Cardiovascular protection from glucagon-like peptide 1 receptor agonists: Mechanisms of immunomodulation

The incidence of type 2 diabetes mellitus is increasing worldwide with serious cardiovascular consequences. Glucagon-like peptide 1 (GLP-1) is an endogenous intestinal hormone that is released upon food intake and results in glucose-based insulin secretion from the pancreas which ultimately lowers blood glucose. GLP-1 receptor agonists (GLP-1-RAs) have become an important part of modern antidiabetic therapy. In addition to the blood-glucose lowering effects, GLP-1-RAs have also been shown in large clinical trials to also prevent cardiovascular events in patients with type 2 diabetes and high cardiovascular risk. Our current understanding is that the cardiovascular protective effects of GLP-1-RAs are mediated in a blood-glucose-independent manner by direct reduction of atherosclerosis-associated end points (e.g., stroke, myocardial infarction, revascularization). Experimental studies found that GLP-1-RAs lead to a reduction in atherosclerosis in various animal models, accompanied by a reduction in systemic and vascular inflammation as a possible mechanism. Although GLP-1-RAs have been shown to reduce low density lipoprotein (LDL) cholesterol, body weight, and blood pressure in addition to their blood-glucose-lowering and renoprotective effects, the cardiovascular protective effects of this class of compounds are generally explained by direct anti-inflammatory and vasoprotective effects. Current clinical trials are investigating whether GLP-1-RAs can improve cardiovascular prognosis in patients with pre-existing cardiovascular disease independently of diabetes mellitus. Novel therapeutic concepts such as dual glucose-dependent insulinotropic peptide (GIP)/GLP-1 receptor activation represent innovative approaches.