DPP-4 Inhibitors - Mechanism Of Action

DPP-4 is a serine protease that is widely distributed throughout the body, expressed as an ectoenzyme on endothelial cells, on the surface of T-lymphocytes, and in a circulating form. DPP-4 cleaves the two N-terminal amino acids from peptides with a proline or alanine in the second position. Although there are many potential substrates for this enzyme, it seems to be especially critical for the inactivation of GLP-1 and GIP glucose-dependent insulinotropic polypeptide; gastric inhibitory peptide . DPP-4 inhibitors increase the AUC of GLP-1 and GIP when their secretion is by a meal. Several agents provide nearly complete and long-lasting inhibition of DPP-4, thereby increasing the proportion of active GLP-1 from 10-20% of total circulating GLP-1 immunoreactivity to nearly 100%. Two of these, sitagliptin and saxagliptin are now available in the U.S.; a third, vildagliptin, is available in the E.U.; a fourth compound, alogliptin, is in advanced stages of clinical trials. Sitagliptin and alogliptin