Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

Abstract

■ AbstractUntil recently, the pathogenesis of type 2 diabetes mellitus (T2DM) has been conceptualized in terms of the predominant defects in insulin secretion and insulin action. It is now recognized that abnormalities in other hormones also contribute to the development of hyperglycemia. For example, the incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), is attenuated in T2DM. Intravenous administration of GLP-1 ameliorates hyperglycemia in patients with T2DM, but an extremely short half-life limits its utility as a therapeutic agent. Strategies to leverage the beneficial effects of GLP-1 include GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous GLP-1 and GIP. The GLP-1 agonist exenatide has been shown to improve HbA1c and decrease body weight. However, exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of antibodies. Studies of a long-acting exenatide formulation suggest that it has improved efficacy and also promotes weight loss. Another prospect is liraglutide, a once-daily human GLP-1 analog. In phase 2 studies, liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than exenatide. DPP-4 inhibitors such as sitagliptin and vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the incretin system with a focus on the role of GLP-1 receptor agonists and DPP-4 inhibitors.

Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials

“…It can be speculated that the longer duration of action of liraglutide, with respect to exenatide, could allow a more accurate control of post-prandial hyperglycaemia throughout the day; however, little data is available on the effects of liraglutide on glycaemic profile to draw any conclusion on this point. It has been reported that liraglutide has a lower immunogenicity than exenatide, with a reduced incidence of antibody formation (18); it is possible that high titres of specific antibodies could interfere with the efficacy of GLP-1 receptor agonists (19).…”

Cinnamtannin A2, a Tetrameric Procyanidin, Increases GLP-1 and Insulin Secretion in Mice

“…19,20) Because of its pleiotropic actions in nutrient homeostasis, GLP-1 is now under investigation as a potential treatment for patients with type 2 diabetes mellitus. Here we have demonstrated that a single oral ingestion of cinnamtannin A2, one of the tetrameric procyanidins, increased the GLP-1 secretion levels and insulin secretion in plasma without an oral glucose load ( Figs.…”

Cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors

“…Many of the drugs currently used for the treatment of type 2 diabetes, induce weight gain (sulphonylureas, thiazolidinediones, insulin). Incretin-based agents are weight-neutral or promote weight reduction [5][6][7][19][20][21][22]. ]…”