Until recently, the only treatments available in the United States for patients with type 2 diabetes were insulin or the sulfonylureas. Several new oral agents have been approved by the U.S. Food and Drug Administration, including metformin, troglitazone and alpha-glucosidase inhibitors such as acarbose. The advantage of these new products is that they have different mechanisms of action that help to reduce blood sugar levels. Inzucchi and colleagues evaluated the efficacy and physiologic effects of a combination of metformin and troglitazone in the treatment of type 2 diabetes.
Twenty-nine patients with type 2 diabetes were enrolled in this study. The patients had a mean age of 53 years, had had diabetes for an average of five years, had a mean body mass index of 33.8 and a mean glycosylated hemoglobin level of 9.5 percent. The patients underwent a drug washout period of two weeks. They were then randomly assigned to receive 1,000 mg of metformin twice daily or 400 mg of troglitazone once daily. Plasma glucose and glycosylated hemoglobin levels were measured at baseline and monthly thereafter. Routine hematologic and chemistry studies were also obtained. After three months, patients were given a combination of the originally assigned drug and the second oral agent. Monthly monitoring continued. The study participants were prescribed a special diet consisting of 50 percent carbohydrate, 34 percent fat and 16 percent protein.
After the first three months, the metformin group had a mean reduction in fasting plasma glucose levels of 58 mg per dL (3.20 mmol per L) and the troglitazone group had a mean reduction of 54 mg per dL (3.00 mmol per L). With the addition of the second drug, there was an additional mean reduction of 41 mg per dL (2.25 mmol per L) in the fasting plasma glucose levels. The total mean decrease for all patients during the six-month study period was 98 mg per dL (5.45 mmol per L), a 35 percent reduction from baseline. The mean glycosylated hemoglobin levels decreased 1.2 percent from month three to month six. There were no significant changes in body weight with either monotherapy or combination therapy. No adverse events were recorded in either study group, including increases in serum lactate levels or abnormalities in liver function tests. One patient developed diarrhea.
The authors conclude that metformin and troglitazone are equally effective in lowering plasma glucose concentrations in patients with type 2 diabetes. In addition, when used in combination, the two drugs are additive in their ability to help patients achieve better glycemic control.
editor's note: Despite some of the hepatic problems recently attributed to troglitazone therapy, it is the opinion of many diabetologists that this agent alone (with or without metformin) should become the therapy of choice in most patients with type 2 diabetes. Historically, most physicians have first prescribed a sulfonylurea for these patients and switched to insulin when sulfonylureas failed. The problem with sulfonylureas is that they work by increasing endogenous insulin production. This may result in symptomatic hypoglycemia and also tends to result in weight gain. Hyperinsulinemia is also now thought to accelerate atherogenesis, and some older data have suggested that sulfonylurea therapy resulted in an increase in cardiovascular deaths. I believe that, once more clinical experience with the newer oral agents has been gained, the sulfonylureas will become third-or fourth-line drugs in the treatment of type 2 diabetes.—j.t.k.