Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults

Background: Orlistat is a gastrointestinal lipase inhibitor that reduces di etary fat absorption by approximately 30%, promotes weight loss, and may re duce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects. Objective: To test the hypothesis that orlistat combined with dietary inter vention improves glucose tolerance status and prevents worsening of diabete s status more effectively than placebo. Methods: We pooled data from 675 obese (body mass index, 30-43 kg/m(2)) adu lts at 39 US and European research centers in 3 randomized, double-blind, p lacebo-controlled multicenter clinical trials. Subjects received placebo pl us a low-energy diet during a 4-week lead-in period. On study day 1, the di et was continued, and subjects were randomized to receive placebo 3 times a day (n=316) or treatment with orlistat, 120 mg 3 times a day (n=359), for 104 weeks. A standard 3-hour oral glucose tolerance test was performed on d ay 1 and at the end of treatment. Main Outcome Measures: The categorical assessment of glucose tolerance stat us (normal, impaired, diabetic) and changes in status from randomization to end of treatment were the primary efficacy measures. The secondary measure s were fasting and postchallenge glucose and insulin levels. Results: The mean length of follow-up was 582 days. Subjects who were treat ed with orlistat lost more weight (mean+/-SEM, 6.72+/-0.41 kg from initial weight) than subjects who received placebo (3.79+/-0.38 kg; P<.001). A smal ler percentage of subjects with impaired glucose tolerance at baseline prog ressed to diabetic status in the orlistat (3.0%) vs placebo (7.6%) group. C onversely, among subjects with impaired glucose tolerance at baseline, gluc ose levels normalized in more subjects after orlistat treatment (71.6%) vs placebo (49.1%; P=.04). Conclusions: The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of p rogression to the development of impaired glucose tolerance and type 2 diab etes.