Combination therapy is logical for patients with non-insulin-dependent (type II) diabetes mellitus, because they often have poor responses to single-drug therapy. We studied the efficacy and physiologic effects of metformin and troglitazone alone and in combination in patients with type II diabetes.

We randomly assigned 29 patients to receive either metformin or troglitazone for three months, after which they were given both drugs for another three months. Plasma glucose concentrations during fasting and postprandially and glycosylated hemoglobin values were measured periodically during both treatments. Endogenous glucose production and peripheral glucose disposal were measured at base line and after three and six months.

During metformin therapy, fasting and postprandial plasma glucose concentrations decreased by 20 percent (58 mg per deciliter [3.2 mmol per liter], P<0.001) and 25 percent (87 mg per deciliter [4.8 mmol per liter], P<0.001), respectively. The corresponding decreases during troglitazone therapy were 20 percent (54 mg per deciliter [2.9 mmol per liter], P = 0.01) and 25 percent (83 mg per deciliter [4.6 mmol per liter], P<0.001). Endogenous glucose production decreased during metformin therapy by a mean of 19 percent (P = 0.001), whereas it was unchanged by troglitazone therapy (P = 0.04 for the comparison between groups). The mean rate of glucose disposal increased by 54 percent during troglitazone therapy (P = 0.006) and 13 percent during metformin therapy (P = 0.03 for the comparison within the group and between groups). In combination, metformin and troglitazone further lowered fasting and postprandial plasma glucose concentrations by 18 percent (41 mg per deciliter [2.3 mmol per liter], P = 0.001) and 21 percent (54 mg per deciliter [3.0 mmol per liter], P<0.001), respectively, and the mean glycosylated hemoglobin value decreased 1.2 percentage points.

Metformin and troglitazone have equal and additive beneficial effects on glycemic control in patients with type II diabetes. Metformin acts primarily by decreasing endogenous glucose production, and troglitazone by increasing the rate of peripheral glucose disposal.