The Effect of Exenatide Once Weekly on Carotid Atherosclerosis in Individuals With Type 2 Diabetes: An 18-Month Randomized Placebo-Controlled Study

Objective: GLP-1 receptor agonists (GLP-1RAs) improved multiple proatherogenic risk factors and reduced cardiovascular events in recent clinical trials, suggesting that they may slow progression of atherosclerosis. We tested whether exenatide once weekly reduces carotid plaque progression in individuals with type 2 diabetes mellitus.

Research Design and Methods: In a double-blind, pragmatic trial, 163 participants were randomized (2:1) to exenatide (n=109) or placebo (n=54). Changes in carotid plaque volume and composition were measured at 9 and 18 months by multi-contrast 3T-MRI. Fasting and post high-fat meal plasma glucose and lipids, and endothelial function responses were measured at 3, 9 and 18 months.

Results: Exenatide reduced hemoglobin A1c (estimated difference vs. placebo 0.55%, p=0.0007), and fasting and post-meal plasma glucose (19 mg/dl, p=0.0002 and 25 mg/dl, p<0.0001). Change in plaque volume in the exenatide group (mean 0.3% ± SD 12%) was not different from the placebo group (-2.2 ± 8%) (p=0.4). The change in plaque volume in the exenatide group was associated with changes in hemoglobin A1c (r=0.38, p=0.0004), body weight and overall plasma glucose (r=0.29, p=0.007 both). There were no differences in changes in plaque composition, body weight, blood pressure, fasting and post-meal plasma triglycerides and endothelial function between the groups.

Conclusions: Exenatide once weekly for up to 18 months improved fasting and postprandial glycemic control but did not modify change in carotid plaque volume or composition. This study raises the possibility that short term anti-atherosclerotic effects may not play a central role in the cardiovascular benefits of GLP-1RAs.