- Click here for explanation of classification scheme.

Pilot study conducted to examine the safety and efficacy of orlistat as an adjunct treatment for very overweight African-American and Caucasian adolescents.

Inclusion criteria included:

1. African-American and Caucasian adolescents aged 12-17 years
2. BMI greater than the National Health and Nutrition Examination Survey (NHANES) I (1971-74) 95th percentile for age, sex, and race 
3. presence of at least one obesity-related co-morbid condition, such as
4. hypertension
5. hyperinsulinemia (insulin > 15 µU/l)
6. impaired fasting glucose (glucose from 110 to 125 mg/dl)
7. impaired glucose tolerance (glucose from 140 to 200 mg/dl 2 h after glucose load)
8. type II diabetes
9. hyperlipidemia (total triglycerides > 200 mg/dl, total cholesterol > 200 mg/dl, or LDL cholesterol > 130 mg/dl)
10. had unsuccessfully attempted weight reduction

Exclusion criteria included:

1. if a compromising pulmonary, hepatic, cardiac, or musculoskeletal disorder was present
2. history of substance abuse or other psychiatric disorder that would impair compliance with study protocol
3. recent use of anorexiant medication
4. significant weight loss (> 5%) in the previous 6 months

Recruitment --recruited for a weight-loss study through newspaper advertisements and letters to local physicians

 

Design --6 month pilot study; non-randomized, no placebo

 

Blinding used (if applicable)--no blinding

Intervention (if applicable)--Subjects who met inclusion criteria were admitted to the research clinic for in-patient evaluation at 3 time points: baseline, 3 months, and 6 months. Intervention consisted of a orlistat (3 times a day) plus a 12 week program emphasizing diet, exercise, and behvaior change strategy with a 3 month follow-up. The intervention was described in McDuffie et al. 2002.

Diet and Exercise

During the baseline hospitalization, all subjects, and at least one parent, met with a dietitian and were provided instructions on a 500-calorie deficit diet (geared for a minimum of 0.5 - 1 lb. week weight loss) containing no more than 30% of calories from fat. Diets were monitored during subsequent visits.

Participants also participated in a 12-week comprehensive behavioral-exercise program led by 2 dietitians and 1 recreation therapist. Subjects were encouraged to include 30 minutes of daily aerobic exercise and lifestyle exercise monitored by pedometer readings. Compliance was measured through self-monitoring recorded in progress books returned to group leaders each week. Subjects returned for follow-up evaluations the last 3 months.  

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

Statistical Analysis --results presented as means ± standard deviation (SD)

paired, t tests to determine differences between weights, laboratory parameters at baseline versus 6 months.

For the analysis between African-American and Caucasian subjects, analysis of covariance (ANCOVA) used to evaluate differences from baseline adjusted for the initial value at baseline.

Because 3 subjects (15%) withdrew from the study prior to the completion of the 12-week treatment program, all comparisons are performed as intent-to-treat analyses.

statistical significance set at p < 0.05

Timing of Measurements

Body Composition

Weight was obtained weekly for the first 12 weeks and then monthly using a calibrated digital scale and standardized protocol

Height was obtained in triplicate using standardized protocol at baseline, 3 months, and 6 months

Waist circumference was obtained using standardized protocol at baseline, 3 months, and 6 months

After an overnight fast, subject underwent air displacement plethysmography (ADP) to determine body density at baseline, at 3 months, and 6 months

Resting Energy Expenditure (REE)

After an overnight fast, REE was assessed by open-circuit indirect calorimetry at baseline, 3 months, and 6 months using a respiratory metabolic cart.  For 1-3 days before determination of REE, subjects consumed a standardized diet consisting of 25 ± 3.7% calories from fat and 56.6 + 2.6% calories from carbohydrate (overall calorie level not discussed).

Before each test, the calorimeter was calibrated with a reference gas mixture. Before measurement, subjects rested for at least 30 minutes and then were assessed while watching children's videos. Measurements were recorded at 1 minute intervals for a minimum of 30 minutes; the first 5 minutes were excluded from analysis (equilibration).

Laboratory

Blood specimens--for total cholesterol, LDL- and HDL- cholesterol, triglycerides, vitamins A, D, E, and K, and fasting glucose and insulin collected at baseline, 3 months, and 6 months

24-hr urine for excretion of calcium, phophorus, creatinine, and oxalate excretion--time points of collection not discussed

72-hr stool for fecal fat excretion-baseline and 6 months

Dietary and Exercise

Subjects were given instructions on a 500 calorie deficit diet and a daily multivitamin supplement. Concomitantly, subjects participated in a 12-week comprehensive behavior-exercise program. Compliance of diet, exercise, and behavioral therapy was self-recorded in progress books returned to group leaders each week. After the 3 month comprehensive programs, subjects returned for follow-up evaluations monthly.

Monitoring of Adverse Effects

Subjects were asked weekly about adverse effects for the first 12 weeks and monthly thereafter, with particular attention directed toward the expected gastrointestinal effects of orlistat

Dependent Variables (changes in after 6 mo)

• BMI
• weight
• body composition (body fat mass and lean body mass)
• waist circumference
• REE
• laboratory measurements

Independent Variables

• orlistat

 Control Variables

• race
• sex
• baseline values

Initial N: 20; 10 girls and 10 boys (same as used in McDuffie, 2002)

Attrition (final N): 15 (75%); it was only presented that 1 subject withdrew because of adverse effects, reasons for other 4 withdrawals not discussed

Age: mean- 14.7 ± 2.0 y

Ethnicity: 10 Caucasian; 10 African-American

Other relevant demographics: N/A

Anthropometrics (Baseline) Subjects' height did not differ by race; mean ± SD = 166.9 ± 10.4 cm

Measurement	Caucasian (mean + SD)	African-American (mean + SD)
Weight (kg)	99.3 ± 1.4	136.7 ± 1.4
BMI (kg/m2)	36.2 ± 1.2	50.5 ± 1.3
Body Fat Mass (BFM), kg	45.0 ± 1.4	68.4 ± 1.4
Lean Body Mass (LBM), kg	53.1 ± 1.3	66.8 ± 1.3
Weight Circumference (WC), (cm)	104.3 ± 1.2	121.8 ± 1.2

Location: Warren Magnuson Clinical Center at the NIH

As a whole (baseline to 6 mo):

• subjects' height increased on average by 1.5 ± 1.8 cm (p < 0.002)
• subjects' weight decreased on average from 117.6 ± 1.4 to 112.2 ± 1.4 kg (range -11.7 to -25.5 kg, p < 0.02) or 3.5 ± 6.0 of original body weight
• mean BMI decreased from 42.7 ± 1.3 to 40.7 ± 1.4 kg/m² (p < 0.001)
• waist circumference decreased from 112.2 ± 109.6 ± 1.2 cm (p = 0.02)
• body fatness and lean body mass as determined by ADP were not different (p > 0.3)
• total cholesterol and LDL cholesterol decreased from 173.8 ± 1.2 to 154 ± 4.6  (p < 0.001), and 117.5 + 1.3 to 97.7 + 1.2  (p < 0.0001)
• fasting insulin and fasting glucose decreased significantly (p < 0.02) and (p < 0.003), respectively
• there were no significant changes in the serum levels in the fat-soluble vitamins A, E, but significant decrease in vitamin D levels was seen at 1 month among 3 African-American subjects; but additional vitamin D supplementation corrected the situation

When the results were separated by race group:

• African-American subjects were significantly more obese than Caucasian subjects (BMI 50.3 ± 1.3 vs. 36 ± 1.2 kg/m², p = 0.0003). There was a uniform and significant difference in response to the intervention between African-American and Caucasian subjects. African-American subjects exhibited less improvements in weight (p < 0.05), BMI (p < 0.01), waist circumference (p = 0.03), and insulin sensitivity (p < 0.05).
• Caucasian subjects exhibited greater decreases in weight (-7.86 vs. 0.36 kg, p < 0.05), BMI (-7.95 vs. -2.14 kg/m², p = 0.003), waist circumference (-8.65 vs. -1.59, p = 0.03) at 6 months.  
• both African-American and Caucasian subjects exhibited improvements in plasma lipids (total and LDL-cholesterol). 
• lean body mass did not change significantly in either Caucasians or African-Americans.
• change in REE was related to change in weight in both Caucasians and African-Americans; change from baseline to 6 months did not reach statistical significance (p = 0.09)

 Other Findings

• one subject cited intolerance of gastrointestinal effects as the main reason for withdrawal from study
• fecal fat excretion increased from 5.41 ± 4.01 g (5.8% of ingested fat kcal) to 17.16 ± 12.87 g (35.2% of fat kcal) with 6 month orlistat treatment (p < 0.001). Reported adverse effects experienced were generally mild and transient.

This study explored the efficacy of 6 months of orlistat with a psychoeducational program in an adolescent population. Because of the open-label nature of the study, conclusions cannot be drawn as to the efficacy of orlistat of orlistat over the psychoeducational program. In general, orlistat was well-tolerated, and no unanticipated adverse events were observed. One subject left the study due to orlistat's gastrointestinal effects. Significant weight reductions were observed in Caucasian subjects, and there were improvements in some of the co-morbid conditions associated with obesity in both Africian-American and Caucasian participants.

The mean weight loss acheived in this study, 3.75 kg., is lower than the mean weight losses, ranging from 3.9 -10.3 kg, achieved in the clinical trials on adult subjects taking orlistat for 1-2 years. There may be several potential reasons for the lesser efficacy of orlistat observed in the present study. First, some of the adolescents in this study had not completed their growth; therefore, some weight change may have been due to bone growth and increases in height. Another reason was that the average BMI in most studies of adults is 30-35 kg/m², whereas the average BMI in this study was 43 kg/m². The greater BMI of the adolescents studied is primarily due to the fact that, unlike previous adult studies, the present investigation required subjects to have a medical complication of their obesity, and therefore recruited subjects with greater adiposity. Our results may therefore be more representative among the severely overweight adolescent for whom pharmacotherapy would be recommended.

When separated by race, the Caucasian subjects lost ~3.5% of initial body weight, but the African-American subjects lost only ~0.6% of initial body weight. It is possible that because the African-American adolescents were more severely overweight at bseline (136.7 ± 1.4 vs 99.3 ± 1.4 kg) in the present study, they may have had more difficulty losing weight because their movement was restricted by their weight and they could not fully exercise in their weight loss efforts. Another possible explanation for the lower weight loss among African-American subjects may lie in the lower REE that has been described for African-Americans. At present, it remains unclear whether differences in REE can account in part for the difficulties African-Americans may experience when attempting weight reduction.

The modest weight reductions among adolescents in the present study improved obesity-related co-morbid conditions. As seen in studies on adults, there were improvements in the cardiac risk factors, total and LDL-cholesterol that were weight loss-independent. Orlistat may also have had a positive effect on indicators of insulin resistence.

We conclude that Caucasians lost more weight and had greater improvements in insulin sensitivity than African-Americans, but both exhibited improvements in plasma lipids. The true benefits of orlistat treatment over a comprehensive behavioral program remains to be determined in placebo-controlled trials.

Limitations include:

• small sample size
• convenience sample; sampling bias?
• without placebo-controlled trial cannot separate the effects of the behavioral effects of the behavioral weight loss program from the effects of orlistat; possible that effects achieved from baseline to 6 months could have been achieved through the use of the comprehensive weight loss program alone
• ? generalizability to other age groups or ethnic groups