- Click here for explanation of classification scheme.

Placebo-controlled studies have demonstrated that orlistat is clinically beneficial in reducing body weight and co-morbidity risk factors in adults. Adverse effects, limited to gastrointestinal effects observed in adults, were generally mild and decreased in time. Based on the results of these studies, orlistat has the potential for a favorable risk-benefit ratio in adolescents. Use of orlistat in overweight adolescents has not been studied previously. Thus, the purpose of this study was estimate the safety, tolerability, and efficacy of orlistat as an adjunct to conventional behavioral weight loss management program for obese adolescents.

Included if:

1. adolescents, age 12 to 17 years
2. BMI greater than the National Health and Nutrition Examination Survey I (1971-1974) 95th percentile for age, sex, and race
3. presence of one of the following obesity-related co-morbidities:
4. hypertension
5. type 2 diabetes or glucose intolerance
6. hyperinsulinemia (insulin > 15 µU/L)
7. hyperlipidemia-- total triglyceride ( > 200 mg/dl), total cholesterol (>200 mg/dL), or LDL cholesterol (> 130 mg/dL)
8. hepatic stenosis
9. sleep apnea (documented by a formal sleep study)

Excluded if had:

1. major pulmonary, hepatic cardiac, or musculoskeletal disorder
2. had a history of substance abuse or other psychiatric disorder that would impair compiance with the study protocol
3. had used an anorexiant in the past 6 months or had lost weight in the past 2 months

Recruitment -- Participants were recruited through newspaper advertisements and letters to local physicians

 

Design -- pilot trial of orlistat as an adjunct to a program emphasizing mildly reduced-calorie diet, exercise, and behavioral modification therapy

Blinding used (if applicable) -- none

Intervention (if applicable)--

After outpatient screening for eligibility, adolescents were admitted to the clinic twice; once for baseline evaluation before starting orlistat, and the other time 3 months of orlistat treatment. Participants were simultaneously enrolled in a 12-week program emphasizing diet, exercise, and strategies for behavior change.

Medication

Subjects were given orlistat (120 mg 3 times daily)

Diet

The subjects, and at least one parent, were instructed by a dietitian on how to follow a 500 calorie deficit diet (geared for a minimum of 0.5-1 lb. week weight loss) no more than 30% fat). In addition, a multivitamin supplement was given.

Comprehensive behavioral program (nutrition, exercise, and behavior modification)

 A 12-week behavioral program was taught by 2 dietitians. The program emphasized:

• nutrition education game format for 15 to 30 minutes during each weekly meeting and homework assignments
• encouraging 30 minutes of daily aerobic exercise and lifestyle exercise monitored by pedometer readings
• stimulus-control and eating-management skills
• self-monitoring of medication taken, food eaten, activity performed, amount of inactive time spent, and pedometer readings recorded in a progress book reviewed by study leaders each week

Whether or not the subjects' parent(s) were included in the behavioral program was not discussed.

Statistical Analysis--Paired, two-tailed Student's t tests and ANOVA used to determine the differences between anthropometrics, laboratory test parameters (cholesterol and triglycerides, insulin, and glucose) before and after orlistat treatment

Because 3 subjects (15%) withdrew from the study before completion of 12-week study, bias due to withdrawals avoided by all comparisons were performed as intention-to-treat analyses; variables measured at baseline and 3 months were reported as n = 17

Statistical significance established as p < 0.05

Timing of Measurements

Anthropometrics:

Anthropometrics were obtained using standardized techniques. Height, and waist circumference were obtained at baseline and at 3 months and weight was obtained weekly (in the evening).

Body density was assessed using the BOD POD air displacement composition system after an overnight fast.  The equation of Siri (1961) was used to estimate body fatness from body density.

Laboratory:

Laboratory blood samples were collected at baseline and end of study for analysis of cholesterol (total low-density lipoprotein [LDL]- and high-density lipoprotein [HDL]- cholesterol), triglycerides, glucose, insulin, and fat-soluble vitamins- A, D, E, and K.

Glucose tolerance tests were conducted at baseline and end of study. Fasting values of insulin and glucose were analyzed. Blood samples were collected using standard methodologies.

Monitoring Adverse Events

Participants were questioned weekly about adverse events, with particular attention directed toward gastrointestinal effects of orlistat.

 Dependent Variables (change baseline to 3 month end of study)

• Weight
• Body mass index (BMI) 
• % Fat
• Lean body mass
• Waist Circumference
• Lab values (total cholesterol, LDL- and HDL-cholesterol, triglycerides, glucose, insulin)

Independent Variables

• Orlistat treatment
• Behavioral program

 Control Variables: none discussed

Initial N: 20 adolescents were recruited; 10 boys and 10 girls

Attrition (final N): 17 (15% attrition); although 3 did not complete treatment, only reason for 1 was given; 1 cited adverse effects as reason for withdrawal from study

Age: 12-17; mean ± SD: 14.6 ± 2.0 years

Ethnicity: 10 white and 10 African-American 

Other relevant demographics: N/A

Anthropometrics:  At Baseline

Measurement	Mean + SD	Range
Weight, kg	123.4 ± 43.0	72.1 to 200.3
BMI	44.1 ± 12.6	28.6 to 69.6

Location: Warren Magnum Clinical Center at the NIH

Baseline and 3-month data

Anthropometrics and Laboratory

 

Variable (n = 17)	Baseline (Mean ± SD)	End of Study (Mean ± SD)	Significance of Difference
Weight (kg)	124.3 ± 43.0	119.0 ± 43.1	p < 0.001
BMI	44.1 ± 12.4	42.2 ± 13.0	p < 0.001
Body fat (%)	47.9 ± 5.4	46.9 ± 6.8	NS
Lean body mass (kg)	62.4 ± 19.8	61.6 ± 16.4	NS
Waist circumference (cm)	114.3 ± 19.6	112.1 ± 21.4	p < 0.05
Cholesterol (mg/dL)	177.8 ± 41.2	156.6 ± 34.2	p < 0.001
LDL-cholesterol (mg/dL)	120.2 ± 30.1	102.9 ± 29.5	p < 0.0001
HDL-cholesterol (mg/dL)	46.5 ± 10.9	43.0 ± 8.3	p < 0.05
Triglycerides (mg/dL)	110.2 ± 55.0	113.8 ± 51.8	NS
Fasting glucose (mg/dL)	101.7 ± 38.3	86.3 ± 6.42	p < 0.01
Fasting insulin µl/mL)	34.9 ± 16.3	20.3 ± 10.6	p < 0.05

Participants' weight change after 3 months ranged from +4.0 kg to -17.1 kg. Weight decreased on average 3.8 ± 4.1 of original body weight.

Weight loss among white female participants was greater than the weight loss among African-American subjects. At the end of 3 months, 7 white, female particpants lost 5% of initial body weight. Three of these subjects lost 10% of initial weight loss. 

Other Findings: There were no significant changes in the serum levels of the  fat-soluble vitamins A, E, or K. A small significant drop in 25-hydroxy vitamin D levels was seen at 1 month (14.9 ± 6.8 vs. 10.6 ± 3.9 ng/mg; p < 0.02) in 3 African-American participants. This was corrected by additional vitamin D supplementation during the 3 month study.

Adverse effects were generally mild, limited  to gastrointestinal effects previously seen in adult studies of orlistat and decreased with time (within the first 6 weeks of treatment) Adverse events included increased defecation, soft stools, fatty or oily stools, and oily spotting on clothing.

One participant withdrew from study because of adverse effects.

The current study was the first clinical trial designed to evaluate the safety, tolerability, and potential efficacy of orlistat in 20 white and African-American adolescents with obesity and obesity-related co-morbid conditions. This study showed that orlistat (120 mg 3 times daily) in combination with a comprehensive program that emphasized moderate calorie reduction, exercise, and behavioral modification significantly reduced subjects' body weight, waist circumference, and BMI. Lipid levels changed significantly during weight-reduction treatment using orlistat; total cholesterol, LDL-cholesterol, and HDL- cholesterol decreased. Indicators of glycemic control improved; fasting insulin and fasting glucose decreased after 3 months of orlistat.

Mean weight reduction over 12 weeks, 4.4 kg (3.8%) was less than the amount reported in adult studies. In placebo-controlled studies, adults treated with orlistat for periods as long as 1 to 2 years, average reported weight loss was 5.9 to 10.3 kg. In lieu of orlistat studies in adolescents for comparison, a review of comprehensive programs emphasizing moderate caloric restriction, exercise, and a behavioral therapy component for adolescents with an average BMI of ~35 kg/m found that weight loss ranged from 2 to 11 kg (mean, 6.6 kg). The initial average BMI in this adolescent study was greater, 44.1 kg/m².

The modest reduction in adolescents' body weight observed in the present study improved obesity-related comorbid conditions. As seen in adult studies, there were improvement in several cardiovascular risk factors--total cholesterol and LDL-cholesterol levels. The improvements in fasting glucose and insulin also agree with those reported in adult studies.

The vitamin D deficiency observed in three African-American adolescents was easily corrected through additional supplementation. Although we did not find other fat-soluble vitamin deficiencies over the short term, it is unknown whether clincally significant decreases in fat soluble vitamins will be observed with long term use of orlistat.

In conclusion, orlistat appears to be a relatively safe and well-tolerated adjacent weight loss therapy for use in an adolescent population. However, there may be a somewhat greater incidence of initial gastrointestinal adverse effects in adolescents.

Limitations:

• Small sample size
• Convenience sample; sampling bias?
• Short duration and no follow-up
• Cannot separate the effects of the behavioral weight-loss program from the effects of orlistat without a placebo-controlled trial
• Cannot determine the significance of the difference in response between whites and African-Americans
• Although parent(s) instructed on calorie-reduction diet, further role not discussed (family-based program?)
• (?) generalizability to other ethnic groups and age groups