GLP-1R Agonists and Endothelial Dysfunction: More Than Just Glucose Lowering?

The treatment of type 2 diabetes (T2D) focuses on glycemic control to reduce microvascular and macrovascular complications. Unfortunately, while pivotal studies using conventional therapies have demonstrated that intensive glycemic control positively impacts microvascular complications, effects on cardiovascular benefit are less robust (1). There is therefore intense interest in newer antidiabetes agents, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, which lower blood glucose and modify cardiovascular risk factors (lipids, adiposity, blood pressure) without increasing hypoglycemic risk (2). Whether GLP-1R agonists improve endothelial dysfunction is less clear, but this potential effect is important as endothelial dysfunction increases the risk for cardiovascular events in T2D (3). While acute GLP-1(7-36) infusion consistently improves forearm vasodilation (a measurement of endothelial function) (4–7), effects with GLP-1R agonists are inconsistent. In a 16-week study of 20 patients with T2D, exenatide improved brachial artery flow-mediated dilation compared with glimepiride (8). In contrast, exenatide therapy for 3 months did not increase vasoreactivity by digital plethysmography compared with metformin in 50 obese, glucose-intolerant patients (9). Similarly, in a separate study involving 49 T2D participants, liraglutide did not improve forearm blood flow measured by venous occlusion plethysmography in response to graded infusions of acetylcholine or sodium nitroprusside relative to placebo or glimepiride (10). The effect of dipeptidyl peptidase-4 (DPP-4) inhibition on endothelial function is also inconsistent, with some indicating beneficial (11,12), neutral (13,14), or even detrimental (15) effects. Possible explanations for differing …