Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study

Objective: To investigate the efficacy and safety of topiramate in obese subjects with type 2 diabetes treated with metformin. Design: This was a multicenter, double-blind, placebo-controlled trial. All subjects received a non-pharmacological program of diet, exercise and behavioral modification throughout the study; the assigned diet was 600 kcal/day less than the subject's individually calculated energy expenditure. After a 6-week single-blind placebo run-in, subjects were randomized to placebo, topiramate 96 mg/day or topiramate 192 mg/day. Following an 8-week titration period, subjects remained on their assigned dose for 52 weeks. However, the sponsor ended the study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. A total of 646 obese men and women ( age: 18-75 years, body mass index: 27-50 kg/m(2)) with an established history of type 2 diabetes mellitus controlled by metformin monotherapy were randomized. Efficacy was assessed in a pre-determined modified intent-to-treat (MITT) population of 307 subjects whose randomization date would have allowed them to complete 24 weeks on study medication before the announcement of study termination. Measurements: Joint primary efficacy parameters were mean percent change in weight and change in glycosylated hemoglobin (HbA(1c)) from baseline to week 24. Results: Subjects in the placebo, topiramate 96 mg/day and topiramate 192 mg/day groups lost 1.7%, 4.5% (P < 0.001) and 6.5% (P < 0.001), respectively, of their baseline body weight and had absolute decreases in HbA(1c) of 0.1%, 0.4% (P < 0.001) and 0.6% (P < 0.001) (MITT, last observation carried forward). Topiramate-treated subjects also experienced statistically significant decreases in systolic blood pressure. Most common adverse events were paresthesia and events related to the central nervous system. Conclusions: Topiramate was effective for weight reduction and improvement in glycemic control in obese subjects with type 2 diabetes treated with metformin monotherapy. Further study in obese diabetics is warranted.