Incretin mimetics as emerging treatments for type 2 diabetes

Objective: To review the physiology, pharmacology, and clinical efficacy of glucagon-like peptide (GLP-1) and the incretin mimetics exenatide and liraglutide in clinical studies. Data Sources: Primary literature obtained via MEDLINE (1966-April 2004) and International Pharmaceutical Abstracts (1970-April 2004) searches; abstracts obtained from meeting sources and manufacturers. Study Selection and Data Extraction: All English-language studies and abstracts evaluating GLP-1, exenatide, and liraglutide in the treatment of patients with type 2 diabetes were reviewed. Data from animal studies were also included if human data were not available. Primary and review articles related to the physiology, development, and evaluation of GLP-1s were reviewed. Data Synthesis: GLP-1, exenatide (exendin-4, AC2993), and liraglutide (NN2211) are incretin mimetics that have been shown in human studies to be an effective treatment to improve glycemic control in patients with type 2 diabetes. Mechanisms by which these compounds improve glycemic control include enhancing glucose-dependent pancreatic secretion of insulin in response to nutrient intake, inhibiting glucagon secretion, delaying gastric emptying, and promoting early satiety. GLP-1 has been shown to promote pancreatic progenitor cell differentiation and improve P-cell function and lifespan. Reported adverse effects of exenatide and liraglutide include nausea, vomiting, and transient headache, as well as increased risk of hypoglycemia when used with sulfonylureas. Conclusions: Clinical studies show that GLP-1, exenatide, and liraglutide improve glycemic control for patients with type 2 diabetes through unique mechanisms not available with current pharmaceutical products. Ongoing Phase III studies will help to further position these compounds as treatment options for patients with type 2 diabetes.