Cardiovascular consequences of drugs used for the treatment of diabetes: potential promise of incretin—based therapies

Cardiovascular disease is the predominant cause of death in diabetic patients, and yet the cardiovascular benefits of traditional drug treatments for hyperglycemia have been elusive. Two new classes of diabetic drugs targeting the glucagon-like peptide-1 (GLP-1) incretin pathway have emerged. The GLP-1 receptor agonists reduce blood glucose levels by stimulating insulin and inhibiting glucagon secretion and gastric emptying. Dipeptidyl peptidase-4 (DPP-4) inhibitors prolong the half-life of endogenous GLP-1 by inhibiting its proteolytic degradation to the metabolite GLP-1(9-36), thereby increasing insulin and reducing glucagon secretion. Here, we review the biology of GLP-1, including studies of GLP-1 in animal models and humans with heart disease. We also highlight the emerging salutary cardiovascular effects of both GLP-1 and GLP-1(9-36). Unlike the GLP-1R agonist Exendin-4, both GLP-1 and GLP-1(9-36) exert vasodilatory actions on coronary and peripheral mouse vessels. Importantly, the effects of GLP-1 on isolated hearts undergoing experimental ischemia and preconstricted mesenteric arteries were reduced but not abolished by the DPP-4 inhibitor Sitagliptin. We posit that GLP-1-based therapeutics represent novel and promising anti-diabetes drugs, the direct cardiovascular actions of which may translate into demonstrable clinical benefits on cardiovascular outcomes.