Background: Preventing progression from impaired fasting glucose or impaired glucose tolerance to type 2 diabetes mellitus has been evaluated using monotherapy and lifestyle changes. In one randomized controlled trial, use of rosiglitazone (Avandia) alone showed a 60 percent relative risk reduction for developing type 2 diabetes. In the Diabetes Prevention Program, use of metformin (Glucophage) alone showed a 31 percent relative risk reduction compared with placebo. No studies to date have determined the effectiveness of combination drug therapy to prevent progression to type 2 diabetes. Zinman and colleagues conducted a double-blind, randomized controlled trial to evaluate the effectiveness of combination therapy with metformin and rosiglitazone on the progression to type 2 diabetes in persons with impaired glucose tolerance.

The Study: Eligible participants 30 to 75 years of age with at least one risk factor for type 2 diabetes were recruited for screening with an oral glucose tolerance test. Patients were determined to have impaired glucose tolerance if they had a fasting plasma glucose level of less than 126.13 mg per dL (7.0 mmol per L), and a plasma glucose level of 140.54 mg per dL (7.8 mmol per L) to less than 200 mg per dL (11.1 mmol per L) two hours after a 75-g oral glucose challenge. Patients were excluded if they did not take at least 80 percent of their placebo pills during a four-month run-in period, or if they were currently taking the trial medication, had previous diabetic therapy, or had renal dysfunction. The primary outcome was the development of type 2 diabetes, defined as two fasting plasma glucose levels of at least 126.13 mg per dL or a plasma glucose level of more than 198.20 mg per dL (11.0 mmol per L) two hours after a 75-g oral glucose challenge. Fasting plasma glucose levels were checked twice a year and the oral glucose tolerance test was performed once a year for approximately four years.

Results: A total of 103 patients were assigned to receive a combination of rosiglitazone (2 mg) and metformin (500 mg) twice a day, and 104 patients were assigned to receive placebo. The primary outcome of progression to type 2 diabetes showed a 66 percent relative risk reduction for persons on the trial medications. A total of 15.9 percent of patients taking the study drugs progressed to type 2 diabetes, whereas 41.8 percent of patients on placebo progressed. Additionally, 79.6 percent of patients on the study drugs regressed to normal glucose tolerance, whereas 53.1 percent of patients on placebo regressed. More patients had diarrhea in the treatment group compared with the placebo group; however, there were no significant differences in other gastrointestinal symptoms, edema, or hypoglycemia.

Conclusion: The authors conclude that using a combination of low-dose rosiglitazone and metformin in patients with impaired glucose tolerance is effective in preventing progression to type 2 diabetes. However, this study was limited because it did not differentiate between the actual prevention of diabetes or early treatment of diabetes that masks its clinical and biochemical detection. The authors note that the study was underpowered to provide adequate information on long-term cardiovascular safety.