Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes.
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones secreted by the enteroendocrine cells of the gut in response to the ingestion of nutrients. These incretin hormones, so called because they increase insulin secretion, are key modulators of pancreatic islet hormone secretion and, thus, glucose homeostasis. The glucoregulatory effects of incretins are the basis for new therapies currently being developed for the treatment of type 2 diabetes mellitus (T2DM). Drugs that inhibit dipeptidyl peptidase-4 (DPP-4), a ubiquitous enzyme that rapidly inactivates both GLP-1 and GIP, increase active levels of these hormones and, in doing so, improve islet function and glycemic control in T2DM. In this review, we briefly describe (1) the role of pancreatic islet dysfunction in the onset and progression of T2DM, (2) the rationale for developing drugs that enhance incretin activity, (3) the evidence that inhibition of DPP-4 is effective in ameliorating islet dysfunction and improving glycemic control in T2DM, (4) the efficacy, safety, and tolerability of DPP-4 inhibitors as monotherapy and in combination with other antidiabetic agents, and (5) the potential utility of DPP-4 inhibitors relative to existing oral antidiabetic agents and newer antidiabetic drugs in the pipeline. The review is based upon MEDLINE literature searches (1966-August 2006) and abstracts and presentations from the American Diabetes Association Scientific Sessions (2002-2006) and the European Association for the Study of Diabetes Annual Meetings (1998-2006). Basic science, preclinical, and clinical studies and review articles published in the English language were evaluated and selected based upon consideration of their originality, relevance, and frequency of citation. DPP-4 inhibitors are a new class of antidiabetogenic drugs that provide comparable efficacy to current treatments. They are effective as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. The DPP-4 inhibitors are well tolerated, carry a low risk of producing hypoglycemia, and are weight neutral. The long-term durability of effect on glycemic control and beta-cell morphology and function remain to be established. Islet cell dysfunction is central to the pathogenesis of T2DM. Incretin-based therapies, including GLP 1 analogues and DPP-4 inhibitors, have been shown to restore glucose homeostasis and improve glycemic control. The DPP-4 inhibitors, which can be used as monotherapy or in combination with other antidiabetic drugs, are a promising new treatment option, especially for patients with early-stage T2DM and more severe hyperglycemia.