New therapies for type 2 diabetes: What place for incretin-based agents and rimonabant compared to the previous ones?

Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin. The UKPDS Study has confirmed metformin (Met) as the initial monotherapy. Accordingly, Met is widely regarded as the first drug of choice for most patients with T2DM. Safety and efficacy of sulphonylureas (SU) have been confirmed by several clinical trials. Recently. thiazolidinediones (TZD) have addressed some aspects of insulin-resistance that characterized several T2DM patients. However, SU and TZD are associated with various side effects that limit their use in many patients. New agents have been recently developed which potentiate the activity of the incretin (GLPI). GLPI, a gut hormone secreted in response to meal ingestion. is rapidly degraded by dipeptidylpeptidase-4 (DPP-4). GLPI enhances insulin secretion and inhibits glucagon secretion ill it glucose-dependent manner, delays gastric emptying and, in animal studies, preserves beta-cell mass by reducing apoptosis and stimulates of P-cell proliferation. GLPI levels are abnormally low in T2DM patients. Two classes of agents based on GLPI have been launched: DPP-4 inhibitors and DPP-4 resistant GLPI analogues. Randomized studies confirmed their efficacy to improve glycemic control in T2DM patients. Orally administered DPP-4 inhibitors reduce HbA 1c by 0.5-1.1%, without hypoglycaemic events and no weight gain. The sub-cutaneous injected GLPI analogues (exenatide and liraglutide) show larger reductions in HbA 1c by 0.8-1.7% and weight loss but are associated with gastrointestinal side effects contributing to a significant treatment interruption. Several studies support the use of DPP-4 inhibitors in combination with Met as a promising second line treatment. (C) 2008 Publie par Elsevier Masson SAS.