PWM: Adjunct Therapies (2006)


McDuffie JR, Callis KA, Uwalo NG, Fallon EM, Frazier TE, Hubbard VS, Yanovski JA. Efficacy of orlistat as an adjunct to behavioral treatment in overweight African-American and Caucasian adolescents with obesity-related co-morbid conditions. J Pediatr Endocrinol Medab 2004;17:307-319.

PubMed ID: 15112907
Study Design:
Non-Randomized Controlled Trial
C - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
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:

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:

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
Description of Study Protocol:

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

Data Collection Summary:

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).


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
Description of Actual Data Sample:

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

Summary of Results:

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.
Author Conclusion:

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.

Funding Source:
Reviewer Comments:

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
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) No
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? No
  4.1. Were follow-up methods described and the same for all groups? No
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) No
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? No
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes