The cardiovascular effects of GLP-1 receptor agonists

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists have been shown to regulate blood glucose concentrations by mechanisms including enhanced insulin synthesis/secretion, suppressed glucagon secretion, slowed gastric emptying, and enhanced satiety. GLP-1 receptors have also been identified in the heart, kidneys, and blood vessels, leading to the hypothesis that GLP-1R agonists may affect cardiovascular function or cardiovascular disease (CVD). The aim of this literature review was to assemble and assess preclinical and clinical data of potential medical importance regarding the cardiovascular effects of GLP-1R agonists. Preclinical studies with the GLP-1R agonists GLP-1, exenatide, or liraglutide provided evidence that GLP-1R stimulation favorably affects endothelial function, sodium excretion, recovery from ischemic injury, and myocardial function in animals. Similar observations have been made in exploratory studies on GLP-1 infusion in normal subjects and patients with type 2 diabetes. Post hoc analyses of phase III studies of patients with type 2 diabetes treated with exenatide(bid or qw) or liraglutide(qd) showed that these GLP-1R agonists reduced blood pressure, an effect largely independent of weight loss, and that liraglutide slightly increased heart rate. Preliminary data also indicated that GLP-1R agonists reduced markers of CVD risk such as C-reactive protein and plasminogen activator inhibitor-1. Ongoing studies are examining the effects of administering GLP-1R agonists to patients at risk of CVD, postangioplasty patients, post-CABG patients, and patients with heart failure. Additional studies should provide meaningful data to determine whether GLP-1R agonists provide unique treatment benefits to patients at risk for or with established CVD.

Figure 1

Nongastrointestinal GLP-1R. (A) Overview of organs and tissues with GLP-1R. (B) Quantitation of GLP-1R expression in mouse tissues. (C) Immunohistochemical staining (green) demonstrating localization of GLP-1R in the endocardium (B, C reproduced with permission from [22]).

Figure 2

Schematic of GLP-1R signaling in heart cells. (A) Intracellular signaling. (B) Vascular consequences of GLP-1R signaling [22].

Figure 3

Systolic blood pressure (SBP) changes from baseline-to-endpoint (6 months) in patients with T2DM treated with exenatide (mean ± SE). (A) Exenatide versus placebo. (B) Exenatide versus insulin (Reprinted from [63]).