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.