GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

Abstract

Type 2 diabetes mellitus (T2DM) is closely associated with cardiovascular diseases (CVD), including atherosclerosis, hypertension and heart failure. Some anti-diabetic medications are linked with an increased risk of weight gain or hypoglycemia which may reduce the efficacy of the intended anti-hyperglycemic effects of these therapies. The recently developed receptor agonists for glucagon-like peptide-1 (GLP-1RAs), stimulate insulin secretion and reduce glycated hemoglobin levels without having side effects such as weight gain and hypoglycemia. In addition, GLP1-RAs demonstrate numerous cardiovascular protective effects in subjects with or without diabetes. There have been several cardiovascular outcomes trials (CVOTs) involving GLP-1RAs, which have supported the overall cardiovascular benefits of these drugs. GLP1-RAs lower plasma lipid levels and lower blood pressure (BP), both of which contribute to a reduction of atherosclerosis and reduced CVD. GLP-1R is expressed in multiple cardiovascular cell types such as monocyte/macrophages, smooth muscle cells, endothelial cells, and cardiomyocytes. Recent studies have indicated that the protective properties against endothelial dysfunction, anti-inflammatory effects on macrophages and the anti-proliferative action on smooth muscle cells may contribute to atheroprotection through GLP-1R signaling. In the present review, we describe the cardiovascular effects and underlying molecular mechanisms of action of GLP-1RAs in CVOTs, animal models and cultured cells, and address how these findings have transformed our understanding of the pharmacotherapy of T2DM and the prevention of CVD.

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

“…A number of studies has found that semaglutide and liraglutide could reduce the levels of blood lipids and blood pressure (BP), hence contributing to the reduction of atherosclerosis and CVDs (117)(118)(119). Moreover, GLP-1RAs were reported to inhibit the development of AS in animal models.…”

Endothelial Dysfunction and Cardiovascular Disease: History and Analysis of the Clinical Utility of the Relationship

“…The functional and therapeutic difference in these two designations are exemplified by the actions of newer anti-diabetes drugs—these drugs including sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists have beneficial effects in large clinical trials where cardiovascular events and deaths are reduced by treatment with the index agents. It has however been very difficult to show consistent favorable actions on endothelial function assessed as enhanced vasodilation [ 25 , 26 ]. This suggests that the favorable cardiovascular effects arise from anti-inflammatory actions on the endothelium; these anti-inflammatory actions are more disparate and difficult to characterize than measures of vasodilatory capacity.…”

Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function

“…Therefore, this evidences the protective effects played by incretins on the atherosclerotic plaque for patients with acute coronary syndrome, in the condition of acute coronary thrombosis 38 and multivessel disease with and ED 39 . For a detailed review of cardiovascular actions and molecular targets of glucagon-like peptide-1 receptor agonists (GLP-1RAs) 36 and sodium glucose cotransporter 2 inhibitors (SGLT2i) 37 , please refer to our recent reviews. As mentioned above, ED can be an independent predictor of cardiovascular events and the first step toward coronary arteriosclerosis 40 .…”

“…As for the efficacy of SGLT2i 37 and GLP-1RAs 36 , numerous clinical studies have shown that metformin can improve vascular endothelial function and reduce CVD in patients with diabetes (see Table 1 152 - 167 ). A study reported in 2001, utilizing a moderate dose of metformin (500 mg twice daily) administered for 12 weeks and compared to placebo, showed improvement in Ach-stimulated flow (and IR) was observed among diet-treated T2D patients.…”