- Background: Type II diabetes is often associated with high blood pressure, elevated sympathetic activity, and high plasma insulin levels. Hypoglycemic agents may negatively interfere with blood pressure control, sympathetic activity, and plasma insulin level; therefore the choice of treatment in type II diabetes may be crucial. We aimed to compare the effects of two hypoglycemic drugs on blood glucose, blood pressure, sympathetic activity, and insulin levels in type II diabetic and hypertensive patients. Methods: Forty-eight (24M, 24F) type II diabetic, hypertensive, and hyperlipidemic subjects were enrolled and treated for 4 weeks with an ACE inhibitor (Cilazapril) and a statin (Simvastatin). They were then randomized into two groups to receive a thiazolidinedione (Rosiglitazone; ROS) or a sulfonylurea (Glibenclamide; GLB) for 8 weeks. Blood biochemistry, blood pressure, plasma insulin, endothelial function, and sympathetic skin activity were measured before and after treatment. Results: A significant drop in systolic and diastolic blood pressure by 6.1 ± 4.1mm Hg and 4.2 ± 1.9 mm Hg respectively; a reduction in plasma insulin concentration by 4.3 ± 1.9mU/L and a decline in skin sympathetic activity were observed in the group receiving ROS. The GLB group showed an increase in systolic blood pressure by 3.1 ± 2.5 mm Hg, no change in diastolic blood pressure, significant elevation in plasma insulin concentration by 2.3 ± 1.4 mu/L, and augmentation of sympathetic activity. No significant changes in endothelial function were observed in either group. Conclusions: Rosiglitazone improved both plasma glucose and blood pressure levels, probably by attenuation of hyperinsulinemia and sympathetic activity, while Glibenclamide worsened blood pressure control possibly by elevation of insulin levels and activation of the sympathetic system.