CONCLUSION: In this managed care setting, the effectiveness and safety of sibutramine were similar to those observed in randomized, double-blind clinical efficacy trials.

9. Rosiglitazone Improves, While Glibenclamide Worsens Blood Pressure Control in Treated Hypertensive Diabetic and Dyslipidemic Subjects via Modulation of Insulin Resistance and Sympathetic Activity.

J Cardiovasc Pharmacol. 2004 Aug;44(2):215-222. Yosefy C, Magen E, Kiselevich A, Priluk R, London D, Volchek L, Viskoper RJ Jr. *Noninvasive Cardiac Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; daggerWHO Collaborative Center for Prevention of CVD, Barzilai Medical Center Campus, Ben-Gurion University of the Negev, Ashkelon, Israel; double daggerNeurology Department, Barzilai Medical Center Campus, Ben-Gurion University of the Negev, Ashkelon, Israel; and section signRadiology Department, Barzilai Medical Center Campus, Ben-Gurion University of the Negev, Ashkelon, Israel.

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.

10. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients.

Diabetes Care. 2003 Jan;26(1):172-8.

Raji A, Seely EW, Bekins SA, Williams GH, Simonson DC. Endocrine-Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

OBJECTIVE: To examine the effect of rosiglitazone on insulin resistance and blood pressure in patients with essential hypertension, classified based on abnormalities of their renin-angiotensin system.

RESEARCH DESIGN AND METHODS: A total of 24 hypertensive nondiabetic patients (age 58 +/- 6 years, BMI 30 +/- 5 kg/m2) were studied before and after rosiglitazone treatment. After 2 weeks off antihypertensive medication, subjects received a euglycemic-hyperinsulinemic clamp (40 mU. m(-2). min(-1)) with 6,6-[2H2]glucose infusion, ambulatory blood pressure monitoring, and blood tests for cardiovascular risk factors. Subjects were then placed on rosiglitazone (4 mg orally b.i.d.) and their usual antihypertensive medications (but not ACE inhibitors) for 16 weeks, and baseline tests were repeated.

RESULTS: There was no change in fasting plasma glucose (83 +/- 2 vs. 82 +/- 2 mg/dl, P = 0.60), but fasting insulin decreased (16.1 +/- 1.4 vs. 12.5 +/- 0.9 micro U/ml, P<0.01). Total glucose disposal during the clamp increased (5.0 +/- 0.4 vs. 5.9 +/- 0.5 mg. kg(-1). min(-1), P < 0.001), with no change in suppression of hepatic glucose output. There were significant decreases in mean 24-h systolic (138 +/- 2 vs. 134 +/- 2 mmHg, P < 0.02) and diastolic (85 +/- 2 vs. 80 +/- 2 mmHg, P < 0.0001) blood pressure, and the decline in systolic blood pressure was correlated with the improvement in insulin sensitivity (r = 0.59, P < 0.005). Triglycerides (135 +/- 16 vs. 89 +/- 8 mg/dl, P < 0.01), LDL cholesterol (129 +/- 6 vs. 122 +/- 8 mg/dl, P = 0.18), and HDL cholesterol (51 +/- 3 vs. 46 +/- 3 mg/dl, P < 0.02) all decreased, with no change in the LDL-to-HDL ratio. Plasminogen activator inhibitor-1 and C-reactive protein also declined significantly.

CONCLUSIONS: Rosiglitazone treatment of nondiabetic hypertensive patients improves insulin sensitivity, reduces systolic and diastolic blood pressure, and induces favorable changes in markers of cardiovascular risk. Insulin sensitizers may provide cardiovascular benefits when used in the treatment of patients with hypertension.

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

Diabetes Care. 2004 Jun;27(6):1349-57.

Natali A, Baldeweg S, Toschi E, Capaldo B, Barbaro D, Gastaldelli A, Yudkin JS, Ferrannini E. Department of Internal Medicine, CNR Institute of Clinical Physiology, University of Pisa, Via Roma 67, 56100 Pisa, Italy. anatali@ifc.cnr.it

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 (30 +/- 1 vs. 41 +/- 3 micromol. min(-1). kg fat-free mass(-1); P<0.001) and reduced maximal response to ACh (586 +/- 42 vs. 883 +/- 81%; P < 0.001). 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 HbA(1c) (-1.2 +/- 0.3 and -1.6 +/- 0.3%). Insulin sensitivity increased with rosiglitazone (+6 +/- 3 micromol. min(-1). kg fat-free mass(-1); P < 0.01) 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-alpha.

CONCLUSIONS: At equivalent glycemic control, rosiglitazone, but not metformin, improves endothelium dependent vasodilatation and insulin sensitivity in type 2 diabetes.

12. Addition of biphasic insulin aspart 30 to rosiglitazone in type 2 diabetes mellitus that is poorly controlled with glibenclamide monotherapy.

Clin Ther. 2003 Dec;25(12):3109-23. Raz I, Mouritzen U, Vaz J, Hershkovitz T, Wainstein J, Harman-Boehm I. Hadassah Ein Karem Medical Center, Jerusalem, Israel. ntv502@netvision.net.il

BACKGROUND: The incidence of type 2 diabetes mellitus (DM) is rapidly increasing worldwide. Results from large-scale studies show that tight blood glucose (BG) control improves the outcome of patients with type 2 DM.

OBJECTIVE: This trial assessed the short-term efficacy and tolerability of adding a thiazolidinedione (rosiglitazone [ROS]) to existing sulfonylurea (SU) therapy (glibenclamide) compared with switching to combination treatment with a premixed insulin (biphasic insulin aspart 30 [BIAsp 30], a rapid-acting insulin analog) and the thiazolidinedione in a select group of patients with type 2 DM whose metabolic control was inadequate with SU monotherapy.