The Cardiovascular Biology of Glucagon-like Peptide-1

Abstract

Glucagon-like peptide-1, produced predominantly in enteroendocrine cells, controls glucose metabolism and energy homeostasis through regulation of islet hormone secretion, gastrointestinal motility, and food intake, enabling development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. GLP-1 also acts on the immune system to suppress inflammation, and GLP-1R signaling in multiple tissues impacts cardiovascular function in health and disease. Here we review how GLP-1 and clinically approved GLP-1R agonists engage mechanisms that influence the risk of developing cardiovascular disease. We discuss how GLP-1R agonists modify inflammation, cardiovascular physiology, and pathophysiology in normal and diabetic animals through direct and indirect mechanisms and review human studies illustrating mechanisms linking GLP-1R signaling to modification of the cardiovascular complications of diabetes. The risks and benefits of GLP-1R agonists are updated in light of recent data suggesting that GLP-1R agonists favorably modify outcomes in diabetic subjects at high risk for cardiovascular events.

Semaglutide seems to be more effective the other GLP-1Ras

“…In addition, GLP-1 RAs reduce blood pressure during chronic treatment and increase pulse rate, both by still unknown mechanisms. The agonists also appear to reduce postprandial triglyceride concentrations (8)(9)(10) by an effect that appears to be independent of the effects on gastric emptying, but may reflect inhibition of chylomicron formation (11). Agonist treatment does not lead to fat malabsorption, though.…”

Discovery, characterization, and clinical development of the glucagon-like peptides

“…Indeed, several randomized controlled clinical trials have demonstrated significant clinical improvement in human subjects with Parkinson's disease (93). Despite the appeal of current GLP-1R agonists for the treatment of T2D, market penetration for many GLP-1R agonists remains disappointing, raising questions about the potential clinical classes used for treatment of T2D, the GLP-1R agonists and SGLT-2 inhibitors, produce weight loss, effective reduction of A1c, a low incidence of hypoglycemia, and reductions in rates of major adverse cardiovascular events and cardiovascular death (75,87).…”

“…Native GLP-1 increases flow-mediated vasodilation, enhances heart rate (HR) and cardiac output, and is cardioprotective in preclinical studies, most notably in animals with ischemic cardiac injury (78). Although degradationresistant GLP-1R agonists have minimal effects on blood vessels (79), they increase HR and reduce cardiac inflammation and infarct size in animals with experimental myocardial infarction (75,80). Understanding the mechanisms through which GLP-1 exerts cardioprotection is challenging, since the GLP-1R is largely expressed in atrial and not ventricular cardiomyocytes (81).…”

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

“…GLP-1 is a hormone released from the gut in response to food intake and acts on GLP-1R to stimulate glucose-dependent insulin secretion from pancreatic β cells, reduce glucagon secretion from pancreatic α cells, as well as decrease gastric motility and appetite 1 . Given its physiological effects, GLP-1R represents an important drug target for type-2 diabetes and obesity 2 , with GLP-1 and its analogs already serving as approved therapeutics.…”