The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin - A multicenter, randomized, double-blind, placebo-controlled trial

Background: The thiazolidinediones are a new class of anti-diabetes medication that enhances the actions of insulin in muscle, liver, and adipose tissue. Data have been lacking on their use in combination with both sulfonylurea and metformin among patients for whom insulin is the usual therapeutic alternative for improved glycemic control. Objective: To determine the effects of troglitazone on hemoglobin A(1c) level in patients treated with maximum tolerated doses of sulfonylurea and metformin who have hemoglobin A(1c) levels of at least 0.085 (8.5%). This trial was completed before troglitazone was taken off the U.S. market. Design: Randomized, double-blind, placebo-controlled trial, followed by an open-label extension during which all patients received troglitazone. Setting: 16 outpatient clinics in Canada. Patients: 200 patients (mean age, 59 years) with type 2 diabetes mellitus and hemoglobin A(1c) levels at least 0.085 (8.5%) (mean hemoglobin A(1c) level, 0.097 [9.7%] and mean fasting plasma glucose level, 12.9 mmol/L [233 mg/dL]) while receiving maximum doses of sulfonylurea and metformin. Measurements: Levels of hemoglobin A(1c), fasting plasma glucose, total insulin, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, Results: Troglitazone, 400 mg/d, when added to sulfonylurea and metformin, significantly decreased hemoglobin A(1c) level by 0.014+/-0.002 (95% CI, 0.0167 to 0.0109; P<0.001) (1.4%+/-0.2% [CI, 1.67% to 1.09%]) and insulin by 19+/-4 pmol/L (CI, 30 to 10 pmol/L; P< 0.001). At 6 months, 43% of troglitazone-treated patients achieved hemoglobin A(1c) levels of 0.08 (8%) or lower compared with 6% of placebo recipients. Efficacy was maintained at 12 months. Conclusions: The thiazolidinedione troglitazone, at a dosage of 400 mg/d, is effective when used in combination with sulfonylurea and metformin. Thiazolidinediones may therefore offer an effective alternative to insulin for patients treated with sulfonylurea and metformin who do not achieve adequate glycemic control.