824 ■ The Annals of Pharmacotherapy ■ 2007 May, Volume 41 www.theannals.com T ype 2 diabetes continues to be a ma- jor health concern in the US. Cur- rently, 20.8 million Americans have dia- betes, leading to an estimated $132 bil- lion in costs associated with diabetes in 2002. 1 Patients with type 2 diabetes rep- resent the majority (90 –95%) of individ- uals with diabetes. Elevated glucose lev- els in patients with type 2 diabetes result from a combination of impaired insulin secretion, excessive and inappropriate hepatic glucose output, and insulin resis- tance in the peripheral tissues. Numerous medications are available for the treat- ment of type 2 diabetes including in- sulin, insulin secretagogues (sulfony- lureas and glinides), insulin sensitizers (metformin and thiazolidinediones), al- pha glucosidase inhibitors, and the re- cently approved agents pramlintide and exenatide. 2-4 Despite the availability of multiple medications with different phar- macologic targets, only 37% of patients diagnosed with diabetes have achieved a hemoglobin A 1c (A1C) less than 7.0%. 5 Current research in diabetes manage- ment has focused on the role of incretin hormones in the pathogenesis of dia- betes. The incretin hormones are consid- ered gut-derived insulinotropic hor- mones. Glucose-dependent insulinotrop- ic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the 2 major in- cretin hormones in humans. 6,7 These hor- mones stimulate pancreatic β-cells within 10 minutes after ingestion of a meal and account for 50 – 60% of the total postprandial insulin response in healthy individuals. 6-8 Table 1 summarizes the incretin hormones and their effects in humans. 7-9 Reduced incretin effect is thought to con- tribute to the abnormalities in β-cell function in patients with type 2 diabetes. 7 Patients with type 2 diabetes do not The Role of Vildagliptin in the Management of Type 2 Diabetes Mellitus Erika L Kleppinger and Kristen Helms New Drug Developments Author information provided at the end of the text. OBJECTIVE: To highlight the role of incretin hormones in the management of type 2 diabetes mellitus with a focus on vildagliptin, a dipeptidyl peptidase IV (DPP IV) inhibitor currently in development. DATA SOURCES: Searches were conducted in MEDLINE (1950–April 2007) and International Pharmaceutical Abstracts (1970–April 2007) using the key words vildagliptin, LAF237, and dipeptidyl peptidase IV inhibitor. Additional data were obtained from abstracts presented at the American Diabetes Association Scientific Sessions (2003–2006) and from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: Articles pertaining to the pharma- cology, pharmacokinetics, safety, and efficacy of vildagliptin for the treatment of type 2 diabetes were reviewed for inclusion. When available, human trials were included over animal studies. DATA SYNTHESIS: Reduced incretin effect is thought to be associated with type 2 diabetes. Glucagon-like peptide-1 (GLP-1), an incretin hormone, stimulates postprandial insulin release; however, it is rapidly degraded by DPP IV. Studies evaluating the use of vildagliptin in patients with type 2 diabetes found significant decreases in DPP IV and increased GLP-1 activity 45 minutes after dosing. Glucagon levels were reduced, with little to no change in insulin levels. With vildagliptin doses ranging from 25 mg daily to 100 mg twice daily, researchers observed consistent reductions in fasting plasma glucose, 4 hour postprandial glucose, and hemoglobin A 1c . Similar benefits were seen when vildagliptin was used in combination with metformin. Vildagliptin was well tolerated after 12 weeks; however, incidences of hypoglycemia increased with longer study duration. Optimal results with minimal adverse effects were achieved with 25 mg twice daily and 50 mg once daily doses. CONCLUSIONS: Vildagliptin represents a safe and effective new approach to targeting GLP-1 deficiencies in patients with type 2 diabetes by inhibiting DPP IV. KEY WORDS: dipeptidyl peptidase IV inhibitor, LAF237, type 2 diabetes mellitus, vildagliptin. Ann Pharmacother 2007;41:824-32. Published Online, 24 Apr 2007, www.theannals.com, DOI 10.1345/aph.1H460 THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-07-013-H01 A For Our Patients summary of this article is available at www.ForOurPatients.info by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from