Dipeptidyl peptidase‐IV inhibitors: a major new class of oral antidiabetic drug

Abstract

Exploiting the incretin effect to develop new glucose‐lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase‐IV (DPP‐IV). These drugs reversibly block DPP‐IV‐mediated inactivation of incretin hormones, for example, glucagon‐like peptide 1 (GLP‐1) and also other peptides that have alanine or proline as the penultimate N‐terminal amino acid. DPP‐IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP‐1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A_1c (HbA_1c) and associated metabolic profile remains open to further investigation. DPP‐IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose‐dependent mechanisms. This review summarizes the major clinical trials with DPP‐IV inhibitors as monotherapy and as add‐on therapy in patients with type 2 diabetes. The magnitude of HbA_1c reduction with DPP‐IV inhibitors depends upon the pretreatment HbA_1c values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP‐IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes.