Our data suggest that combination treatment with once-daily metformin-rosiglitazone improves glycemic control, insulin sensitivity, and beta-cell function more effectively than treatment with metformin alone.

OBJECTIVE -To determine the efficacy of rosiglitazone compared with placebo in reducing hyperglycemia. RESEARCH DESIGN AND METHODS-After a 4-week placebo run-in period, 959 patients were randomized to placebo or rosiglitazone (total daily dose 4 or 8 mg) for 26 weeks. The primary measure of efficacy was change in the HbA 1c concentration. Approximately 33% of drug-naive patients treated with rosiglitazone achieved HbA 1c Յ7% at study end. The proportions of patients with at least one adverse event were comparable among the rosiglitazone and placebo groups. There was no evidence of hepatotoxicity in any treatment group. There were statistically significant increases in weight and serum lipids in all rosiglitazone treatment groups compared with placebo. For LDL and HDL cholesterol, the observed increase appeared to be dose related. RESULTSCONCLUSIONS -Rosiglitazone at total daily doses of 4 and 8 mg significantly improved glycemic control in patients with type 2 diabetes and was well tolerated.

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A 1c ; other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A 1c relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ␤-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions. (J Clin Endocrinol Metab 86: 280 -288, 2001) I NSULIN RESISTANCE contributes to the pathophysiology of several major chronic diseases. Insulin resistance precedes the development of type 2 diabetes mellitus and contributes to the hyperglycemic state in about 80 -85% of patients with this disorder (1, 2). In addition, evidence suggests that insulin resistance and hyperinsulinemia are also associated with other disease states, such as polycystic ovarian syndrome, an insulin-resistant state that leads to hyperinsulinemia, thus stimulating excessive ovarian androgen production in genetically susceptible individuals (3, 4). Insulin resistance and hyperinsulinemia have also been associated with increased risks of atherosclerosis and hyperten-

Because insulin resistance plays a prominent part in the development of Type II diabetes [1,2], therapeutic interventions to improve insulin action are likely to be of considerable benefit in the management of the condition. The thiazolidinediones (or glitazones) are a new class of orally active drugs that reduce insulin resistance [3] and hence increase glucose uptake in skeletal muscle and adipose tissue, as well as decrease hepatic glucose production. These effects are thought to be mediated through interactions of these drugs with the gamma subtype of the peroxisome proliferator-activated receptor gamma (PPARg) [4,5].The thiazolidinediones currently marketed, or in late-phase clinical trials, include troglitazone, rosiglitazone and pioglitazone. Although these compounds share a common thiazolidine-2±4-dione structure, Diabetologia (2000) Abstract Aims/hypothesis. The short-term efficacy, safety and tolerability of rosiglitazone were compared with placebo in patients with Type II (non-insulin-dependent) diabetes mellitus in a dose-ranging study. Methods. After a 2-week placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone. Results. All rosiglitazone doses significantly reduced fasting plasma glucose compared with baseline. All rosiglitazone treatment groups showed significantly reduced peak postprandial glucose concentrations compared with baseline (p < 0.001) and with placebo (p < 0.0001) and reduced postprandial glucose excursion, without an increase in the area under the postprandial insulin concentration-time curve. Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA 1 c observed in the placebo group. C peptide and serum insulin concentrations were significantly reduced from baseline in all rosiglitazone treatment groups. In all rosiglitazone treatment groups, nonesterified fatty acids decreased significantly (p < 0.0001) and triglycerides did not change. Although total LDL and HDL cholesterol increased significantly in the rosiglitazone treatment groups, total cholesterol/HDL ratios did not change significantly. The proportion of patients with one or more adverse event was similar in all four treatment groups. No patient showed evidence of hepatotoxicity. Conclusion/interpretation. Rosiglitazone given twice daily significantly reduced fasting and postprandial glucose concentrations, C peptide, insulin and nonesterified fatty acids in Type II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice daily should be the maximum clinical dose. [Diabetologia (2000) 43: 278±284]

Overall, the combination of rosiglitazone and a sulphonylurea was safe, well tolerated and effective in patients with Type 2 diabetes.

No abstract

A total of 52 weeks of therapy with RSG (4 mg b.i.d.) did not adversely affect cardiac structure or function in patients with type 2 diabetes and produced significant and sustained reductions in hyperglycemia. Decreases in ambulatory diastolic blood pressure with RSG were superior to those with GLB.

Rosiglitazone improves glycaemic control when given once daily to treat Type 2 diabetes mellitus and is well tolerated at doses up to and including 12 mg.