Peroxisome proliferator-activated receptor-γ activation with pioglitazone improves endothelium-dependent dilation in nondiabetic patients with major cardiovascular risk factors

Background - Patients with cardiovascular risk factors have endothelial dysfunction, a key element in the pathogenesis of atherosclerosis. The thiazolidinediones have been shown to exert multiple antiatherosclerotic actions in diabetic patients. This study tested the hypothesis that pioglitazone improves endothelial function in nondiabetic patients with major risk factors. Methods and Results - The study had a randomized, double-blind, placebo-controlled, crossover design. Eighty patients with either hypertension or hypercholesterolemia were enrolled. Insulin sensitivity was assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), and patients were further classified as insulin sensitive or insulin resistant. In each treatment phase, patients received either pioglitazone 45 mg daily or placebo for 8 weeks. Endothelial function and laboratory tests were performed at the end of each 8-week period. Treatment with pioglitazone significantly lowered plasma insulin (-22.9%; P < 0.001), improved QUICKI insulin sensitivity index (3.7%; P < 0.001), increased HDL cholesterol (8.2%; P < 0.001), and reduced triglycerides (-15.1%; P = 0.003), free fatty acids (-14%; P = 0.005), and C-reactive protein (-28.6%; P = 0.001). Pioglitazone treatment significantly improved endothelium-dependent dilation to bradykinin (P = 0.01) without affecting the response to sodium nitroprusside (P = 0.31). In multivariable analysis, only changes in total cholesterol were predictors of improved endothelial reactivity with pioglitazone. Conclusions - In nondiabetic patients with cardiovascular risk factors, pioglitazone treatment enhances insulin sensitivity, decreases C-reactive protein, and improves endothelial vasodilator function. These effects do not appear to be closely related, suggesting that pioglitazone may have beneficial vascular properties independent of its effect on insulin sensitivity and inflammation.