Vascular effects of improving metabolic control with metformin or rosiglitazone in type 2 diabetes

OBJECTIVE— The aim of this study was to test whether vascular reactivity is modified by improving metabolic control and peripheral insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODS— In a randomized, double-blind design, we assigned 74 type 2 diabetic patients to rosiglitazone (8 mg/day), metformin (1,500 mg/day), or placebo treatment for 16 weeks and measured insulin sensitivity (euglycemic insulin clamp), ambulatory blood pressure, and forearm blood flow response to 1) intra-arterial acetylcholine (ACh), 2) intra-arterial nitroprusside, 3) the clamp, and 4) blockade of nitric oxide (NO) synthase. RESULTS— Compared with 25 nondiabetic subjects, patients had reduced insulin sensitivity (301 vs. 413 mol min1 kg fat-free mass1; P0.001) and reduced maximal response to ACh (58642 vs. 88381%; P0.001). Relative to placebo, 16 weeks of rosiglitazone and metformin similarly reduced fasting glucose (2.3 0.5 and 2.3 0.5 mmol/l) and HbA1c (1.2 0.3 and 1.6 0.3%). Insulin sensitivity increased with rosiglitazone (6 3 mol min1 kg fat-free mass1; P0.01) but not with metformin or placebo. Ambulatory diastolic blood pressure fell consistently (2 1 mmHg; P 0.05) only in the rosiglitazone group. Nitroprusside dose response, clamp-induced vasodilatation, and NO blockade were not affected by either treatment. In contrast, the slope of the ACh dose response improved with rosiglitazone (40% versus baseline, P 0.05, 70% versus placebo, P 0.005) but did not change with either metformin or placebo. This improvement in endothelium-dependent vasodilatation was accompanied by decrements in circulating levels of free fatty acids and tumor necrosis factor. CONCLUSIONS— At equivalent glycemic control, rosiglitazone, but not metformin, improves endothelium dependent vasodilatation and insulin sensitivity in type 2 diabetes.