GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage

Abstract

Atherosclerotic cardiovascular disease is a chronic condition that often co-presents with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. While the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well-established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight to the anti-atherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent pre-clinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, including systemic inflammation, monocyte recruitment, pro-inflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development.

Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study

“…In agreement with some previous reports our study highlighted that one-year treatment with GLP-1RAs determined a statistically signi cant reduction in carotid IMT, a surrogate marker of atherosclerosis [28,29]. Although the mechanisms by which GLP-1RAs drugs determine an antiatherosclerotic effect have not yet been well de ned, it is conceivable that the improvement of the lipid pro le, the reduction of in ammation and the modi cations of the cytokine pro le play an important role [30,31]. This data, contributes to underlining the favorable role of GLP-1RAs in reducing the risk of major cardiovascular events.…”