Orlistat for the long-term management of obesity.

The incidence of obesity has reached epidemic proportions in the United States and in many regions of the industrialized world. Findings from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that 35% of adults in the United States aged 20 and over are overweight and 14% are severely overweight [1]. In this survey, obesity was defined as a body mass index (BMI, a measure of body fatness based on weight in kilograms divided by the square of height in meters) of greater than 27.8 for men and greater than 27.3 for women. The costs associated with this condition are staggering. Annual health care costs for obesity, including direct costs of hospitalization, physician services, and loss of productivity, have been estimated at $99 million in the United States by the National Institutes of Health [2]. Because obesity is a chronic illness that is seldom cured, it ranks as one of the most common forms of malnutrition facing clinicians of all types. Medical treatment of patients with obesity is most successful if it incorporates multiple interventions, including dietary therapy, exercise, and behavior modification. Such a program can result in weight loss of 5% to 10%, an amount associated with a reduction in cardiovascular and other complications associated with obesity [3]. Unfortunately, with time, most patients will regain weight. Therefore, pharmacologic therapy has been of great interest in establishing and maintaining weight loss in patients with obesity. Medications used in the treatment of obesity can be classified as those that suppress appetite, enhance thermogenesis, and impair energy absorption. Within the last year, two reports on short- and long-term effects of orlistat (Xenical; Hoffman La Roche, Nutley, NJ), a gastrointestinal lipase inhibitor that works by the latter mechanism. The impact of orlistat on weight loss has recently been reported by investigators from two large randomized, double-blinded, controlled clinical trials, one in Europe [4] and the other in the United States [5]. Both studies were of similar design. Subjects were enrolled in a 4-week lead-in period during which they received a placebo capsule and a hypocaloric diet as a means to assess overall compliance. If subjects took more than 75% of the placebo, they were then randomized to orlistat, 120 mg, or placebo, three times a day for 52 weeks. The randomization scheme differed slightly between the two trials, with subjects divided in a 1:1 ratio in the European study and a 3:1 ratio in the US study. A total of 683 (European) and 880 (US) subjects made up the intention-to-treat population for these studies after a total of 2124 subjects were screened. After 1 year, patients who demonstrated continued compliance were studied for a second year to determine the effect of orlistat on the maintenance of weight loss. In the European trial, subjects were again randomized to either orlistat or placebo along with a weight maintenance diet regardless of their previous group assignment. In the United States, trial subjects in the orlistat group were randomized to placebo, orlistat, 60 mg, or orlistat, 120 mg, while subjects in the placebo group continued to take placebo three times daily. Results from both studies demonstrate that treatment with orlistat leads to a significantly greater degree of weight loss and that maintenance of weight loss is improved compared with results from the placebo group. Orlistat led to a 10.3-kg and 8.8-kg weight loss over the first year of the study for the European and US trials, respectively, while subjects in the placebo group lost 6.1 kg and 5.8 kg. The percentage of weight lost was almost numerically identical because the average weight for each subject was 100 kg. The greater amount of weight loss in the European study reflects the inclusion of weight loss during the lead-in period in the total. During the second year of the study, orlistat subjects lost an additional 0.9 kg, while subjects in the placebo group regained 2.5 kg in the European trial. In the United States, all subjects regained weight: 3.2 kg, 4.2 kg, and 5.6 kg for the orlistat 120 mg group, the orlistat 60 mg group, and the placebo group, respectively. While weight loss was the primary end point for both studies, the impact of orlistat on cardiovascular risk factors was also assessed. Blood pressure, cholesterol, and lowdensity lipoprotein cholesterol (LDLC) levels improved during the lead-in period, a finding that is consistent with the effects of weight loss on these risk factors. After randomization, a further decrease occurred in the total cholesterol and LDLC levels in the treatment group, whereas in the placebo group these lipids returned to baseline levels. Analysis of covariance suggests that the further decline in