Review: DPP IV inhibitors - current evidence and future directions

Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for the higher insulin response after oral versus intravenous glucose administration. This effect is called the incretin effect. An impaired incretin effect in patients with type 2 diabetes focused attention on the possible importance of GIP and GLP-1 in diabetes mellitus. Metabolic control can be markedly improved by administration of exogenous GLP-1, but the native peptide is almost immediately degraded by the enzyme dipeptidyl peptidase IV (DPP IV) and, therefore, has little clinical value. Orally active inhibitors of DPP IV have now been developed and have been shown to enhance endogenous levels of GLP-1, resulting in improved glucose tolerance, lasting improvement of HbA1C and improved beta-cell function. In general the DPP IV inhibitors are weight neutral, and well tolerated. One DPP IV inhibitor, sitagliptin, was approved as a once-daily oral therapy for the treatment of type 2 diabetes mellitus in Mexico and USA in 2006, and Europe in 2007. Other DPP IV inhibitors are in late-stage clinical development.