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A Randomized Controlled Trial

Vivian Fonseca, MD; Julio Rosenstock, MD; Rita Patwardhan, PhD; Alan Salzman, MD, PhD

JAMA. 2000;283:1695-1702.

Context  Most antidiabetic agents target only 1 of several underlying causes of diabetes. The complementary actions of the antidiabetic agents metformin hydrochloride and rosiglitazone maleate may maintain optimal glycemic control in patients with type 2 diabetes; therefore, their combined use may be indicated for patients whose diabetes is poorly controlled by metformin alone.

Objective  To evaluate the efficacy of metformin-rosiglitazone therapy in patients whose type 2 diabetes is inadequately controlled with metformin alone.

Design  Randomized, double-blind, placebo-controlled trial from April 1997 and March 1998.

Setting  Thirty-six outpatient centers in the United States.

Patients  Three hundred forty-eight patients aged 40 to 80 years with a mean fasting plasma glucose level of 12.0 mmol/L (216 mg/dL), a mean glycosylated hemoglobin level of 8.8%, and a mean body mass index of 30.1 kg/m² were randomized.

Interventions  Patients were assigned to receive 2.5 g/d of metformin plus placebo (n = 116); 2.5 g/d of metformin plus 4 mg/d of rosiglitazone (n = 119); or 2.5 g/d of metformin and 8 mg/d of rosiglitazone (n = 113) for 26 weeks.

Main Outcome Measures  Glycosylated hemoglobin levels, fasting plasma glucose levels, insulin sensitivity, and -cell function, compared between baseline and week 26, by treatment group.

Results  Glycosylated hemoglobin levels, fasting plasma glucose levels, insulin sensitivity, and -cell function improved significantly with metformin-rosiglitazone therapy in a dose-dependent manner. The mean levels of glycosylated hemoglobin decreased by 1.0% in the 4 mg/d metformin-rosiglitazone group and by 1.2% in the 8 mg/d metformin-rosiglitazone group and fasting plasma glucose levels by 2.2 mmol/L (39.8 mg/dL) and 2.9 mmol/L (52.9 mg/dL) compared with the metformin-placebo group (P<.001 for all). Of patients receiving 8 mg/d of metformin-rosiglitazone, 28.1% achieved a glycosylated hemoglobin level of 7% or less. Dose-dependent increases in body weight and total and low-density lipoprotein cholesterol levels were observed (P<.001 for both rosiglitazone groups vs placebo). The proportion of patients reporting adverse experiences was comparable across all groups.

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

Author Affiliations: Department of Medicine, Endocrinology Section, Tulane University, New Orleans, La (Dr Fonseca); Dallas Diabetes Center, Dallas, Tex (Dr Rosenstock); Departments of Biometrics (Dr Patwardhan) and Clinical Research and Development (Dr Salzman), SmithKline Beecham Pharmaceuticals, Collegeville, Pa.

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