Sitagliptin Phosphate: a DPP-4 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

Background: Sitagliptin phosphate, the first dipeptidyl peptidase 4 (DPP-4) inhibitor, provides a new treatment option for patients with type 2 diabetes.

Objective: The purpose of this article is to review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, and cost of sitagliptin in adults with type 2 diabetes.

Methods: A literature search of MEDLINE (1966-May 10, 2007), Iowa Drug Information Service (1966-May 10, 2007), and International Pharmaceutical Abstracts (1970-May 10, 2007) was performed using the terms sitagliptin and MK-0431. English-language, original research and review articles were reviewed, as were citations from these articles. The 2005 and 2006 American Diabetes Association Scientific Abstracts were searched, and the US Food and Drug Administration review of the new drug application for sitagliptin and select information from the manufacturer were consulted.

Results: By inhibiting DPP-4, sitagliptin enhances postprandial levels of active glucagon-like peptide-1 (GLP-1), leading to a rise in insulin release and decrease in glucagon secretion from pancreatic alpha-cells. Sitagliptin is 87% orally bioavailable, undergoes minimal hepatic metabolism, and is primarily excreted unchanged (approximately 79%) in the urine. At doses >or=100 mg QD, DPP-4 activity is inhibited by >80%, with a consequent 2-fold rise in active GLP-1 levels. The reduction in glycosylated hemoglobin (HbA(1c)) observed with 100 mg QD of sitagliptin in Phase III monotherapy trials ranged from approximately 0.5% to 0.6% (P <or= 0.001 vs placebo). In Phase III combination trials, HbA(1c) was reduced by approximately 0.7% when added to metformin and approximately 0.9% with pioglitazone (P < 0.001 vs placebo). Markers of beta-cell function, including proinsulin/insulin ratio and homeostasis model assessment of beta-cell function, were improved with sitagliptin treatment. In studies, sitagliptin has been well tolerated; significant hypoglycemia and weight gain have not been noted.

Conclusions: When used alone or in combination with metformin or pioglitazone, sitagliptin has been associated with significant reductions in HbA(1c) and has been well tolerated. Before its place in therapy can be firmly established, long-term studies evaluating the safety of prolonged DPP-4 inhibition are necessary.