Potentiation of
glucagon-like peptide-1 (GLP-1) action through selective
GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of
type 2 diabetes mellitus by
glucose-dependent control of
insulin and
glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce
body weight by reduction of food intake and lower
circulating lipoproteins,
inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and
DPP-4 inhibitors exhibit cardioprotective actions in animal models of
myocardial ischemia and
ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with
type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists
liraglutide (LEADER trial [
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and
semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with
Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist
lixisenatide (ELIXA trial [Evaluation of
Lixisenatide in Acute Coronary Syndrom]) and the
DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [
Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With
Diabetes Mellitus-Thrombolysis in
Myocardial Infarction 53]),
alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With
Alogliptin Versus Standard of Care in Patients With
Type 2 Diabetes Mellitus and
Acute Coronary Syndrome]), and
sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With
Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and
DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of
type 2 diabetes mellitus,
obesity, and
nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of
cardiovascular disease.