Filtering Through the Evidence

A CME symposium supported by an educational grant from Merck

Christopher Saudek, MD
David D’Alessio, MD, PhD
Anne Peters, MD
Virginia Valentine, CNS, BC-ADM, CDE

Reported by Joelle Escoffery, PhD

An incretin is defined as a hormone that is released during nutrient absorption that augments insulin secretion at physiologic concentrations and works in a glucose-dependent manner. Receptors for the incretin hormone glucagon-like peptide (GLP-1) are present in the β cells, α cells, adipocytes, the brain, the stomach, and the small intestine, suggesting that it exerts its effects in on a variety of different targets. Research has demonstrated that GLP-1 has a number of effects that promote glucose tolerance, including stimulation of glucose-dependent insulin secretion, delay of gastric emptying, promotion of satiety, suppression of glucose production, and augmentation of glucose disposal. Additionally, GLP-1 promotes β-cell transcription, promotes β-cell responsiveness, and improves the dynamics of the insulin response. In terms of islet growth, GLP-1 stimulates β-cell replication, increases β-cell mass, and decreases apoptosis.

In patients with type 2 diabetes, GLP-1 concentrations are diminished. Replacing GLP-1 in patients with type 2 diabetes using a continuous infusion resulted in improved glycemic control and β-cell function, as well as weight reduction and promotion of satiety. Because native GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) and continuous infusion of GLP-1 would present numerous challenges, 2 strategies for increasing available GLP-1 are being explored: use of compounds that mimic the action of GLP-1, and compounds that block the degrading enzyme DPP-IV. Research with incretin mimetics has shown beneficial effects on A1C and promotes weight loss. DPP-IV inhibitors have also been shown to improve A1C, but they are weight-neutral.

The incretin mimetic exenatide has shown durable effects on weight loss over a period of 2 years, along with a consistent weight loss over the same time period. In terms of adverse events, exenatide use may promote hypoglycemia when used in conjunction with a sulfonylurea, and it has been shown to cause some dose-dependent nausea that decreases over time. The DPP-IV inhibitor vildagliptin has been shown to have durable effects on glycemic control for a year. Future research with exenatide includes use of combination therapy with thiazolidionediones, use among insulin-requiring patients, and as use as a monotherapy. A long-acting formulation is also under investigation.