title: Therapeutic potential of aleglitazar, a new dual PPAR-α/γ agonist: implications for cardiovascular disease in patients with diabetes mellitus.
abstract: Preventing morbidity and mortality from diabetes mellitus is of paramount importance as the incidence of this disease is increasing across the world. While microvascular complications of diabetes such as nephropathy, retinopathy, and neuropathy are reduced with intensive glycemic control, treatment of hyperglycemia has not been consistently shown to have effects on the macrovascular complications of diabetes such as coronary artery, cerebrovascular, and peripheral vascular disease. Preventive efforts have accordingly shifted toward the modification of other cardiovascular risk factors in diabetic patients. Agonism of the peroxisome proliferator-activated receptors (PPARs) has long been an attractive target for antidiabetic therapy due to the role of PPARs in glycemic control and lipid metabolism. PPAR-α agonists such as rosiglitazone and pioglitazone are used in clinical practice for the treatment of diabetes, and there is some evidence that pioglitazone may have positive effects on cardiovascular complications by virtue of its favorable effects on lipid profiles. However, they have not been shown to reduce macrovascular events. PPAR-α agonism is the mechanism of action in the fibrate class of medications; these agents have been shown to increase high-density lipoprotein cholesterol (HDL-C) levels, reduce triglyceride levels, and improve cardiovascular outcomes. Given the prevalence of lipid abnormalities in patients with diabetes, dual PPAR-α/γ agonists (glitazars) could potentially benefit patients with diabetes. A phase II trial examining a novel dual PPAR agonist, aleglitazar, showed that therapy with this agent reduced hyperglycemia and favorably modified levels of HDL-C and triglycerides with an acceptable safety profile. Aleglitazar is currently being studied in large-scale clinical trials to assess whether it will reduce the risk of major cardiovascular endpoints (death, myocardial infarction, or stroke) among patients with diabetes and coronary artery disease. If ongoing studies confirm the theoretical benefit and safety of dual PPAR-α/γ agonism, aleglitazar may become the first therapy demonstrated to reduce macrovascular complications in patients with diabetes.
authors.affiliation: Department of Cardiovascular Medicine, The Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cavender
authors.forename: A Michael
authors.initials: AM
authors.lastname: Lincoff
mesh_terms: D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D012307:Risk Factors; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D013876:Thiophenes; C542437:aleglitazar