P = .001 for body mass index (orlistat
vs placebo). P<.001 for weight change (orlistat
vs placebo). Body Mass Index is calculated as weight in kilograms divided
by the square of height in meters. Coefficient of variation is about 14% for
each data point for body mass index and about 16% for weight.
Chanoine J, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of Orlistat on Weight and Body Composition in Obese AdolescentsA Randomized Controlled Trial. JAMA. 2005;293(23):2873-2883. doi:10.1001/jama.293.23.2873
Author Affiliations: Endocrinology and Diabetes
Unit, British Columbia Children’s Hospital, Vancouver (Dr Chanoine);
Children’s Mercy Hospitals and Clinics, Kansas City, Mo (Dr Hampl);
Department of Medicine, Baylor College of Medicine, Houston, Tex (Dr Jensen);
and Hoffmann-La Roche Inc, Nutley, NJ (Mr Boldrin and Dr Hauptman).
Context The prevalence of overweight and obesity in children and adolescents
is increasing rapidly. In this population, behavioral therapy alone has had
limited success in providing meaningful, sustained weight reduction, and pharmacological
treatment has not been extensively studied.
Objective To determine the efficacy and safety of orlistat in weight management
Design, Setting, and Patients Multicenter, 54-week (August 2000-October 2002), randomized, double-blind
study of 539 obese adolescents (aged 12-16 years; body mass index [BMI] ≥2
units above the 95th percentile) at 32 centers in the United States and Canada.
Interventions A 120-mg dose of orlistat (n = 357) or placebo (n = 182)
3 times daily for 1 year, plus a mildly hypocaloric diet (30% fat calories),
exercise, and behavioral therapy.
Main Outcome Measures Change in BMI; secondary measures included changes in waist and hip
circumference, weight loss, lipid measurements, and glucose and insulin responses
to oral glucose challenge.
Results There was a decrease in BMI in both treatment groups up to week 12,
thereafter stabilizing with orlistat but increasing beyond baseline with placebo.
At the end of the study, BMI had decreased by 0.55 with orlistat but increased
by 0.31 with placebo (P = .001). Compared
with 15.7% of the placebo group, 26.5% of participants taking orlistat had
a 5% or higher decrease in BMI (P = .005);
4.5% and 13.3%, respectively, had a 10% or higher decrease in BMI (P = .002). At study end, weight had increased 0.53 kg with
orlistat and 3.14 kg with placebo (P<.001). Dual-energy
x-ray absorptiometry showed that this difference was explained by changes
in fat mass. Waist circumference decreased in the orlistat group but increased
in the placebo group (–1.33 cm vs +0.12 cm; P<.05).
Generally mild to moderate gastrointestinal tract adverse events occurred
in 9% to 50% of the orlistat group and in 1% to 13% of the placebo group.
Conclusions In combination with diet, exercise, and behavioral modification, orlistat
statistically significantly improved weight management in obese adolescents
compared with placebo. The use of orlistat for 1 year in this adolescent population
did not raise major safety issues although gastrointestinal adverse events
were more common in the orlistat group.
The prevalence of overweight in adolescents is increasing worldwide.
In the United States, the proportion of adolescents with a body mass index
(BMI) at or above the 95th percentile for age, a widely accepted definition
of obesity in adolescents,1,2 has
increased 15.5% to 23.4% in certain ethnic minorities.3 A
similar picture is seen in European countries: the prevalence of overweight
in adolescents has increased 8% to 21% in northern European countries and
17% to 23% in southern European countries.4
Excess weight in adolescents is associated with an increased risk of
disorders such as hyperlipidemia and type 2 diabetes5 and
can result in decreased emotional and physical quality of life.6,7 In
addition, childhood obesity results in increased risk of morbidity and mortality
in adulthood.8,9 Long-term follow-up
studies of children and adolescents indicate that overweight children have
a 15-fold greater risk of becoming overweight adults compared with those children
and adolescents who were not overweight.8 Effective
weight management in children and adolescents may therefore have important
immediate and future societal health benefits.
Treatment of obesity in the pediatric age group, and in particular during
adolescence,10 is notoriously difficult. While
behavioral therapy has had some success in treating obesity in young children
(aged 6-12 years), most studies have found that the long-term success of such
therapy depends on the type of intervention used.11- 14 It
is possible that pharmacotherapy could play a significant role in improving
the results obtained with behavioral therapy. Pharmacological treatments have
not been extensively studied in children and adolescents although sibutramine
plus behavioral therapy has previously been examined in a 1-year study in
obese adolescents.15 However, anorexiants that
act on the central nervous system currently used in the treatment of adult
obesity may not be appropriate in children and adolescents.15,16
Orlistat is a gastrointestinal tract lipase inhibitor which decreases
intestinal fat absorption by up to 30%. In adults, it has a good safety profile,
is generally well tolerated, has minimal systemic absorption, and produces
clinically meaningful and sustained decreases in weight and BMI when combined
with a mildly hypocaloric diet and exercise.17- 19 Orlistat
is approved for use in weight management in overweight and obese adults in
more than 120 countries and to date there have been more than 22 million patients
who have received the drug. Based on these clinical and safety characteristics
in adult populations, it was believed that orlistat may be a useful adjunct
to diet, exercise, and behavioral counseling in the treatment of obese adolescents.
In December 2003, based partly on the unpublished results of the present study,
the use of orlistat in an adolescent population at the dose of 120 mg 3 times
daily was added to the approved label in the United States.
The primary objective of this study was to characterize the efficacy
and safety of orlistat plus diet, exercise, and behavioral therapy in treating
obese adolescents. Secondary objectives were to assess the impact of orlistat
treatment on obesity-related risk factors, including waist circumference,
lipid levels, blood pressure, and glucose and insulin responses to an oral
Participants were recruited at institutions with established pediatric
obesity treatment programs and clinical research expertise. Patients were
recruited through advertisements posted in clinics, through direct referrals
from family physicians, or through spontaneous reply to newspaper advertising.
Adolescents (aged 12-16 years) were eligible for enrollment if they (1) had
a BMI (calculated as weight in kilograms divided by the square of height in
meters) 2 units or higher than the US weighted mean for the 95th percentile
based on age and sex1 (2) had a parent or guardian
prepared to attend study visits with them, and (3) were willing to be actively
involved in behavioral modification. Because this was the first long-term
study investigating the safety and efficacy of orlistat in the pediatric age
group, 2 units were added to the 95th percentile of BMI at the request of
the US Food and Drug Administration to ensure that only patients with the
greatest potential for benefiting from study participation were included.
Using these criteria, minimum BMI for inclusion ranged from 28.5 in boys and
29.5 in girls at 12 years to 31.8 and 31.9, respectively, at 16 years.
Exclusion criteria were BMI of 44 or higher (to increase homogeneity
of the group); body weight of 130 kg or higher or less than 55 kg; weight
loss of 3 kg or higher within 3 months prior to screening; diabetes requiring
antidiabetic medication; obesity associated with genetic disorders; history
or presence of psychiatric disease; use of dexamphetamine or methylphenidate;
active gastrointestinal tract disorders; ongoing bulimia or laxative abuse;
and use of anorexiants or weight-reduction treatments during the 3 months
We conducted a 54-week, multicenter, placebo-controlled study from August
2000 to October 2002 at 32 centers located in the United States and Canada.
Following a 2-week, single-blind, placebo lead-in period, participants entered
a 52-week, double-blind treatment period in which they were randomized at
a 2 to 1 ratio to receive 120 mg of orlistat or placebo 3 times daily (Figure 1). Placebo and orlistat capsules looked
identical and, except for the active ingredient, had exactly the same composition.
General guidelines for diet, exercise, and behavioral modification were supplied
to all centers involved in the study (as detailed below), but each center
remained free to use its own strategy. There was no study-specific assessment
of the compliance with these general guidelines.
Screening included a physical examination consisting of Tanner stage
assessment; vital signs and physical measurements (weight, height, waist and
hip circumference); and clinical laboratory tests (hematology, blood chemistry,
vitamin levels, glucose and insulin responses to a 2-hour oral glucose challenge).
Following the placebo lead-in period, vital signs were taken and weight and
height were measured every 2 weeks for the first 4 months, and then every
month until the end of the study (18 visits in total). Waist and hip circumferences
were measured every month for the first 4 months and then every 2 months until
study end. Tanner stage was graded 1 to 5 after 6 and 12 months and based
on breast development in girls and genital development in boys. Clinical laboratory
tests were repeated on day 1 and after 3, 6, 9, and 12 months. Sex hormone
measurements (estradiol, free testosterone, and sex hormone-binding globulin)
were taken on day 1 and after 6 and 12 months. Blood samples were drawn in
the morning following an overnight fast and all samples were analyzed by a
central laboratory. Twelve-lead electrocardiographic examinations, gallbladder
and renal ultrasound examinations, and bone mineral content and body composition
measurements (determined by whole body dual-energy x-ray absorptiometry for
patients at centers that had such equipment) were performed at baseline among
a subset of participants and at week 52. All radiology technicians followed
specific guidelines to ensure that standard operating procedures were adhered
to across all centers.
The study was conducted in accordance with good clinical practice, the
Declaration of Helsinki, and the laws and regulations of the countries in
which the research was conducted, whichever afforded greater protection to
the individual. The study was approved by the institutional review board at
each participating center. Written informed consent was received from the
parents or guardians and written assent was received from each patient.
Participants were maintained on a nutritionally balanced, hypocaloric
diet designed to produce an initial weight loss of 0.5 to 1.0 kg per week.
The caloric distribution of the diet was 30% as fat (10% saturated, 10% monounsaturated,
and 10% polyunsaturated; ≤70 g/d maximum), 50% as carbohydrate, and 20%
as protein. Maximum intakes of cholesterol and calcium were 300 mg/d and 1300
mg/d, respectively. The caloric intake prescribed in this study was calculated
to provide a reduction in estimated caloric requirements of approximately
40%. Caloric requirements were determined by sex and baseline body weight,
using estimates of total energy requirements based on the World Health Organization’s
equations for basal metabolic rate20 and corrected
for activity. Assigned caloric intake ranged from 1400 kcal/d (body weight
<70 kg) to 1800 kcal/d (body weight >100 kg) in boys and from 1200 to 1600
kcal/d in girls. The daily caloric intake was adjusted during the double-blind
treatment period if the participant reached a BMI of 22 or if the participant
was losing weight too rapidly (>1 kg per week). At each study visit, the dietician
spoke with the patient about compliance with diet. Participants in both treatment
groups received a commercially available daily multivitamin supplement (Centrum
Kids Extra Calcium; Wyeth Consumer Healthcare, Madison, NJ) throughout the
active period of the study.
All study centers had behavioral modification programs in place, but
used a study-specific manual as a guideline.21 Programs
generally involved recording food intake and activity; limiting high-calorie
and high-fat foods in the household; restricting food intake to the dining
area at meal times; eating slowly; avoiding snacking; encouraging participants
to understand their cues for overeating; and substituting new behaviors for
overeating. Staff at the study centers were to support and reinforce behavioral
modification techniques regularly.
Guidelines were provided to encourage regular physical activity and
reduce sedentary behavior. Strength, flexibility, and aerobic activities were
included as part of the exercise plan wherever possible. A behavioral psychologist
spoke with patients about compliance with the exercise program at each study
The primary efficacy parameter was the change in BMI from baseline to
study end (or study exit). Secondary efficacy parameters included change in
body weight, levels of total, high-density lipoprotein, and low-density lipoprotein
cholesterol, ratio of low-density lipoprotein to high-density lipoprotein
cholesterol, triglyceride levels, systolic and diastolic blood pressure, waist
and hip circumference, glucose and insulin responses to an oral glucose challenge,
and changes in body composition.
At each visit, the participant was systematically questioned by the
investigator on the presence of gastrointestinal tract adverse effects, using
a specially designed dictionary of standard terms for defecation patterns
for reproducibility and consistency of reporting. Nongastrointestinal tract
adverse events were noted by investigators at each clinic visit following
general questioning. Any adverse event was discussed at each subsequent visit
until resolution. For adverse events extending beyond the end of the study,
the participant was contacted 4 weeks after the last visit to assess the outcome.
All adverse events were considered resolved at the time of the last contact
with the participant. Other safety parameters that were directly measured
included physical and sexual maturation, vitamin levels, sex hormone levels,
gallbladder and renal structure, cardiac function, and bone mineral content.
We planned to enroll at least 450 individuals to provide more than 80%
power to detect a difference of 1 BMI unit, assuming a 30% dropout rate. Patients
were randomized centrally according to a computer-generated randomization
schedule prepared by the study’s sponsor, with stratification by body
weight (<80 kg or ≥80 kg) on day 1 and by weight loss during the lead-in
period (<1 kg or ≥1 kg). The allocation process was triple-blind; the
allotted treatment group was obtained through an automated telephone system.
The safety population consisted of all randomized participants who received
at least 1 dose of study drug and had at least 1 follow-up assessment. Efficacy
was assessed in a modified intent-to-treat population, comprising all randomized
participants with a baseline assessment and at least 1 postbaseline efficacy
measurement. Efficacy analyses were performed using the last observation carried
forward method for those who dropped out.
Primary and secondary efficacy analyses were performed using mixed-model
analysis of variance. For the primary efficacy parameter, the analysis of
variance model included change from baseline as the response variable, with
treatment, center, treatment by center interaction and baseline stratification
as terms. Between-group treatment differences with 95% confidence intervals
and P values were calculated based on least-squares
means. Body weight and BMI were corrected for age and sex by z score (the difference between the value and the mean, divided by
the SD) based on Centers for Disease Control and Prevention charts.22 In contrast, a simplified repeated-measures analysis
of variance was used to analyze secondary quantitative efficacy variables.
Change from baseline was analyzed using center, treatment, and treatment by
center as covariates. P<.05 was considered significant.
All analyses were performed using SPSS statistical software 12.0.2 for Windows
(SPSS Inc, Chicago, Ill).
A total of 539 patients were randomized (357 to orlistat and 182 to
placebo; Figure 1). Similar proportions
of participants in each treatment group completed the study (65% for orlistat
and 64% for placebo). The baseline characteristics of those who dropped out
were similar to those participants who completed the study in each treatment
group (Table 1). A total of 190 participants
did not complete the study. Reasons for noncompletion were similar for the
2 groups (Figure 1). Mean study drug
compliance rates, assessed by pill counts, were 73% for orlistat and 72% for
placebo. Two hundred fifteen participants in the orlistat group and 107 in
the placebo group underwent dual-energy x-ray absorptiometry.
Demographic and clinical characteristics of the safety population were
similar for the orlistat and placebo groups (Table 1). Overall, 25.3% of participants at randomization had the
metabolic syndrome using the Adult Treatment Panel III criteria.23 Few
participants had elevated blood pressure (<3%); the proportions of participants
with elevated levels of low-density lipoprotein cholesterol or triglycerides,
impaired glucose tolerance, or type 2 diabetes were also low (Table 2). Most participants had an elevated waist circumference
or high fasting insulin levels (Table 2).
During the first 12 weeks after randomization, both groups experienced
a mean decrease in BMI. Subsequently, the BMI tended to stabilize in the orlistat
group, but increased to beyond baseline in the placebo group (Figure 2). By the end of the study, the least-squares mean BMI of
participants treated with orlistat had decreased from baseline by 0.55 and
increased by 0.31 in the placebo group (P = .001; Table 3). There was no significant center by
treatment interaction (P = .81), indicating
that the treatment effect across centers was similar. Compared with 15.7%
of the placebo group, 26.5% of orlistat-treated participants had a 5% or higher
decrease in BMI and 4.5% of the placebo group and 13.3% of the orlistat group
had a 10% or higher decrease in BMI (Table 3).
Compared with baseline, both groups lost weight during the first 4 weeks
of the study, although participants receiving orlistat lost more weight (Figure 2). Starting at week 4, participants treated
with orlistat continued to lose weight steadily to a maximum weight loss at
week 12. In contrast, placebo-treated participants’ weight was stable
during weeks 4 through 12. Subsequently, both groups regained weight, but
the effect attributable to the drug (ie, the between-group difference in body
weight) after 6 months was sustained.
No significant differences were found between the 2 groups with respect
to changes in lipid or glucose levels. By the end of the study, 2-hour insulin
levels for orlistat recipients were lower than at baseline, but the decrease
was not significantly different from that in the placebo group (Table 4). In contrast, participants treated with orlistat experienced
significantly greater decreases from baseline to end point in both waist circumference
and hip circumference than participants receiving placebo (Table 4). From baseline to study end, diastolic blood pressure decreased
in participants treated with orlistat and increased in placebo recipients
(P = .04; Table 4). There was no statistically significant change in systolic
blood pressure in either treatment group.
In total, 97% of participants in the orlistat group and 94% in the placebo
group reported at least 1 adverse event during the 1-year study. Twelve orlistat
and 3 placebo participants discontinued treatment because of adverse events
(Figure 1); the timing of participant
withdrawals in the 2 groups was similar. The baseline characteristics of the
participants who dropped out were similar to those of the participants who
completed the study in each group (Table 1).
The most common adverse events were gastrointestinal tract–related;
these were more common in the orlistat group (Table 5). The majority of participants reporting gastrointestinal
tract adverse events reported 1 event. Gastrointestinal tract adverse events
were mostly mild to moderate in intensity and led to discontinuation in 2%
of the orlistat group. The decrease in BMI was not affected by gastrointestinal
tract adverse events in the orlistat group.
Overall, 3% of participants in each group had at least 1 serious adverse
event. The 5 serious adverse events in the placebo group were acute demyelinating
encephalomyelitis, facial palsy, pneumonia, worsening of asthma, and pain
in the right side (Table 6). The 11
serious adverse events in the orlistat group were pilonidal abscess, depression
(n = 2), asthma attack, seizure, admission for repair of deviated
nasal septum, appendicitis, cholelithiasis, gallbladder disorder followed
by cholecystectomy, adenoidal hypertrophy, and aseptic meningitis. Only the
symptomatic cholelithiasis that led to cholecystectomy in a 15-year-old girl
treated with orlistat was considered possibly related to study medication
by the investigators; the patient had lost 15.8 kg by the time of the adverse
event. Ultrasound revealed multiple tiny gallbladder calculi but no gallbladder
thickening, pericholecystic fluid, or dilated biliary tree. No patient developed
acute cholecystitis during the study. One placebo and 10 orlistat recipients
developed abnormalities during the study that were detected on electrocardiograms.
None of these were believed to be related to the medication based on review
by an independent cardiologist. Pulse (76/min) and QT segment length (410
ms) were similar in both groups and were not affected by the intervention.
In general, levels of vitamins A, D, E and beta carotene were within
the normal range and increased in both groups during treatment (Table 7). The levels of estradiol among girls decreased from baseline
in the orlistat group compared with a slight increase in the placebo group
(–7.5 pg/mL vs +0.7 pg/mL; P = .05)
at study end. There was no significant difference in height gain between groups
(Table 3). Participants in both groups
experienced normal sexual maturation, as shown by changes in Tanner stage
over the 52 weeks of the study (Table 8).
In the orlistat group, 14 participants had a baseline abnormality revealed
by gallbladder ultrasound, including 8 participants with fatty liver infiltration
or hepatomegaly and 3 participants with gallstones. Of these, 2 patients still
had gallstones at the end of the study; the third patient did not have a follow-up
examination. At the end of the study, 6 participants in the orlistat group
were found to have asymptomatic gallstones not seen at baseline; 5 of these
patients had lost large amounts of weight (8.2-29.4 kg) and 2 were siblings.
Another patient had multiple gallstones on ultrasound at day 167 after a 15.8-kg
weight loss and had a subsequent cholecystectomy.
In the placebo group, 8 participants had a baseline abnormality, including
4 who had a fatty liver, 1 who had previously had a cholecystectomy, and 2
with gallstones that were still evident at the final visit. At the end of
the study, 1 participant in the placebo group was found to have gallstones
not seen at baseline. Ultrasound also identified 2 additional new renal abnormalities
in the orlistat group (mild left hydronephrosis and 6-mm echogenic focus without
evidence of renal calculus).
In the subgroup of participants undergoing dual-energy x-ray absorptiometry
evaluation, bone mineral content (+182 g in the orlistat group and +177 g
in the placebo group) and bone mineral density (+0.04 g/cm2 in
both groups) increased similarly in the 2 treatment groups independently of
sex. Participants in the orlistat group (+2312 g) gained a similar amount
of fat-free body mass as those in the placebo group (+2116 g). However, participants
in the orlistat group lost significantly more fat mass than those in the placebo
group (−2401 g in the orlistat group vs −380 g in the placebo
group; P = .03).
This study evaluates the use of orlistat, a lipase inhibitor, in the
treatment of obese adolescents. In conjunction with a reduced-calorie diet,
exercise, and behavioral modification, treatment with 120 mg of orlistat 3
times daily for 52 weeks statistically significantly decreased BMI, waist
circumference, and body fat compared with placebo. This effect is probably
due to the decrease in the absorption of fat and its associated calories.24 Gastrointestinal tract adverse effects were observed
more frequently with orlistat. In these 352 adolescents studied over a 1-year
period, no major safety issues were raised.
Orlistat has been shown to cause meaningful and sustained weight loss
in overweight or obese adults when given at a dose of 120 mg 3 times daily
and combined with a mildly reduced-calorie diet for up to 4 years.17- 19,25 Because
of the nonsystemic mechanism of action of orlistat, it was considered a logical
choice for study in the obese pediatric population. In the current study,
the same dosage of orlistat was associated with a statistically significant
decrease in BMI over the course of 1 year in contrast to a BMI increase in
the placebo group. This result must be interpreted considering the characteristics
of an adolescent rather than an adult population. Because adolescents’
bodies are growing and acquiring muscle, bone, and skin, accurately quantifying
the effects of weight management therapy in adolescents requires the use of
age- and sex-corrected growth curves and BMI values.22 Second,
adolescents represent a notoriously difficult-to-treat population. In the
absence of intervention, overweight and obese adolescents can continue to
gain weight rapidly well into adulthood. For instance, while only 10% of 10-
to 15-year-old children and adolescents with a BMI below the 85th percentile
will become obese adults, the vast majority (83%) of those with a BMI greater
than the 95th percentile will become obese adults.26 Finally,
the prevalence of metabolic syndrome among obese children and adolescents
has been shown to increase faster with more rapid weight gain, and the onset
of cardiovascular complications may also be more rapid when type 2 diabetes
develops in adolescence rather than in adulthood.5 In
obese adolescents, slower weight gain has been associated with delayed development
of complications such as type 2 diabetes over a 2-year period,27 suggesting
that a therapeutic approach that contributes to decreased weight gain is important.
Body mass index decreased with orlistat but increased with placebo.
The relationship between the changes in BMI and body composition is explained
through the dual-energy x-ray absorptiometry results obtained from a subset
of our study population. The increase in fat-free mass and bone mineral content
was similar in both groups, reflecting normal growth. In contrast, change
in fat mass was markedly different between groups. In the subset with dual-energy
x-ray absorptiometry measurements, the placebo group experienced an increase
in body weight (+1.68 kg) with a decrease of 0.6 kg in fat mass while the
orlistat group experienced a decrease in body weight (−0.35 kg) and
a decrease of 2.53 kg in fat mass. Thus, the difference in absolute weight
experienced by participants receiving orlistat was mostly due to a loss in
fat mass, suggesting a favorable change in body composition.
Orlistat treatment resulted in decreases in weight of 2.61 kg and in
BMI of 0.86. Although the latter is lower than the power goal of the study,
it is within the 95% confidence interval of the difference (0.37-1.34). This
improvement in BMI was similar to that observed after 1 year in 5 major placebo-controlled
studies in adults (between-group BMI difference of –0.74 to –1.32
in favor of orlistat [data on file]). Compared with 15.7% of the placebo group,
26.5% of the orlistat group had a 5% or higher decrease in BMI; and 4.5% and
13.3%, respectively had a 10% or higher decrease in BMI. These values are
similar to those reported in studies of obese adults without severe comorbidities
in which orlistat-treated participants were up to 2.0 times more likely to
experience a 5% or higher decrease in weight than placebo recipients and up
to 2.5 times more likely to experience a 10% or higher decrease in weight
than placebo recipients.28
We attempted to clarify the baseline characteristics of those patients
achieving these decreases. While the study was not powered to address this
question, these descriptive data may enhance the design of future studies
attempting to predict which participants will benefit most from pharmacotherapy.
Within the orlistat group, 35% of participants were male, as were 32% of participants
achieving a less than 5% decrease in BMI; males accounted for 41% of the participants
achieving a 5% or higher decrease in BMI and 44% of those achieving a 10%
or higher decrease in BMI. Blacks represented 19% of patients assigned to
orlistat at baseline and 21% of those in the orlistat group who had a less
than 5% decrease in BMI; blacks accounted for 18% of those achieving a 5%
or higher decrease in BMI and 7% of those achieving a 10% or higher decrease
in BMI. Thus, from this study, orlistat appears to have similar efficacy in
males and females and there is no evidence of any influence of ethnic origin.
Baseline age and BMI were not predictive of a greater decrease in BMI over
the duration of the study. In contrast, a weight loss of greater than 5% after
12 weeks of orlistat treatment was associated with a decrease of 7.6 kg or
a decrease in BMI of 3.7.
Secondary efficacy parameters, including lipid and glucose levels and
diastolic and systolic blood pressure, were mostly normal at baseline. This
contrasts with an earlier, pilot study of weight loss with orlistat in 20
adolescent participants, in which obesity was extremely severe (mean BMI,
44), and obesity-related metabolic risk factors (hypertension, sleep apnea,
abnormalities in lipid levels, and glycemic control) were more frequent.29 As such, orlistat generally demonstrated minimal
effects on these metabolic risk factors, although it did significantly reduce
waist circumference and diastolic blood pressure compared with placebo.
In this 1-year trial, orlistat did not raise any safety issues, and
the adverse event profiles—except for gastrointestinal tract adverse
events—were similar between the orlistat and placebo groups. However,
the efficacy and tolerability of orlistat for more than 1 year of treatment
has only been confirmed in adults.17- 19,30- 32 Additional
longer-term studies in a larger number of adolescents will be needed to confirm
the safety of orlistat in this population. Gastrointestinal tract adverse
events were reported by a higher proportion of orlistat-treated participants
than placebo recipients, although the majority of the participants did experience
a specific adverse event only once; these adverse events were generally mild
to moderate in intensity and may relate to the mechanism of action of orlistat.33,34 However, they did not affect outcome
as shown by similar BMI decreases in orlistat-treated participants with or
without gastrointestinal tract adverse events. Gastrointestinal tract adverse
events also occurred in a small percentage of placebo recipients, which has
been previously reported in adult studies. This is consistent with the specific
questioning for named gastrointestinal tract adverse events and also the known
occurrence of gastrointestinal tract adverse events in obese patients not
receiving any pharmacotherapy.35
There were no clinically relevant differences in any of the laboratory
tests between the 2 groups. Fat-soluble vitamins A, D, E, and beta-carotene
increased in both groups at the end of the study as expected with daily multivitamin
Levels of the sex hormones, estradiol, free testosterone, and sex hormone-binding
globulin were also assessed. The only notable difference between treatment
groups was the greater decrease in estradiol levels in girls treated with
orlistat rather than placebo. This is consistent with the known effect of
weight loss on estradiol levels in adolescent girls.36 In
our study, girls treated with orlistat had greater decreases in BMI and lost
more weight than those receiving placebo.
It is well established that there is an increased incidence of gallstones
in obese adults and adolescents.37 In adults,
gallstones are more frequent in females than males and this is mirrored in
adolescents.38 In adults, both excess weight
and rapid weight loss are associated with gallstone development. In our study,
placebo recipients, who generally did not have significant weight reductions
from baseline, did not develop gallstones. In contrast, a greater proportion
of orlistat-treated participants achieved significantly greater weight loss
from baseline and would therefore be at higher risk of developing gallstones.
At study end, 6 of the orlistat-treated participants, all girls aged 13 to
15 years with a mean weight loss of 17.6 kg, had asymptomatic cholelithiases
identified on ultrasound. Five of these participants developed gallstones
during the study and 1 additional participant already had a cholecystectomy
prior to study entry. However, the absence of gallstone formation in orlistat-treated
participants who had BMI decreases without large weight reductions suggests
that gallstone development was related to weight loss and not to the intrinsic
effect of orlistat. Indeed, previous studies have shown no increase in the
lithogenic index of bile and no evidence of microcrystal formation in the
gallbladder with orlistat treatment.33 There
were no cases of acute cholecystitis, although 1 patient who lost approximately
15 kg and was taking oral contraceptives had symptomatic cholelithiasis and
a subsequent cholecystectomy.
Certain limitations of this study should be considered. First, diet,
exercise, and behavioral modification were not standardized. However, the
absence of a significant center by treatment interaction suggests that the
treatment effect across centers was similar. Second, the study was performed
in a predominantly white population and as is common in such studies,39 most participants were female. The average participant
was at the 98th percentile for BMI, a significant degree of obesity, so it
is not known if less obese adolescents would achieve similar results. The
present study excluded participants with certain characteristics more likely
to be associated with metabolic syndrome, although one quarter of the participants
did have the metabolic syndrome at randomization. How these characteristics
affect the generalizability of our results is not clear. However, recent results
in obese adults attending community weight clinics40 or
in general practice41 were similar to those
from double-blind, randomized trials.17,18 Third,
the number of participants and the study duration do not allow adequate assessment
of safety beyond 1 year. Fourth, quality of life was not investigated in this
study, making an objective assessment of tolerability difficult. It should
be noted that, although similar between groups, the dropout rate was 35% to
36%. This rate is well within that usually seen in obesity trials, particularly
those of more than 1-year duration, in which dropout rates range from 10%
to 80%. Trials of obesity therapies face the added problem of patients stopping
treatment when weight loss plateaus in addition to the common issue of patient
perseverance seen in most long-term trials. It would be useful in the future
to study other adolescent populations for longer periods.
Study withdrawals were handled by the last observation carried forward
method, which assumes that individual data at the time of drop out are representative
of data at the end of the study if the participant had completed it. Therefore,
the results of the study may be affected if participants with lower success
drop out more often, or if the characteristics or timing of drop out differs
between the 2 groups. However, we have verified that this was not the case:
the timing of drop out was similar in the 2 groups (P = .90;
Mann-Whitney test), and similar primary efficacy results were obtained for
completers (BMI difference between the orlistat and placebo groups at 12 months:
0.70, 95% confidence interval, 0.19-1.21; P = .007).
In addition, baseline characteristics among participants who dropped out were
similar to those of completers within each study group (Table 1), and the timing of withdrawals was similar between the
2 groups. Taken together, these analyses show that last observation carried
forward analysis did not affect the interpretation of our results.
We conclude that treatment with 120 mg of orlistat 3 times daily for
52 weeks, in conjunction with a reduced-calorie diet, exercise, and behavioral
modification, statistically significantly improves weight management in obese
adolescent participants. Body composition analysis showed that orlistat did
not affect the normal increase in lean body mass physiologically observed
in adolescents. In contrast, the weight difference between the placebo and
orlistat groups was due to a difference in fat mass. In these 352 adolescents
studied over a 1-year period, orlistat did not raise major safety issues and
the adverse event profiles revealed that gastrointestinal tract adverse events
were more common in the orlistat group.
Corresponding Author: Jean-Pierre Chanoine,
MD, PhD, Endocrinology and Diabetes Unit, K4-212, British Columbia Children’s
Hospital, 4480 Oak St, Vancouver, British Columbia V6H 3V4, Canada (firstname.lastname@example.org).
Author Contributions: Dr Chanoine had full
access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Boldrin, Hauptman.
Acquisition of data: Chanoine, Hampl, Jensen,
Analysis and interpretation of data: Chanoine,
Hampl, Jensen, Boldrin, Hauptman.
Drafting of the manuscript: Boldrin, Hauptman.
Critical revision of the manuscript for important
intellectual content: Chanoine, Hampl, Jensen, Hauptman.
Statistical analysis: Boldrin.
Administrative, technical, or material support:
Study supervision: Chanoine, Jensen, Hauptman.
Financial Disclosures: Dr Chanoine has received
honoraria from Hoffmann-La Roche for speakers presentations. No other authors
reported financial disclosures.
Funding/Support: This study was funded by F.
Hoffmann-La Roche Ltd.
Independent Statistical Review: All study data
were transferred from Hoffman-La Roche to the Department of Statistics at
the British Columbia Children’s Hospital for independent reanalysis.
Statistical reanalyses of the raw data were performed by Ruth Milner and Victor
M. Espinosa, MSc. There were only minor discrepancies between the reanalysis
and the original interpretation of the results and conclusions. When there
was a discrepancy Dr Chanoine included the results from the reanalyses performed
at the British Columbia Children’s Hospital.
Role of the Sponsor: Hoffmann-La Roche was
involved in the study design and conduct and in the analysis and interpretation
of the data. All data were independently reanalyzed by an academic statistician.
The sponsor was permitted to review the manuscript, but the final decision
on content was with the corresponding author in conjunction with the other
Participating Investigators: J. Anderson (University
of Kentucky, Lexington); T. Bravender (Duke Children’s Primary Care,
Durham, NC); L. Cheskin (John Hopkins Bayview Medical Center, Baltimore, Md);
E. Cummings (IWK Grace Health Centre for Children, Women and Families, Halifax,
Nova Scotia); W. Dahms (University Hospitals of Cleveland, Cleveland, Ohio);
H. Dean (Children’s Hospital, Winnipeg, Manitoba); M. A. Drehobl (Scripps
Clinic, San Diego, Calif); K. Ellis (Memorial Family Practice Center, Savannah,
Ga); F. Franklin (Children’s Hospital, Birmingham, Ala); K. Fujioka
(Scripps Clinic, San Diego, Calif); K. Hasan (Phoenix Children’s Hospital,
Phoenix, Ariz); R. Heptulla (Bay State Medical Center, Springfield, Mass);
T. Higgins (Boulder Medical Center, Boulder, Colo); A. G. Hudnut (Sutter Medical
Group Family Practice, Elk Grove, Calif); C. Huot (Hospital St Justine, Montreal,
Quebec); M. S. Jacobson (Schneider Children’s Hospital, New Hyde Park,
NY); G. Kletter (Children’s Hospital and Regional Medical Center, Seattle,
Wash); L. Legault (Montreal Children’s Hospital, Montreal, Quebec);
P. O’Neill (Medical University of South Carolina, Charleston); D. Pacaud
(Alberta Children’s Hospital, Calgary); T. Poling (Heartland Research
Associates, Wichita, Kan); R. Portman (University of Texas—Houston Health
Science Center, Houston); J. Sanchez (Riley Hospital for Children, Indianapolis,
Ind); L. Schnell (Aurora, Ill); D. Smith (CSRA Partners in Health, Augusta,
Ga); J. Spitzer (Kalamazoo, Mich); R. S. Strauss (UMDMJ-Robert Wood Johnson
Medical School, New Brunswick, NJ); S. Travers (Denver, Colo); I. Vargas (New
Acknowledgment: We are grateful to Victor M.
Espinosa, MSc, for his statistical expertise and assistance.