Double-masked, placebo-controlled, dose-ranging study of troglitazone 10 to 200 mg once daily in non—insulin-dependent diabetes mellitus

Abstract

Troglitazone is an insulin action-enhancing agent currently being investigated clinically for the treatment of non—insulin-dependent diabetes mellitus (NIDDM). Dose-ranging studies of the metabolic effects of troglitazone in NIDDM patients at doses of up to 800 mg/d have shown effective glycemic control, good tolerability, and favorable effects on dyslipidemic profiles. To determine the minimum effective dose of troglitazone required to achieve glycemic control in NIDDM, 10-mg, 30-mg, 100-mg, and 200-mg doses of troglitazone were administered once daily for 16 weeks in this double-masked, placebo-controlled, parallel-group, dose-ranging study. A total of 284 patients of both sexes (mean age, 60 years; range, 35 to 84 years) with a diagnosis of NIDDM and two consecutive fasting capillary blood glucose levels of 7 to 15 mmol/L, within 4 mmol/L of each other, were randomized to treatment. After 16 weeks of treatment an adjusted geometric mean glycated hemoglobin A 1c (Hb A 1c) value of 7.6% was seen in the 200-mg group compared with 8.2% in the placebo group, resulting in a statistically significant 7% overall reduction in Hb A 1c compared with placebo. Reductions in Hb A 1c in the other treatment groups were not statistically significant when compared with placebo. A definite linear dose-response relationship over the range of 10 to 200 mg of troglitazone for adjusted geometric mean fasting serum glucose level was seen during the 16-week treatment period; doses of 30, 100, and 200 mg showed statistically significant reductions compared with placebo after 16 weeks of treatment. Both adjusted geometric mean fasting serum insulin and proinsulin levels were lower for troglitazone 200 mg compared with placebo at all visits. A 10% reduction in insulin and a 16% reduction in proinsulin compared with placebo were seen at week 16, with only the latter reaching statistical significance. Troglitazone was well tolerated at all doses. The incidence and nature of adverse events were similar for all doses of troglitazone and placebo, with no hypoglycemic events occurring in any study group. This study demonstrated that troglitazone 200 mg once daily may be considered the minimum effective dose for establishing glycemic control in NIDDM