR 1.02 (0.94, 1.11) log Rank p = 0.63 (NS) Years of follow-up Glargine Standard Care N Engl J Med 2012;367:

34 2nd Co-primary endpoint: MI, stroke, or CV death Revascularization, heart failure 0.5 Proportion with event Adj. HR 1.04 (0.97, 1.11) log Rank p = 0.27 (NS) Glargine Standard Care 0.0 Nb at risk: Glargine Standard Care Years of follow-up N Engl J Med 2012;367:

35 Cancers overall & by type (N = 953) HR (95%CI) p Glargine Standard N (%) Rate N (%) Rate Cancer Death 0.94 (0.77, 1.15) (3.0) (3.2) 0.54 Any Cancer 1.00 (0.88, 1.13) (7.6) (7.6) 1.32 Lung 1.21 (0.87, 1.67) (1.3) (1.1) 0.18 Colon 1.09 (0.79, 1.51) (1.2) (1.1) 0.19 Breast 1.01 (0.60, 1.71) (0.4) (0.4) 0.08 Prostate 0.94 (0.70, 1.26) (2.1) (2.2) 0.38 Melanoma 0.88 (0.44, 1.75) (0.2) (0.3) 0.05 Other 0.95 (0.80, 1.14) (3.7) (3.9) 0.67 Any Skin 1.02 (0.78, 1.33) (1.8) (1.7) 0.29 HR Favors Insulin Favors Standard N Engl J Med 2012;367:

36 New Diabetes OR (95% CI) p Glargine (n = 737) Standard (n = 719) New Diabetes* 0.72 (0.58, 0.91) (24.7) 225 (31.2) After 2 nd OGTT 0.80 (0.64, 1.00) (29.7) 248 (34.5) Adjudicated + Uncertain Cases 0.69 (0.56, 0.86) (34.5) 310 (43.1) Favors Insulin Odds Ratio Favors Standard * Predefined New Diabetes Outcome results up to & including first OGTT N Engl J Med 2012;367:

37 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 = had a neutral effect on cancers modestly increased weight & hypoglycemia incidence

39 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

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