The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients.

OBJECTIVES: We sought to assess the effect of rosiglitazone on markers of endothelial cell activation and acute-phase reactants in non-diabetic patients with coronary artery disease (CAD). BACKGROUND: Inflammation plays a key role in all stages of atherosclerosis and in the genesis of acute coronary syndromes. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, is used in the treatment of type 2 diabetes mellitus, and previous data suggest that it may have anti-inflammatory effects on atherosclerosis. METHODS: Patients with stable, angiographically documented CAD without diabetes mellitus were investigated. Patients were randomized in a double-blind manner to receive treatment with placebo or rosiglitazone (4 mg/day for 8 weeks followed by 8 mg/day for 4 weeks) for 12 weeks. Eighty-four patients completed the study. Fasting glucose, insulin, lipid profile, markers of endothelial activation, and inflammatory markers were measured at baseline and after 12 weeks. RESULTS: Rosiglitazone treatment resulted in a significant reduction in E-selectin (p = 0.03), von Willebrand factor (p = 0.007), C-reactive protein (p < 0.001), fibrinogen (p = 0.003) and the homeostasis model of insulin resistance index (p = 0.02), compared with placebo. Significant elevations in low-density lipoprotein and triglyceride levels were observed in the rosiglitazone group (p < 0.01). Within the rosiglitazone-treated group, reductions in C-reactive protein and von Willebrand factor were significantly correlated with a reduction in insulin resistance. CONCLUSIONS: Rosiglitazone significantly reduces markers of endothelial cell activation and levels of acute-phase reactants in CAD patients without diabetes. Potential underlying mechanisms include insulin sensitization and direct modification of transcription within the vessel wall.

Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease.

BACKGROUND: Rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, is used in the treatment of type 2 diabetes mellitus, and in vitro data has shown that it may have anti-platelet effects independent of its hypoglycemic effects. The aim of this study was to assess the effect of rosiglitazone on circulating platelet activity in patients without diabetes mellitus who had coronary artery disease. METHODS: Ninety-two patients with stable, documented coronary artery disease without diabetes mellitus were studied. Patients were randomized (double-blind) to receive placebo or rosiglitazone for 12 weeks. Circulating platelet activity was measured at baseline and after 12 weeks of therapy with whole blood flow cytometry to quantify platelet P-selectin expression. RESULTS: The percentage of P-selectin positive platelets was significantly reduced by rosiglitazone treatment compared with placebo (P =.04). In the rosiglitazone group, the percentage of P-selectin positive platelets (median with interquartile range) decreased from 0.1 % (0.05-0.24) to 0.05 % (0.01-0.15). Rosiglitazone treatment significantly reduced the insulin resistance index (HOMA-R) compared with placebo (P =.02). No significant correlation was observed between change in platelet activity and change in HOMA-R. CONCLUSIONS: Rosiglitazone significantly reduces circulating platelet activity in patients without diabetes mellitus who have coronary artery disease. This effect appears to be independent of any insulin-sensitising effect.

Effects of rosiglitazone on endothelial function in men with coronary artery disease without diabetes mellitus.

Recent data have shown that peroxisome proliferator-activated receptor-gamma agonists may exert protective effects on the vascular endothelium by amelioration of insulin resistance and through direct anti-inflammatory effects. In this study we assessed the effect of rosiglitazone on biochemical and biophysical indexes of endothelial function in male, nondiabetic patients with coronary artery disease. Consecutive male subjects (n = 71) with clinically stable, angiographically documented coronary artery disease and without diabetes mellitus were investigated. Patients were randomized in a double-blind manner to placebo or rosiglitazone for a total of 24 weeks. Flow-mediated dilation (FMD) of the brachial artery, C-reactive protein, von Willebrand factor, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels, and parameters of glucose and lipid metabolism were measured at baseline and after 12 and 24 weeks of treatment. Rosiglitazone treatment significantly reduced C-reactive protein (median 0.56 mg/L [interquartile range 0.33 to 1.02] to 0.33 mg/L [interquartile range 0.26 to 0.40], p <0.01), von Willebrand factor (139 +/- 47 to 132 +/- 44 IU/dl, p = 0.02), insulin resistance index (p = 0.05), and mean low-density lipoprotein (LDL) density (p <0.001) compared with placebo. However, no significant differences were seen between the rosiglitazone and placebo groups with regard to brachial artery FMD, intercellular adhesion molecule-1, or vascular cell adhesion molecule-1 levels. Rosiglitazone treatment significantly increased LDL (2.62 +/- 0.72 to 2.95 +/- 0.84 mmol/L, p = 0.03) and triglyceride (1.23 +/- 0.63 to 1.56 +/- 0.98 mmol/L, p = 0.04) levels. Thus, rosiglitazone reduced markers of inflammation and endothelial activation, but this did not translate into an improvement in FMD. Increased LDL and triglyceride levels may have played a role.