Approximately one third of the population of the United States is obese, and effective treatment for these patients has been problematic. Evidence suggests that a 5 to 10 percent loss of initial body weight substantially improves the health status of most patients. Diet and exercise remain the cornerstones of obesity treatment, but long-term weight loss and maintenance are limited. The search for a safe and effective pharmacologic agent as adjunctive therapy to diet and exercise has also been problematic because of adverse side effects. Orlistat, a selective and potent inhibitor of gastrointestinal lipases involved in triglyceride hydrolysis, restricts the absorption of triglycerides. It reduces dietary fat absorption in a dose-dependent fashion, with a maximum inhibition of 30 percent fat absorption at a dosage of 120 mg three times daily. Hauptman and associates conducted a multi-center, randomized, double-blind, placebo-controlled trial to assess the long-term efficacy and tolerability of this medication.

The two-year study enrolled 796 obese patients; 635 completed the four-week, single-blind placebo lead-in period and were randomized to receive placebo (212 patients), 60 mg of orlistat (213 patients) or 120 mg of orlistat (210 patients) three times daily with meals. All patients began a reduced-energy diet at the onset of the placebo lead-in period and followed the diet for the first 52 weeks. The same treatment was followed for the second 52 weeks in combination with a weight-maintenance diet intended to prevent weight regain rather than to induce further weight loss. Four times during the first year, patients viewed videos of behavior modification techniques for weight control. At four times during the second year, they were given weight management and diet pamphlets designed to assist in weight maintenance. Registered dietitians and behavioral psychologists were not a part of the study during any phase. Participating physicians did not receive any specific training in nutrition or in weight management techniques. Throughout the study, patients were encouraged to increase physical activity by walking briskly for 20 to 30 minutes, three to five times per week.

Dropout rates were high. By the completion of the study, 121 of the 212 patients (57.1 percent) in the placebo group, 94 of 213 patients (44.1 percent) in the 60-mg orlistat group and 97 of 210 patients (46.2 percent) in the 120-mg orlistat group withdrew for a variety of reasons (e.g., lost to follow-up, administrative factors, adverse effects, uncooperative patients, protocol violation). Weight loss in patients who completed the two-year trial, measured at 52 weeks and 104 weeks, respectively, was as follows: 4.26 and 1.54 kg (9.37 and 3.39 lb) in the placebo group; 7.92 and 4.58 kg (17.42 and 10.08 lb) in the 60-mg orlistat-treatment group; and 8.78 and 5.16 kg (19.32 and 11.35 lb) in the 120-mg orlistat-treatment group. The adverse side effects in 20 to 25 percent of the patients in the orlistat-treatment groups included fecal urgency, oily spotting, fatty stool and flatulence. The weight loss in patients who were treated with orlistat and completed the study was sufficient to produce changes in total cholesterol levels, low density lipoprotein (LDL) cholesterol levels and the LDL/high density lipoprotein cholesterol ratio. At the conclusion of the study, LDL cholesterol levels remained lower in both orlistat-treatment groups, more likely reflecting an independent lipid-lowering effect of orlistat than simply the effect of weight loss.

This trial, the first to be conducted in a primary care setting, demonstrated that a combination of diet and pharmacotherapy is more effective than diet alone in weight loss. While modest weight loss was experienced by patients in the orlistat-treatment groups and was associated with some health benefits, it is unlikely that this agent will meet the treatment expectations of patients and physicians.