Objective To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years.

Design Randomized, double-blind, placebo-controlled study conducted from October 1992 to October 1995.

Setting and Participants Obese adults (body mass index [weight in kilograms divided by the square of height in meters], 30-43 kg/m(2)) evaluated at 18 US research centers.

Intervention Subjects received placebo plus a controlled-energy diet during a 4-week lead-in. On study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, subjects began a weight-maintenance diet, and the placebo group (n = 133) continued to receive placebo and orlistat-treated subjects were rerandomized to receive placebo 3 times a day (n = 138), orlistat, 60 mg (n = 152) or 120 mg (n = 153) 3 times a day, for an additional 52 weeks.

Main Outcome Measures Body weight change and changes in blood pressure and serum lipid, glucose, and insulin levels.

Results A total of 1187 subjects entered the protocol, and 892 were randomly assigned on day 1 to double-blind treatment. For intent-to-treat analysis, 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated. During the first year orlistat-treated subjects lost more weight (mean +/- SEM, 8.76 +/- 0.37 kg) than placebo-treated subjects (5.81 +/- 0.67 kg) (P<.001). Subjects treated with orlistat, 120 mg 3 times a day, during year 1 and year 2 regained less weight during year 2 (3.2 +/- 0.45 kg; 35.2% regain) than those who received orlistat, 60 mg (4.26 +/- 0.57 kg; 51.3% regain), or placebo (5.63 +/- 0.42 kg; 63.4% regain) in year 2 (P<.001). Treatment with orlistat, 120 mg 3 times a day, was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels.

Conclusions Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors.