Glucagon-like peptide-1 receptor action in the vasculature

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists augment insulin secretion and are thus used clinically to improve glycemia in subjects with type 2 diabetes (T2D). As recent data reveal marked improvements in cardiovascular outcomes in T2D subjects treated with the GLP-1R agonists liraglutide and semaglutide in the LEADER and SUSTAIN-6 clinical trials respectively, there is growing interest in delineating the mechanism(s) of action for GLP-1R agonist-induced cardioprotection. Of importance, negligible GLP-1R expression in ventricular cardiac myocytes suggests that cardiac-independent actions of GLP-1R agonists may account for the reduced death rates from cardiovascular causes in T2D subjects enrolled in the LEADER trial. Conversely, vascular smooth muscle cells (VSMCs) appear to express the canonical GLP-1R, and GLP-1/GLP-1R agonists exhibit a number of salutary actions on the vascular endothelium that could potentially contribute to GLP-1R agonists directly improving cardiovascular outcomes in subjects with T2D. We review herein the described actions of GLP-1/GLP-1R agonists on the vascular endothelium, which include antiproliferative actions on VSMCs and endothelial cells, reductions in oxidative stress, and increases in nitric oxide generation. GLP-1 also increases microvascular recruitment and microvascular blood flow. Taken together, such actions may explain the antihypertensive and/or antiatherosclerotic actions attributed to GLP-1/GLP-1R agonists in preclinical and clinical studies. Nonetheless, further mechanistic studies are still necessary to determine the relative importance of such actions in accounting for reductions in macrovascular cardiovascular disease in human subjects with T2D treated with GLP-1R agonists.