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Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes
Rury R Holman1, M Angelyn Bethel1, Robert J Mentz1
1From the Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford (R.R.H., M.A.B.), and the International Centre for Circulatory Health, Imperial College London, London (N.P.) - both in the United Kingdom; Duke Clinical Research Institute, Duke University School of Medicine, Durham (R.J.M., V.P.T., Y.L., N.J.P., A.F.H.), and the Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill (J.B.B.) - both in North Carolina; the Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong (J.C.C.); AstraZeneca Research and Development, Gaithersburg, MD (J.C., S.M.G., N.I., P.Ö.); Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO) Research Center, Florence, Italy (A.P.M.); the Department of Cardiology, University of Texas Southwestern Medical Center, Dallas (S.P.M.); the India Diabetes Research Foundation and Dr. A. Ramachandran's Diabetes Hospitals, Chennai, India (A.R.); and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and University of Toronto, Toronto (B.Z.).
Background:
The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.
Methods:
We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.
Results:
In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.
Conclusions:
Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).
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