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Metformin Plus Rosiglitazone Therapy for Type 2 Diabetes



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Am Fam Physician. 2000 Oct 1;62(7):1659.

By three years after diagnosis, nearly one half of patients with type 2 diabetes mellitus (formerly known as non–insulin-dependent diabetes) require more than one pharmacotherapeutic agent to control glycosylated hemoglobin (HbA1c) levels. Rosiglitazone is a recently approved agent that promotes synthesis of glucose transporters and activates adipocyte differentiation. Metformin, another antidiabetic agent, decreases hepatic glucose production and gluconeogenesis by increasing uptake of glucose peripherally. Fonseca and colleagues conducted a randomized controlled trial to determine if rosiglitazone was safe and efficacious when added to metformin in patients with type 2 diabetes whose disease was not well controlled.

Patients were included in the study if they had a diagnosis of type 2 diabetes and were between 40 and 80 years of age. All patients were required to have been taking a 2.5 g per day dosage of metformin and to have a demonstrated ability to secrete insulin (as determined by a C-peptide level at or above a cut point). Patients with significant hepatic, cardiac or renal disease were excluded from the study. Use of all antidiabetic agents, except metformin, was discontinued before the study began. Metformin was titrated to a dosage of 2.5 g per day, and patients then began a four-week metformin-placebo phase. Patients whose blood-glucose control was not adequate at that point were then randomized to receive metformin plus placebo, 4 mg of rosiglitazone or 8 mg of rosiglitazone daily. This phase lasted 26 weeks. A large number of laboratory tests were performed on each patient, and safety monitoring was also done.

Of the 437 patients who enrolled in the study, 348 were randomized to one of the three treatment arms. Withdrawal from the double-blind phase (due to adverse effects or lack of efficacy) occurred in 22 patients in the placebo group, and 18 each in the 4 mg and 8 mg rosiglitazone groups. Significant decreases in HbA1c levels occurred in both rosiglitazone groups (0.56 percent in the 4-mg group and 0.78 percent in the 8-mg group). An increase of 0.45 percent was observed in the placebo group. The mean HbA1c levels decreased after one month of combined treatment and leveled off after about 18 weeks of combined treatment. About one third of the participants in the 4 mg and the 8 mg rosiglitazone groups (32.8 and 37.2 percent, respectively) had a 1 percent decrease in HbA1c levels, compared with 7 percent of the placebo group. The target HbA1c levels (7 percent) were achieved in 28.1 percent of participants taking 8 mg of rosiglitazone daily; a level of 8 percent (the American Diabetes Association point for taking action) was achieved in 57.3 percent of the 8-mg group. In the placebo group, these levels were 7.6 and 35.9 percent, respectively. Mean fasting plasma glucose levels also decreased significantly in both rosiglitazone groups in a dose-dependent fashion. Diarrhea, headache and upper respiratory infection were the most commonly reported adverse events in each group. There were no significant differences between groups in terms of the serious adverse effects that occurred, and no effects were determined to be caused by the study medication. Two patients receiving rosiglitazone had their metformin dose reduced because of mild hypoglycemia.

The authors conclude that adding rosiglitazone to metformin treatment in patients whose type 2 diabetes is not well controlled is associated with a reduced mean fasting plasma glucose level and a reduction in HbA1c level. This combination also appears to be safe and well-tolerated. Further studies are needed to determine if such combination therapy has a beneficial effect on cardiovascular end points and diabetes progression.

Fonseca V, et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus. A randomized controlled trial. JAMA. April 5, 2000;283:1695–1702.


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