Cardiovascular Biology of the Incretin System

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that enhances glucose-stimulated insulin secretion and exerts direct and indirect actions on the cardiovascular system. GLP-1 and its related incretin hormone, glucose-dependent insulinotropic polypeptide, are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4), a key determinant of incretin bioactivity. Two classes of medications that enhance incretin action, GLP-1 receptor (GLP-1R) agonists and DPP-4 inhibitors, are used for the treatment of type 2 diabetes mellitus. We review herein the cardiovascular biology of GLP-1R agonists and DPP-4 inhibitors, including direct and indirect effects on cardiomyocytes, blood vessels, adipocytes, the control of blood pressure, and postprandial lipoprotein secretion. Both GLP-1R activation and DPP-4 inhibition exert multiple cardioprotective actions in preclinical models of cardiovascular dysfunction, and short-term studies in human subjects appear to demonstrate modest yet beneficial actions on cardiac function in subjects with ischemic heart disease. Incretin-based agents control body weight, improve glycemic control with a low risk of hypoglycemia, decrease blood pressure, inhibit the secretion of intestinal chylomicrons, and reduce inflammation in preclinical studies. Nevertheless, there is limited information on the cardiovascular actions of these agents in patients with diabetes and established cardiovascular disease. Hence, a more complete understanding of the cardiovascular risk to benefit ratio of incretin-based therapies will require completion of long-term cardiovascular outcome studies currently underway in patients with type 2 diabetes mellitus.

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

“…Furthermore, these new compounds do not expose patients to hypoglycaemia (except when added to insulin or sulphonylureas) 78 and may also exert favourable effects on various CV risk factors 79 . Similar positive effects are observed with GLP-1RAs 80 , with the add-on value of promoting weight loss in obese patients with T2DM 22 . Furthermore, GLP-1RA effects on bodyweight are also apparent in non-diabetic obese individuals, offering a potential for use in the treatment of obesity 81 .…”

“…Finally, GLP-1RAs were shown to improve various CV risk factors in overweight/obese T2DM patients, especially blood pressure, postprandial lipid profile, endothelial dysfunction, inflammatory markers and oxidative stress 80 . All these pleiotropic effects may lead to improvement in CV prognosis, although this hypothesis remained to be confirmed in ongoing large prospective RCTs 80 .…”

Effects of exogenous glucagon-like peptide-1 on blood pressure, heart rate, gastric emptying, mesenteric blood flow and glycaemic responses to oral glucose in older individuals with normal glucose tolerance or type 2 diabetes

“…GLP-1 and GLP-1 receptor (GLP-1R) agonists induce a sustained elevation of BP in rodents [2,3,27], attributable to central and peripheral mechanisms, but not in largeranimal models [28] or apparently humans [29,30]. However, in a recent study, a modest (~5 mmHg) increase in systolic (but not diastolic) BP, associated with an increase in cardiac output attributable to rises in stroke volume as well as HR, was evident in healthy middle-aged men in response to an i.v.…”

“…There is considerable interest in the cardiovascular effects of glucagon-like peptide-1 (GLP-1) and its agonists [1][2][3]. Phase 3 studies focusing on the blood-glucose-lowering effects of GLP-1 agonists indicate durable, modest reductions in systolic and, less consistently, diastolic blood pressure (BP), and a slight rise in heart rate (HR) [4][5][6][7].…”

Gut hormones and gut microbiota: implications for kidney function and hypertension

“…9,10 Glp-1 is rapidly degraded by the dipeptidyl peptidase-4 inhibitor (DPP-4), which circulates in the plasma and limits the half-life of Glp-1 to w2 minutes. 11 Cumulative evidence supports a role for GLP-1 in modulation of renal function and regulation of BP. [12][13][14] The effect of chronic administration of GLP-1 was explored in a genetic model of experimental hypertension, the Dahl salt-sensitive rat, fed a high-salt diet for 2 week.…”