Orlistat

Obesity among adolescents in the United States is a problem of increasing concern. The results of the National Health and Nutrition Examination Survey III suggest that the prevalence of overweight, defined as the age- and sex-specific 95th percentile for body mass index (BMI), has risen from 6% to 14% in adolescents in the last 25 years. With the increase in obesity, the comorbid conditions associated with excess weight have been more common among adolescents as well. Weight loss results with this population have been disappointing. A review of nine programs for adolescents found an average loss ranged from 2 to 11 kg (mean, 6.6 kg). The programs were all comprehensive and emphasized moderate caloric restriction, exercise, and specific behavior components. The adolescents enrolled in these programs had a BMI average of ~35kg/[m.sup.2].

The objective of the current research was to study the safety, tolerability, and potential efficacy of orlistat in adolescents with obesity and its comorbid conditions. Orlistat is a gastric and pancreatic lipase inhibitor that alters energy balance by reducing the absorption of triglycerides and cholesterol from the gastrointestinal tract. In adults, orlistat, at the standard dose of 120 mg three times daily, inhibits -30% of triglyceride absorption. Orlistat has few known adverse consequences in adults; therefore it has the potential for a favorable risk-benefit ratio in children and adolescents. Use of orlistat in overweight children > 16 years of age has not been studied previously.

Twenty obese white and African-American adolescents (age 12-17 years; 10 boys and 10 girls; BMI 44.1 [+ or -] 12.6 kg/ [m.sup.2]) were recruited through newspaper advertisements and letters to local physicians. Inclusion criteria were BMI greater than the National Health and Nutrition Examination Survey I (1971-1974), 95th percentile for age, sex, and race, and the presence of one of the following obesity-related comorbidities: hypertension, type 2 diabetes or glucose intolerance, hyperinsulinemia, hyperlipidemia, hepatic stenosis, or sleep apnea documented by a formal sleep study. Subjects were enrolled in an open-label pilot trial of orlistat as an adjuvant to a conventional behavioral weight-loss management program for adolescents. After outpatient screening for eligibility, the subjects were admitted to the Warren Magnuson Clinical Center at the NIH twice: once for baseline evaluation before starting medication and the other time after three months of orlistat treatment.

The subjects were instructed by a registered dietitian regarding how to follow a 500-kcal-deficit diet containing no more than 30% of calories from fat. Subjects were given orlistat, 120 mg, and instructed to take it thrice a day with meals. In addition, a multivitamin supplement was supplied to be taken at night: 5000 UI of vitamin A, 400 IU of vitamin D, 30 IU of vitamin E, and 25 [micro]g of vitamin [K.sub.1]. Concomitantly, subjects participated in a 12-week comprehensive behavioral program, team-taught by two registered dietitians, one of whom had additional graduate training in psychology and exercise physiology. The program used nutrition education, an exercise program and behavior modification skills training.

Eight-five percent of subjects completed 3 months of treatment and reported taking 80% of prescribed medication doses. Adverse effects related to increased fat excretion were generally mild and transient, resolving within the first six weeks of treatment. All but one subject reported two adverse effects on at least one occasion. Five of the twelve adverse effects queried, increased defecation, soft stools, fatty or oily stools, oily spotting on clothes, and increased flatus, were reported in >50% of subjects. Only one subject cited intolerance of adverse effects as the reason for withdrawing from the study.

There were no significant changes in the serum levels of the fat-soluble vitamins A, E, or K. A small, but significant drop in 25-hydroxy vitamin D levels was seen at one month. This decrease was ameliorated after extra vitamin D supplementation (50,000 U/d for 1 month) was given to three subjects with vitamin D levels below the normal range. Subjects weight decreased on average by 4.4 [+ or -] 4.6 kg (range +4.0kg to -17.7 kg), waist circumference decreased 2.4 [+ or -] 4.0 cm, and mean BMI decreased 1.9 [+ or -] 2.5 kg/[m.sup.2], although percentage of body fat and lean body mass remained unchanged. Overall, the weight loss among white subjects was greater than the weight loss among African-American subjects.

Lipid levels changed significantly during weight-reduction treatment using orlistat. Total cholesterol, LDL-cholesterol, and HDL-cholesterol decreased, whereas the HDL/LDL ratio and serum triglycerides remained unchanged. Indicators of glycemic control also improved. Fasting glucose and insulin decreased after three months of orlistat treatment.

In general, orlistat was well tolerated and no unanticipated adverse events were observed. The modest reduction in adolescents' body weight observed in the present study improved obesity-related comorbid conditions. Orlistat appears to be relatively safe and well-tolerated for use in the adolescent population. However, it is possible that it will be necessary to monitor for hypovitaminosis D in African-American adolescents who are taking orlistat. These findings support the need for further randomized, double-blind, placebo-controlled trials of this drug in a large, multiracial adolescent population. There is no FDA approval of the drug for use in children and adolescents at this time.

J McDuffie, K Calis, G Uwaifo, N Sebring, E Fallon, V Hubbard, J Yanovski. Three-Month Tolerability of Orlistat in Adolescents with Obesity-Related Comorbid Conditions. Obes Res 10(7):642-650 (duly 2002) [Correspondence: Jennifer McDuffie, PhD, Unit on Growth and Obesity; DEB, NICHD, NIH, 10 Center Drive, Building 10, Room 10N262, MSC 1862, Bethesda, MD, 20892-1862. E-mail: Mcduffj@mail.nih.gov

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