Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

Abstract

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 .).

Figure 1. Effects of Once-Weekly Exenatide.

Shown are the effects of once-weekly administration of exenatide on glycated hemoglobin levels, body weight, systolic blood pressure, and heart rate. Overall least-squares mean differences were estimated from the model that included only the patients in whom a baseline value and at least one postbaseline value were obtained.

Figure 2. Trial Outcomes.

Shown are the rates of the primary cardiovascular outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), death from any cause, death from cardiovascular causes, and hospitalization for heart failure in the exenatide and placebo groups. The inset in each panel shows the same data on an enlarged y axis.

Figure 3. Primary Composite Outcome According to Prespecified Subgroups.

Race or ethnic group was reported by the patient. The body-mass index is the weight in kilograms divided by the square of the height in meters. DPP-4 denotes dipeptidyl peptidase 4, and GFR glomerular filtration rate.