Achieving sustained weight loss is difficult for obese patients, even those who follow a diet and exercise program. Because obesity is associated with an increased risk of morbidity and mortality, a need for a new and effective therapeutic treatment exists. Orlistat is a gastrointestinal (GI) lipase inhibitor that prevents GI uptake of about 30 percent of consumed fat. Davidson and colleagues conducted a randomized, double-blind, placebo-controlled study to test the hypothesis that patients who are treated with orlistat combined with dietary intervention would lose more weight and be better able to maintain the weight loss than patients treated with placebo plus diet. They also studied the effectiveness of orlistat in the reduction of risk factors, such as cardiovascular risk, hypertension and insulin resistance, in obese patients.

The trial included adults whose body mass index was between 30 and 43 kg per m² and who had not had a weight loss of more than 4 kg (8 lb, 13 oz) in the previous three months. Patients with significant medical or psychiatric problems and patients who used medications that could alter lipid levels or appetite were excluded. Initially, a medical history was taken for all patients. They also had a physical examination, an electrocardiogram and a wide range of laboratory tests. During the four-week lead-in period patients followed a diet that allowed each one a calculated amount of energy per day based on each patient's estimated daily energy requirement. Patients were also given placebo capsules during this time to determine compliance.

At the end of the four-week period, patients were classified into either the group that lost less than 2 kg (4 lb, 6 oz) or the group that lost at least 2 kg. Those who had a treatment compliance of 75 percent or more were then randomized to receive either placebo or 120 mg of orlistat three times per day, along with the low-calorie diet. After one year of treatment, patients who had been taking orlistat and had compliance rates of at least 70 percent were randomized to receive either placebo, or 60 or 120 mg of orlistat three times per day for another year. The patients who had taken placebo continued to use placebo. Patients began a maintenance diet during the second year of the study to prevent or diminish weight regain rather than to continue weight loss. Body weight, the primary outcome measured, was assessed frequently throughout the two-year study period.

Of the 892 patients who were initially enrolled in the lead-in, 880 completed at least one follow-up measurement. There were 591 patients who completed one year of the study, and 403 who completed both years, for a two-year completion rate of 45 percent. Reasons for withdrawal were similar among all groups. The four-week lead-in low-calorie diet led to a weight loss of about 2.3 kg (5 lb, 1 oz) per participant. Subsequently, patients in the orlistat group lost more weight than patients in the placebo group. By the end of the first year, 65.7 percent of patients in the orlistat group had lost more than 5 percent of their initial body weight compared with only 43.6 percent of patients in the placebo group. More than 10 percent of initial body weight was lost by 38.9 percent of patients taking orlistat compared with only 24.8 percent of patients taking placebo. Patients treated with 120 mg of orlistat during the second year had significantly less weight regain than those whose dosage of orlistat was halved and those taking placebo. Two years of taking 120 mg of orlistat led to a 7.6 percent (± 0.9 percent) weight loss. Those who took placebo for two years lost only 4.5 percent (± 0.9 percent) of their initial body weight by the end of the study.

Risk factor reduction was also examined. Patients taking 120 mg of orlistat had a significant reduction in systolic and diastolic blood pressures between weeks zero and 52 of treatment compared with the placebo group. Total cholesterol levels also decreased in the orlistat group, while they rose in the placebo group. This finding was independent of weight loss. The orlistat group had more GI side effects, but generally these were self-limited and only moderate in intensity.

The authors conclude that orlistat, when taken for two years and combined with a hypocaloric diet, can assist obese patients with weight loss and may reduce some obesity-related risk factors.