1. ¹Diabetes and Endocrinology Research Group, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK
2. ²Department of Endocrinology, University Hospital, Antwerp, Belgium
3. ³Obesity Research Unit, Helsinki University Hospital, Helsinki, Finland
4. ⁴Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
5. ⁵Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ, USA

Correspondence: Dr J Wilding, Diabetes and Endocrinology Research Group, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, UK. E-mail: j.p.h.wilding@liverpool.ac.uk

Received 4 November 2003; Revised 11 June 2004; Accepted 23 June 2004; Published online 21 September 2004.

Abstract

BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study.

OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects.

DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/day. All subjects also participated in a nonpharmacological weight-loss programme.

SUBJECTS: The study included 1289 subjects 18–75 y with a body mass index 30 kg/m² and <50 kg/m² in the absence of comorbidities, or 27 kg/m² and <50 kg/m² in the presence of controlled hypertension and/or dyslipidaemia.

DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose (modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication.

RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively (P<0.001, MITT, last observation carried forward). Weight loss 5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively; weight loss 10% was achieved by 6 vs 29, 40, and 44%, respectively (P<0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of +0.4/+1.0, -3.1/-1.3, -5.7/-3.4, and -4.6/-2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, P<0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramate-treated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing.

CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.