Beyond glucose: cardiovascular effects of incretins and dipeptidyl peptidase-4 substrates

Abstract

The incretins are naturally occurring peptides that are pro-glucagon derivatives that have been implicated in the control of appetite and satiety. The class includes both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins, particularly GLP-1 (7–36) amide, have been exploited clinically by virtue of their insulinotropic properties that are glucose dependent, thus mitigating the risk of hypoglycaemia that accompanies conventional secretagogues and exogenous insulins. However, the short circulating half-life of the native peptide limits their use as a therapeutic option. Dipeptidyl peptidase-4 (DPP-4) is an enzyme with multiple substrates, including GLP-1 and GIP. Dipeptidyl peptidase-4 inactivates GLP-1 and GIP via cleavage at specific sites within the molecules. This has led to the development of novel GLP-1 receptor (GLP-1R) agonists and analogues that are DPP-4 resistant and have a longer duration of action than GLP-1, and agents that inhibit DPP-4 to increase the circulating half-life of the native GLP-1 peptide. Dipeptidyl peptidase-4 inhibitors reduce fasting and post-prandial glucose concentrations and haemoglobin A1C in patients with type 2 diabetes mellitus (T2DM), similar to the effects of the GLP-1-like peptides. Preliminary evidence suggests that the native GLP-1 peptide, its active metabolites, GLP-1R agonists (exenatide) and analogues (liraglutide, albiglutide), and DPP-4 inhibitors themselves may also have direct cardiovascular (CV) benefits outside of glycaemic control. Whereas the on-target effects of these classes of anti-diabetic agents are similar in their ability to improve glycaemic control, the off-target effects are agent-specific and mediated through discrete cellular mechanisms. Randomized controlled trials are under way to determine whether GLP-1 analogues and DPP-4 inhibitors confer cardioprotective effects in patients with T2DM. This review discusses the potential CV benefits of native GLP-1, its metabolites, receptor agonists and analogues, and DPP-4 inhibition mediated through distinct DPP-4 substrates.