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

Abstract

OBJECTIVE Glucagon-like peptide 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. 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 multicontrast 3 Tesla 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 (HbA1c) (estimated difference vs. placebo 0.55%, P = 0.0007) and fasting and postmeal plasma glucose (19 mg/dL, P = 0.0002, and 25 mg/dL, P < 0.0001, respectively). Mean (SD) change in plaque volume in the exenatide group (0.3% [2%]) was not different from that in the placebo group (−2.2% [8%]) (P = 0.4). The change in plaque volume in the exenatide group was associated with changes in HbA1c (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 postmeal 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 antiatherosclerotic effects may not play a central role in the cardiovascular benefits of GLP-1RAs.

Differential importance of endothelial and hematopoietic cell GLP-1Rs for cardiometabolic versus hepatic actions of semaglutide

“…Although human studies examining atherosclerosis remission with GLP-1RAs are limited, open-label observational studies of several hundred people with T2D treated with liraglutide ( 45 ) or exenatide once weekly ( 46 ) detected reduction in carotid intima media thickness, as assessed by carotid Doppler examination. In contrast, no change in carotid artery plaque volume or composition, as assessed by carotid MRI, was detected in 631 people with T2D randomized to receive placebo or exenatide once weekly for 18 months ( 47 ). Hence, it seems premature, based on the available evidence, to conclude that GLP-1RAs are uniformly capable of inducing atherosclerosis regression.…”

Effect of Oral Semaglutide on Cardiovascular Parameters and Their Mechanisms in Patients with Type 2 Diabetes: Rationale and Design of the Semaglutide Anti-Atherosclerotic Mechanisms of Action Study (SAMAS)

“…Similarly, cIMT reduction has been proven for liraglutide [17]. However, conflicting results on the atherosclerosis process (cIMT reduction, plaque volume and composition) were published for exenatide, as expected [11][12][13].…”

“…Nevertheless, the cardiovascular protective mechanisms of GLP-1 receptor agonists are still poorly understood, even though some have been proposed, such as anti-inflammatory properties, improvement of endothelial dysfunction and reduction of myocardial ischaemia injury; however, not all GLP-1 receptor agonists have proven to have cardio-renal protective actions [10]. Those with a proven ability to reduce major adverse cardiovascular events (MACE) are liraglutide, dulaglutide, albiglutide and subcutaneous semaglutide; in contrast, oral semaglutide was found to show only a trend towards MACE reduction, but this effect was not statistically significant as the cardiovascular noninferiority study lasted \ 2 years [11][12][13]. Further studies are ongoing that will show whether treatment with oral semaglutide could reach the same beneficial effect on MACE as its injectable counterpart [11,14].…”

Impact of a dual glucose‐dependent insulinotropic peptide/glucagon‐like peptide‐1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta‐analysis

“…[3][4][5] However, research on the use of GLP-1RAs has shown an association of such treatment with an increase in heart rate. [6][7][8][9] Heart rate is directly inversely associated with survival in the general population and in individuals with cardiovascular conditions. 10,11 For every 5-bpm increase in heart rate in patients with coronary artery disease and left ventricular dysfunction, the risk of cardiovascular mortality and hospital admission for worsening heart failure increased by 16%.…”