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
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 1.3 1.8 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. www.fda.gov
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
AleCardio Cardiovascular Outcomes Study of Aleglitazar in Subjects With Type 2 Diabetes and Acute Coronary Syndrome JAMA 2014; xxx:yyyy-zzzz
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 nonfatal stroke Study Duration: up to 3.3 years, median 2.0 years
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:10.1001/jama.2014.3321
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:10.1001/jama.2014.3321
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,0.99-1.66],p =.06) More patients receiving aleglitazar developed peripheral edema (14.0%for aleglitazar vs 6.6% for placebo, p <.001)
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:10.1001/jama.2014.3321 p<0.001 Baseline A1c, 7.8% for both placebo and aleglitazar Figure Legend:
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:10.1001/jama.2014.3321 p<0.001 p<0.001 Figure Legend:
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:10.1001/jama.2014.3321 p<0.001 Figure Legend:
Mean Change from Baseline in Weight and Serum Creatinine over Time According to Study Group. JAMA. 2014;():. doi:10.1001/jama.2014.3321 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
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: Q4 2011 Median (IQR) Follow-up: 6.2 y (5.8-6.6) *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;367:319-328
Insulin use by allocated Glargine vs. other insulins in standard care N Engl J Med 2012;367:319-328
Median FPG IQR 103 142 IQR 79-104 Secondary endpoint N Engl J Med 2012;367:319-328
Median A1C levels IQR 5.8 6.9 p < 0.001 IQR 5.5 6.5 Secondary endpoint N Engl J Med 2012;367:319-328
1st Co-primary endpoint: MI, stroke, or CV death 0.5 Nb at risk: Proportion with event Glargine Standard Care 0.4 0.3 0.2 0.1 0.0 0 6264 6273 Adj. HR 1.02 (0.94, 1.11) log Rank p = 0.63 (NS) 1 6057 6043 2 5850 5847 3 4 5 Years of follow-up 5619 5632 5379 5415 5151 5156 Glargine Standard Care 6 3611 3639 7 766 800 N Engl J Med 2012;367:319-328
2nd Co-primary endpoint: MI, stroke, or CV death Revascularization, heart failure 0.5 Proportion with event 0.4 0.3 0.2 0.1 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 0 6264 6273 1 5827 5833 2 5474 5493 3 4 5 Years of follow-up 5153 5186 4835 4880 4523 4555 6 3076 3142 7 631 663 N Engl J Med 2012;367:319-328
Cancers overall & by type (N = 953) 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 Favors Insulin 0.25 0.5 1 2 Favors Standard N Engl J Med 2012;367:319-328
New Diabetes OR (95% CI) p Glargine (n = 737) Standard (n = 719) New Diabetes* 0.72 (0.58, 0.91) 0.006 182 (24.7) 225 (31.2) After 2 nd OGTT 0.80 (0.64, 1.00) 0.050 219 (29.7) 248 (34.5) Adjudicated + Uncertain Cases 0.69 (0.56, 0.86) 0.001 254 (34.5) 310 (43.1) 0.5 1 2 Favors Insulin Odds Ratio Favors Standard * Predefined New Diabetes Outcome results up to & including first OGTT N Engl J Med 2012;367:319-328
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