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OBJECTIVE—Sulfonylureas block the activation of vascular potassium-dependent ATP channels and impair the vasodilating response to ischemia in nondiabetic individuals, but it is not known whether this occurs in type 2 diabetic patients under chronic treatment with these drugs. Glimepiride, a new sulfonylurea, apparently has no cardiovascular interactions. The aim of our study was to compare the effect of the widely used compound glibenclamide, the pancreas-specific glimepiride, and diet treatment alone on brachial artery response to acute forearm ischemia. RESEARCH DESIGN AND METHODS—Brachial artery examination was performed by a high-resolution ultrasound technique on 20 type 2 diabetic patients aged (mean ± SD) 67 ± 2 years and on 18 nondiabetic patients matched for age, hypertension, and dislipidemia. Diabetic subjects underwent three separate evaluations at the end of each 8-week treatment period, during which they received glibenclamide, glimepiride, or diet alone according to crossover design. Scans were obtained before and after 4.5 min of forearm ischemia. Postischemic vasodilation and hyperemia were expressed as percent variations in vessel diameter and blood flow. RESULTS—Postischemic vasodilation and hyperemia were, respectively, 5.42 ± 0.90 and 331 ± 38% during glibenclamide, 5.46 ± 0.69 and 326 ± 28% during glimepiride, and 5.17 ± 0.64 and 357 ± 35% during diet treatment (NS). These results were similar to those found in the nondiabetic patients (6.44 ± 0.68 and 406 ± 42%, NS). CONCLUSIONS—In type 2 diabetic patients, the vasodilating response to forearm ischemia was the same whether patients were treated with diet treatment alone or with glibenclamide or glimepiride at blood glucose–lowering equipotent doses.