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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.
The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.
Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.
]From Diabetes Center Bochum-Hattingen, St Josef-Hospital, Ruhr-University Bochum,
Germany (M.A.N., J.J.M., M.A.E.A.); Department of Medicine, University of North Carolina,
Chapel Hill (M.A.C.); and Department of Medicine, Lunenfeld-Tanenbaum Research Institute,
Mt Sinai Hospital, University of Toronto, Ontario, Canada (D.J.D.).