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Steven B. Heymsfield, MD; Karen R. Segal, PhD; Jonathan Hauptman, MD; Charles P. Lucas, MD; Mark N. Boldrin, MS; Aila Rissanen, MD; John P. H. Wilding, MD; Lars Sjöström, MD

Arch Intern Med. 2000;160:1321-1326.

Background  Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, promotes weight loss, and may reduce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects.

Objective  To test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes status more effectively than placebo.

Methods  We pooled data from 675 obese (body mass index, 30-43 kg/m²) adults at 39 US and European research centers in 3 randomized, double-blind, placebo-controlled multicenter clinical trials. Subjects received placebo plus a low-energy diet during a 4-week lead-in period. On study day 1, the diet 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 day 1 and at the end of treatment.

Main Outcome Measures  The categorical assessment of glucose tolerance status (normal, impaired, diabetic) and changes in status from randomization to end of treatment were the primary efficacy measures. The secondary measures were fasting and postchallenge glucose and insulin levels.

Results  The mean length of follow-up was 582 days. Subjects who were treated 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 smaller percentage of subjects with impaired glucose tolerance at baseline progressed to diabetic status in the orlistat (3.0%) vs placebo (7.6%) group. Conversely, among subjects with impaired glucose tolerance at baseline, glucose 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 progression to the development of impaired glucose tolerance and type 2 diabetes.

From Columbia University College of Physicians and Surgeons, St Luke's-Roosevelt Hospital Center, New York, NY (Dr Heymsfield); Hoffmann La Roche Inc, Nutley, NJ (Drs Segal, Hauptman, and Lucas and Mr Boldrin); Helsinki University Central Hospital, Helsinki, Finland (Dr Rissanen); University Hospital Aintree, Liverpool, England (Dr Wilding); and Sahlgrenska University Hospital, Göteborg, Sweden (Dr Sjöström).

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