Glucagon-like peptide-1 receptor agonists and the endothelium: molecular and clinical insights into cardiovascular protection

Endothelial dysfunction represents the critical pathophysiological mediator linking the modern epidemics of obesity, type 2 diabetes mellitus, and cardiovascular disease. Persistent hyperglycemia and metabolic dysregulation promote oxidative stress, reduce nitric oxide bioavailability, and activate inflammatory pathways, thereby accelerating atherosclerosis and cardiovascular complications. Therefore, strategies aimed at restoring endothelial function are crucial to mitigate cardiovascular complications in individuals with cardiometabolic disorders. Among antidiabetic therapies, glucagon-like peptide-1 receptor agonists have demonstrated cardiovascular benefits in large-scale outcome trials, but the underlying mechanisms remain only partially elucidated. In this mini-review, we critically examine both clinical and experimental evidence, with emphasis on the direct effects of glucagon-like peptide-1 receptor agonists on endothelial function. Moreover, we address the heterogeneity within this drug class, noting how differences may contribute to variability in vascular outcomes. By integrating clinical findings with molecular data, this review aims to refine our understanding of the potential endothelial mechanisms underlying cardiovascular protection. Our critical synthesis provides a clearer framework for interpreting the vascular effects of glucagon-like peptide-1 receptor agonists beyond glycemic control, thereby offering a more comprehensive view of their role in managing cardiometabolic disease.