Therapeutic Potential of Aleglitazar, a New Dual PPAR Agonist

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-γ 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.

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.

Type 2 diabetes is prevalent across the world and leads to substantial disability and reduced life expectancy. While macrovascular complications such as stroke, myocardial infarction, and peripheral vascular disease remain the most common causes of morbidity and mortality in diabetic patients, studies evaluating the efficacy of intensive glycemic control have failed to convincingly demonstrate a reduction in these macrovascular events. Given the lack of impact on cardiovascular endpoints achieved through the reduction of hyperglycemia alone, increased attention has turned toward additional risk factors that are common in patients with diabetes.

Hypoglycemic agents with a positive impact on lipid parameters may be a promising approach to reduce morbidity and mortality of patients with diabetes. Aleglitazar, a novel agonist of both PPAR-γ and PPAR-α, appears to be effective in the treatment of hyperglycemia while reducing triglyceride levels and increasing HDL-C levels. A large-scale clinical trial of the effect of aleglitazar on cardiovascular death, myocardial infarction, and stroke is currently ongoing. If successful, this investigation may lead to approval of the first agent specifically targeted to reduce the burden of cardiovascular disease in patients with diabetes.

Am J Cardiovasc Drugs. 2010;10(4):209-216