Effects of peroxisome proliferator-activated receptor-gamma activation with pioglitazone on plasma adipokines in nondiabetic patients with either hypercholesterolemia or hypertension

Adipokines are substances produced by the adipose tissue that may play significant roles in the mechanisms contributing to the development of atherosclerosis. Thiazolidinediones have been shown to improve endothelium-dependent vasodilation and to exert multiple antiatherosclerotic effects. This study tested the hypotheses that nondiabetic patients with cardiovascular risk factors have altered levels of adipokines that can be modified by pioglitazone treatment. Eighty patients with hypertension or hypercholesterolemia were in a double-blinded, placebo-controlled, crossover study. In each treatment phase, patients received pioglitazone 45 mg/day or placebo for 8 weeks. Endothelial function studies and biochemical assays were performed at the end of each 8-week treatment period. Twenty-two normal volunteers, matched with patients for age, gender, and body mass index, were recruited as a control group. Compared with controls, placebo-treated patients had lower adiponectin levels (11,160 +/- 763 vs 6,078 +/- 385 ng/ml, p <0.001) and similar plasma leptin levels (21.5 +/- 3.8 vs 16.2 +/- 1.5 ng/ml, p = 0.128) and resistin levels (5.1 +/- 0.4 vs 4.4 +/- 0.2 ng/ml, p = 0.250). In patients, pioglitazone treatment markedly increased adiponectin (+121%, p <0.001) and decreased resistin (-10.5%, p = 0.03). Leptin was not significantly decreased (-7.1%, p = 0.10). In multivariate analysis, pioglitazone-induced changes in endothelial reactivity to acetylcholine were the only significant predictor of increases in adiponectin. In conclusion, in nondiabetic patients with major cardiovascular risk factors, pioglitazone treatment beneficially influences circulating adipokine levels. The relation between the increase in adiponectin levels and the improvement in endothelial vasodilator activity suggests a mechanistic link between vascular effects and adiponectinemia.