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.


METHODS
Primary literature obtained via MEDLINE (1966-April 2004) and International Pharmaceutical Abstracts (1970-April 2004) searches; abstracts obtained from meeting sources and manufacturers.


METHODS
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.


RESULTS
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 beta-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.
Joy
Scott V
SV
Duke University Medical Center, Durham, NC 27705-0493, USA. joy00002@mc.duke.edu
Rodgers
Philip T
PT
Scates
Ann C
AC
D000818:Animals; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D000077270:Exenatide; D005934:Glucagon / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000502:physiology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069450:Liraglutide; D010446:Peptide Fragments / Q000009:adverse effects / Q000502:physiology / Q000627:therapeutic use*; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011498:Protein Precursors / Q000009:adverse effects / Q000502:physiology / Q000627:therapeutic use*; D014688:Venoms / Q000493:pharmacokinetics / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide