Aleglitazar, a dual PPARalpha and PPARgamma agonist for the potential oral treatment of type 2 diabetes mellitus.

摘要

PPARgamma and PPARalpha are nuclear receptors mainly involved in the regulation of glucose homeostasis and lipid levels, respectively. Aleglitazar, being developed by Roche Holding, is a dual agonist for PPARgamma and PPARalpha for the potential simultaneous treatment of hyperglycemia and dyslipidemia in patients with type 2 diabetes mellitus (T2DM). In preclinical studies, aleglitazar decreased non-fasted glucose levels, increased glucose clearance and improved insulin resistance, while also increasing HDL-cholesterol and decreasing LDL-cholesterol levels in serum. In phase I and II clinical trials in patients with T2DM, aleglitazar demonstrated beneficial antidiabetic activities and had a higher antihyperglycemic efficacy than pioglitazone (a PPARgamma agonist). Aleglitazar improved the lipid profile in patients and decreased levels of cardiovascular markers of inflammation and clotting. The observed adverse events were characteristic of either PPARgamma or PPARalpha agonists; however, when compared to pioglitazone-PPARgamma-mediated effects, such as edema and weight gain, these were less severe. PPARgamma-mediated adverse events on bone have not been measured and should be addressed in the future. The PPARalpha-mediated adverse effects on renal function are of concern and are a primary endpoint of ongoing phase II clinical trials in patients with T2DM. A phase III clinical trial was also ongoing in patients with T2DM who had recently experienced a cardiac event.