Published online June 18, 2007
PEDIATRICS Vol. 120 No. 1 July 2007, pp. e147-e157 (doi:10.1542/peds.2006-2137)
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ARTICLE

Cardiovascular Effects of Sibutramine in the Treatment of Obese Adolescents: Results of a Randomized, Double-Blind, Placebo-Controlled Study

Stephen R. Daniels, MD, PhDa, Barbara Long, MD, MPHb, Scott Crow, MDc, Dennis Styne, MDd, Melinda Sothern, PhDe, Ileana Vargas-Rodriguez, MDf, Lisa Harris, MDg, Julia Walch, BSh, Olga Jasinsky, BS, MBAh, Kristine Cwik, RN, MBAh, Ann Hewkin, MSch, Vicky Blakesley, MD, PhDh for the Sibutramine Adolescent Study Group

a Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
b Department of Pediatrics, University of California, San Francisco, California
c Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota
d Department of Pediatrics, University of California Davis School of Medicine, Sacramento, California
e Department of Pediatrics, Louisiana State University Health Sciences and Pennington Research Centers, New Orleans, Louisiana
f Comprehensive Weight Control Program, New York, New York
g Chase Wellness Center, Virginia Beach, Virginia
h Abbott Laboratories, Abbott Park, Illinois


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. Adolescent obesity is a major public health problem. Treatment options in addition to behavioral therapy could include pharmacotherapy with sibutramine.

OBJECTIVES. Concerns regarding increases in blood pressure and heart rate after sibutramine treatment in some adult patients precipitated the present analysis, which evaluated the cardiovascular safety of sibutramine plus a behavioral therapy program in obese adolescents.

PATIENTS AND METHODS. With this 12-month, randomized, double-blind, placebo-controlled trial in 33 US clinics we studied 498 adolescents aged 12 to 16 years with multiethnic backgrounds and BMIs of 28.1 to 46.3 kg/m2.

RESULTS. The subjects were randomly assigned to behavioral therapy plus 10 mg of sibutramine or behavioral therapy plus placebo daily. At the end point, there was a mean treatment group difference in BMI of 2.6 kg/m2 in favor of sibutramine. Small mean decreases in blood pressure and pulse rate were seen in both sibutramine and placebo groups at the end point (systolic blood pressure: –2.1 vs –2.1 mmHg; diastolic blood pressure: –0.1 vs –1.1 mmHg; pulse rate: –0.2 vs –1.8 bpm). In both treatment groups, these reductions in vital signs were greater at the end point when BMI reduction was ≥5% compared with <5%.

CONCLUSIONS. Sibutramine may have some direct cardiovascular effects on obese adolescents. These cardiovascular effects may be balanced by a reduction in BMI, which, in adolescents, seems to be greater than that observed in adults.

Key Words: adolescents • obesity • weight loss • sibutramine • blood pressure

Abbreviations: SBP—systolic blood pressure • DBP—diastolic blood pressure • PR—pulse rate • BT—behavioral therapy • bpm—beats per minute

Obesity is an increasingly important medical problem among children and adolescents. Data from the National Health and Nutrition Examination Surveys show that the combined prevalence of overweight and at-risk-for-overweight alone among US children and adolescents has more than doubled since the early 1970s, whereas the prevalence of overweight has increased fourfold. Today, 16.1% of adolescents aged 12 to 19 years are overweight (≥95th percentile for age- and gender-specific measures for BMI).1,2

This epidemic has led to concern regarding the management of overweight and its complications. Although prevention is the ideal strategy, even with appropriate preventive approaches, it is likely that many children will become overweight and require treatment to prevent the long-term consequences of adult obesity, such as cardiovascular morbidity and mortality.3

In adults, excess body fat is associated with an increased risk for developing type 2 diabetes, heart disease, and a variety of other obesity-related conditions.4 Many of these diseases, previously considered diseases of adults, are now affecting children. In particular, overweight children and adolescents are known to suffer from hypertension, dyslipidemia, left ventricular hypertrophy, sleep apnea, and social and psychological problems. There has also been a dramatic increase in the incidence of type 2 diabetes in the pediatric population, for which the most important risk factor is obesity.5–8

The first-line therapy for overweight and obesity in both adults and adolescents is reduced-calorie diet, increased physical activity, and behavior modification.4,7,9 In overweight adolescents, comprehensive behavioral approaches have shown promise in short-term studies. Research is mixed with regard to whether adolescents benefit from family-based or individual behavioral programs.10,11 If family-based programs are initiated when the child is relatively young (6–12 years), the effects can persist into young adulthood. This argues, therefore, for starting weight management at an early age. Early treatment of overweight is also supported by a number of behavioral and metabolic factors, including a shorter history of the habits that lead to overweight. Because children are still growing and have a larger relative increase in height than weight, they are able to decrease their percent overweight.

Nevertheless, despite widespread and long-standing appreciation of the importance of diet and exercise to reduce childhood overweight, the evidence suggests that weight-loss programs for adolescents may be unsuccessful.12,13 In adults, such approaches are often supplemented by adjunctive drug therapy.4 There are no pharmacologic agents currently indicated for the management of pediatric overweight; however, in the United States, the approved labeling for orlistat has been modified to add pediatric use information.14 The serotonin and norepinephrine reuptake inhibitor sibutramine is approved for the management of adult obesity. It has been shown to produce dose-related weight loss and long-term weight maintenance with improvements in obesity-associated comorbidities for ≤2 years.15–17 However, in clinical trials, treatment with sibutramine in some patients is associated with small mean increases in systolic and diastolic blood pressure (SBP and DBP) and pulse rate (PR) relative to placebo.18,19 Given the potential consequences of long-term elevations in blood pressure, and because both the risks and benefits associated with pharmacotherapy cannot be assumed to be the same in this younger patient population as for adults, a full understanding of the benefit/risk profile of sibutramine in adolescents is important. The present analysis considers the cardiovascular effects of sibutramine in conjunction with behavioral therapy (BT) in a randomized, double-blind, placebo-controlled trial in obese adolescents.20


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
This was a 12-month, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of sibutramine in addition to BT in obese adolescents 12 to 16 years of age. The study was sponsored by Abbott Laboratories (previously Knoll Pharmaceuticals) and conducted at 33 centers in the United States from July 2000 to February 2002. Individual institutional review boards reviewed and approved the study. Written informed consent was obtained from the parent or legal guardian of each subject, and assent was obtained from the adolescent. Abbott Laboratories conducted data management and analysis in association with the lead investigators who contributed significantly to the development of the study protocol.

Adolescents aged 12 to 16 years in good general health with a BMI (calculated as weight in kilograms divided by the square of the height in meters) not less than a lower limit of ≥2 units above the US weighted mean for the 95th percentile based on age and gender21 and ≤44 kg/m2 were enrolled in the study. Contraindications included cardiovascular disease (including arrhythmias), type 1 or type 2 diabetes mellitus, major psychiatric disorders, pregnancy, use of medications promoting weight loss or weight gain or those contraindicated with the use of sibutramine,22 or cigarette smoking. Candidates with SBP >130 mmHg, DBP >85 mmHg, or a PR >95 bpm were excluded, but hypertensive subjects stable on therapy were permitted.

Study Procedures
After an initial screening visit, eligible subjects were randomly assigned in a 3:1 ratio to receive either single daily doses of sibutramine 10 mg or placebo (Fig 1). Randomization was stratified by center and by low (≤37 kg/m2) and high (>37 kg/m2) baseline BMI. At month 6, all of the subjects who had not lost >10% of their initial BMI were up-titrated in a blinded fashion to 15 mg of sibutramine or placebo. Study drugs were manufactured and supplied by Abbott Laboratories; identical placebo capsules were dispensed in the same way.


Figure 1
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  		FIGURE 1 Flow of subjects throughout the trial. SIB indicates sibutramine; PLA, placebo. Eight participants (5 sibutramine and 3 placebo) did not record any postbaseline data and were excluded from the intention-to-treat population data set. Proportions of participants who prematurely discontinued because of an adverse event included those in the sibutramine (23 of 368 [6%]) and placebo (7 of 130 [5%]) groups (P = .832). a P = .84 versus placebo ({chi}2 test); b P = .001 versus placebo ({chi}2 test).

 
Subjects whose vital signs increased at a single visit to >150 mmHg (SBP), and/or 95 mmHg (DBP), and/or 110 bpm (PR) or increased by 20 mmHg (SBP), and/or 15 mmHg (DBP), and/or 20 bpm (PR) from baseline were either discontinued from study medication or closely monitored until their blood pressure returned to within acceptable limits. This decision was made at the discretion of the study physician. There was a protocol-driven algorithm for repeating visits and/or withdrawing subjects whose vital signs did not return to protocol-defined limits. There was no provision, however, for dose reduction from 15 to 10 mg in the event of intolerance. Throughout the study, all of the participants received site-specific instruction in lifestyle behavior modification.

Subjects were seen weekly until week 2, biweekly until week 12, and then monthly until study completion. At each scheduled visit, subjects were assessed for receipt of behavior modification instruction, and medication adherence was evaluated by capsule count.

Full physical examinations and focused cardiovascular examinations were also performed. Blood pressure was determined at all of the visits manually with the subject seated using an appropriately sized cuff and a calibrated mercury or aneroid sphygmomanometer. The onsets of the first and fifth Korotkoff phases were used to determine SBP and DBP, respectively. PRs were measured by palpation of the radial or brachial artery for ≥30 seconds. All of the readings were taken at approximately the same time of day. Three readings were taken at 2-minute intervals and averaged. Adverse events were assessed and recorded at each visit.

Data Analysis
All of the data are presented according to randomly assigned treatment group. Demographic and subject disposition data were summarized. All of the subjects receiving ≥1 dose of study medication were included in the safety summary of adverse events; 8 subjects recorded no postbaseline data and were excluded from all of the other analyses. The end point was defined as the latest postbaseline result. Statistical significance was to be determined by reference to the 5% level. The primary measure of efficacy was absolute change from baseline to the end point in BMI. Additional secondary efficacy variables that included anthropometric, glycemic, and lipids parameters were also determined and have been reported elsewhere.20

Adverse events were summarized by using Coding Symbols for Thesaurus of Adverse Reaction Terms V. Fisher's exact test was used to test for differences between treatment groups.

Vital signs data were summarized at each visit. The change from baseline to the end point in SBP, DBP, and PR was analyzed using analysis of covariance with a factor for treatment group and baseline value as a covariate. In an exploratory analysis, the same analyses were performed for the patient subgroups achieving <5%, ≥5%, and ≥10% reduction in BMI at the end point.

The number and percentage of subjects, with either values above absolute thresholds or high changes from baseline, using the protocol-specified criteria in Table 1 were summarized ("vital sign outlier events"). Adverse events associated with these outlier events were reported.


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  		TABLE 1 Protocol-Defined Vital Sign Outlier-Event Criteria

 
To assess the persistence of elevations in vital signs after baseline, the proportions of subjects with selected elevations at any visit, at ≥3 visits, and at ≥3 consecutive visits were summarized. To compare the observed blood pressure data to expected values in this adolescent population, subjects were classified in an exploratory analysis as normal (<90th percentile), prehypertensive (90th to <95th percentile or, if blood pressure exceeded 120/80 mmHg, even if <90th percentile up to <95th percentile), stage 1 hypertensive (95th to 99th percentile plus 5 mmHg), or stage 2 hypertensive (>99th percentile plus 5 mmHg), adjusting for age, height, and gender at baseline and the end point. The highest follow-up rating for each subject was also obtained.23 All of the statistical analyses were performed by using SAS 6.12 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A total of 498 subjects were randomly assigned to 10 mg of sibutramine or placebo. The study population was 56.6% white, 21.1% black, and 15.7% Hispanic/Mexican American. At baseline, the treatment groups were well balanced (Table 2), and there were no important differences between treatment groups with respect to SBP or DBP, although seated PR was higher in the sibutramine treatment group (77.2 bpm) compared with the placebo treatment group (75.2 bpm).


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  		TABLE 2 Baseline Characteristics for Subjects Assigned to BT Plus Sibutramine or Placebo

 
Overall, 72% of the enrolled subjects completed the study: 76% (281 of 368) of the subjects in the sibutramine group and 62% (80 of 130) in the placebo group (P = .001). Postbaseline data were not recorded in 8 subjects (5 taking sibutramine and 3 taking placebo).

Mean exposure to study drug was 294 and 254 days in the sibutramine and placebo groups, respectively. Mean compliance was high (sibutramine: 89.1%; placebo: 83.9%). Overall, 47.9% subjects (174 of 363) in the sibutramine treatment group required a dose increase to 15 mg at month 6; mean exposure to 15 mg of sibutramine was 159 days.

Efficacy
Treatment with sibutramine plus BT resulted in a statistically significant reduction in mean (SE) BMI from baseline to the end point in the intention-to-treat population of –2.9 kg/m2 (0.15 kg/m2) compared with –0.3 kg/m2 (0.24 kg/m2) for placebo plus BT with a mean treatment difference of 2.6 kg/m2 (SE: 0.27 kg/m2; 95% confidence interval: 2.0–3.1; P < .001), in favor of sibutramine.20 A BMI reduction of ≥5% and ≥10% occurred in 62.3% and 38.8% of subjects treated with sibutramine compared with 18.1% and 5.5% of subjects treated with placebo, respectively (odds ratio: 10.1 for ≥5% and 14.2 for ≥10% reduction; P < .001 for each).

Adverse Events
The incidence of adverse events reported was similar between subjects in the sibutramine and placebo treatment groups. Only 1 event, tachycardia, resulted in a significant difference between treatment groups (13% [46 of 368] sibutramine vs 6% [8 of 130] placebo; P = .049). Overall, adverse events led to 6% (23 of 368) withdrawals in the sibutramine group and 5% (7 of 130) in the placebo group (P = .832). Tachycardia and hypertension were the adverse events most commonly resulting in premature discontinuation of study drug. Of the 2% (9 of 368 and 2 of 130) of subjects discontinued for tachycardia in each treatment group, all had also been identified as PR outliers. Only 1% (5 of 368) of subjects in the sibutramine group (and none in the placebo group) were discontinued for hypertension; 4 of these 5 subjects were identified as blood pressure outliers.

Changes in Vital Signs
There were no violations of the assumptions of normality for the changes from baseline to the end point in blood pressure or PR data. In the intention-to-treat analysis, after adjusting for baseline values, the mean change in vital signs from baseline to the end point for SBP was –2.1 and –2.1 mmHg for the sibutramine and placebo groups, respectively; for DBP, –0.1 and –1.1 mmHg, respectively; and for PR, –0.2 and –1.8 bpm, respectively. The differences between treatment groups for the changes in blood pressure were not statistically significant (P = .988 and .136, respectively). For PR, the difference between treatment groups was P = .055. The mean changes in vital signs over time are displayed in Figs 2 through 4. Overall, mean changes from baseline to each visit were small and not clinically significant. For sibutramine, SBP ranged from –2.4 to 0.3 mmHg and DBP –0.9 to 1.5 mmHg and for placebo, SBP –3.3 to –0.1 mmHg and DBP –2.9 to –0.4 mmHg. For PR, mean changes ranged from –0.9 to 2.6 bpm for sibutramine and –1.4 to 1.2 bpm for placebo.


Figure 2
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  		FIGURE 2 Mean absolute change in SBP from baseline to each visit (observed set). SIB indicates sibutramine; PLA, placebo.

 

Figure 3
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  		FIGURE 3 Mean absolute change in DBP from baseline to each visit (observed set). SIB indicates sibutramine; PLA, placebo.

 

Figure 4
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  		FIGURE 4 Mean absolute change in PR from baseline to each visit (observed set). SIB indicates sibutramine; PLA, placebo.

 
In subjects who completed the study, the mean absolute changes in the last 6 months of the study did not increase with continued drug exposure in either group. Subjects who were up-titrated to 15 mg of sibutramine at month 6 did not demonstrate the same reduction in SBP, DBP, and PR as did the placebo and sibutramine 10-mg groups (data not shown). In an exploratory analysis, the absolute changes from baseline to the end point were analyzed for subjects by change in BMI (Table 3).


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  		TABLE 3 Mean Change in Vital Signs for <5%, ≥5%, and ≥10% BMI Responders From Baseline to the End Point

 
There were no statistically significant differences in the mean changes to the end point for any variable between subjects taking sibutramine and placebo who achieved BMI reductions of ≥5% or ≥10%. The differences in mean changes in vital signs were statistically significant (P ≤ .02) in subjects taking sibutramine who achieved a BMI reduction of <5% compared with placebo subjects who achieved a BMI reduction of <5%. In both treatment groups, reductions to the end point in SBP, DBP, and PR were greater for subjects with ≥5% reduction in BMI at the end point compared with subjects with <5% change.

The overall incidence of subjects who ever recorded a vital sign outlier event was 32% (117of 363) in the sibutramine group and 17% (21 of 127) in the placebo group (P = .001 for the difference). The incidence for blood pressure outlier events was similar in both treatment groups (SBP, sibutramine versus placebo: 5% [19 of 363] vs 4% [5 of 127], respectively [P = .561]; DBP, sibutramine versus placebo: 12% [43 of 363] vs 8% [10 of 127], respectively [P = .218]). There was a statistically significant difference between treatment groups in the incidence of PR outlier events (sibutramine versus placebo: 21% [75 of 363] vs 6% [8 of 127], respectively [P < .001]; Table 4).


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  		TABLE 4 Vital Sign Observations Meeting Outlier-Event Criteria

 
Vital signs outlier events were reported more frequently during the first half of the study for both treatment groups. The number of subjects reporting ≥1 event before month 6 was 26% (95 of 368) in the sibutramine group and 14% (18 of 130) in the placebo group, compared with the number reporting ≥1 event after month 6, which was 14% (43 of 310) in the sibutramine group and 4% (4 of 91) in the placebo group.

Of the 138 subjects who experienced a vital sign outlier event during the treatment period, 51 had ≥1 vital sign–related adverse event (38.5% sibutramine [45 of 117] and 28.6% placebo [6 of 21]; eg, hypertension or tachycardia). The majority of these events were reported as mild in severity, and none was considered severe. There were no reports of serious adverse events related to vital signs in the subjects who experienced an outlier event, and the proportion of subjects who prematurely discontinued the study drug because of adverse events that were related to vital sign outlier events was similar (9.4% sibutramine [11 of 117] versus 9.5% placebo [2 of 21]).

Maintenance of Vital Sign Changes
At multiple and consecutive study visits, the proportion of subjects who had elevated SBP and DBP values above the absolute threshold or from baseline was small and similar between groups (Table 5). This was also the case for absolute PR increases, although the percentages were larger but not significant in the sibutramine group compared with the placebo group. Exploratory analyses found no correlation between maximum SBP or DBP and associated PR or between maximum PR and associated SBP or DBP.


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  		TABLE 5 Persistence of Increases in Vital Signs

 
Stratification According to Baseline Blood Pressure
In an exploratory analysis, subjects were stratified according to their baseline blood pressure.20 The analysis in Table 6 shows baseline blood pressure classification and the maximum follow-up classification during the treatment period. At baseline, blood pressure classification for all of the subjects was normal, prehypertensive, or stage 1; no subjects were classified with stage 2 blood pressure elevation. Only 7 (SBP = 5 and DBP = 2) of the 363 subjects in the sibutramine group and 1 (SBP) of the 127 subjects in the placebo group recorded shifts in their values to stage 2 hypertension during the treatment period, and only 1 subject (10 mg of sibutramine) remained at stage 2 after repeat testing. This subject presented with increased SBP on day 83, and after repeat blood pressure measurements, study medication was permanently withdrawn on day 166, and the subject was discontinued from the study. The event resolved 15 days after sibutramine was stopped. No subject in either group was classified with stage 2 hypertension at the end point.


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  		TABLE 6 Maximum Follow-up Classification for SBP and DBP According to Baseline Classification

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The results of this study show that obese adolescents can achieve a significantly greater reduction in BMI when sibutramine, as compared with placebo, is used in combination with BT. The anthropometric changes in obese adolescents treated with sibutramine are similar to the results observed previously in obese adults.15–17 Importantly, the study suggests that sibutramine is well tolerated in this adolescent population. The occurrence of adverse events reported among obese adolescents was also comparable to the results from clinical trials of sibutramine treatment in obese adults.15–17 The study had an overall completion rate of 72%, which is high for a 1-year weight-loss study. Overall, 6% of subjects in the sibutramine group withdrew from this study compared with 5% in the placebo group (P = .832).

In previous clinical studies in obese adults, sibutramine treatment has been associated with small mean increases in blood pressure and PR relative to placebo in some obese subjects.18 Published clinical studies in overweight adolescents are limited24–26; only 124 has shown effects similar to adults. Although the long-term consequences of untreated or undertreated hypertension in adults are well documented, they are less clear in children and adolescents. In addition, no data are available on the long-term effects of antihypertensive drugs on growth and development.23 Hence, it is important to explore the cardiovascular effects of sibutramine in this population.

The present study resulted in statistically significant and clinically important improvements in BMI. A mean absolute change in BMI of –2.9 kg/m2 (–8.2%) for the sibutramine group compared with –0.3 kg/m2 (–0.8%; P < .001 for both) for the placebo group was evident at the end point.20 The odds ratio for achieving ≥5% BMI reduction at the end point with sibutramine treatment compared with placebo was 10.1 (P < .001). Furthermore, there were no statistically significant differences in blood pressure between obese adolescents treated with sibutramine and those given placebo. Both treatment groups showed small mean decreases in SBP, DBP, and PR. In those subjects with ≥5% reduction in BMI at the end point, these decreases in blood pressure and PR were greater compared with subjects with <5% reduction in BMI. The decrease in mean blood pressure in subjects treated with sibutramine was less than that in subjects who achieved an equivalent change in BMI by BT alone, but it is important to consider the effectiveness of BT to induce a decrease in BMI. Only 38.8% of the adolescents treated with BT alone achieved a reduction in their BMI of >5% compared with 62.3% of those treated with sibutramine plus BT. In subjects with >10% weight loss, the difference was even more marked: 5.5% of subjects treated with BT alone compared with 18.1% when sibutramine was added to BT.

These findings are similar to those seen in adult subjects who achieve clinically meaningful weight loss (ie, ≥5%) when treated with sibutramine and lifestyle modification.18 Exploratory analyses were performed to assess the magnitude and persistence of vital sign changes between the treatment groups, while accounting for the substantial intrasubject variability in blood pressure and PR observed in adolescents.27,28 The incidence of vital signs outlier events was higher in subjects randomly assigned to sibutramine because of a statistically significant difference in PR outliers between groups. However, the increases in vital sign measurements did not persist over time and, therefore, are not likely to be clinically important. The data are reassuring, because they included values recorded from the first few weeks of therapy with sibutramine when weight loss was at a minimum and its potential beneficial effects on blood pressure would be absent. In addition, there was no correlation between PR and SBP or PR and DBP. The primary end point of this study was change in BMI, and although the study was not specifically powered to assess changes in blood pressure and vital signs, a sample size of 100 placebo subjects was considered adequate to assess the anticipated treatment-group differences.

It is not clear why blood pressure and heart rate respond differently to treatment with sibutramine in adolescents compared with adults. It may be that autonomic balance differs in adolescents, favoring the parasympathetic system, because vagal tone is known to be higher in adolescents. If this is the case, the sympathetic activation characteristically associated with sibutramine may be counteracted.

Sibutramine is a serotonin and norepinephrine reuptake inhibitor, which is generally assumed to act centrally. Recent research suggests that the cardiovascular effects of sibutramine may result from a complex interaction of peripheral and central nervous system effects. For example, mechanisms that drive the peripheral effects of sibutramine dominate and promote resting blood pressure increases in healthy young subjects with low sympathetic activity. It is also proposed that the central clonidine-like inhibitory effects of sibutramine become apparent when sympathetic nervous system activity is acutely increased, attenuating the pressor response to sympathetic stimuli. This may explain the blood pressure reduction observed in obese subjects.29 The results of the present study suggest a dominant role for the central clonidine-like action. This highlights the need for additional work to elucidate the precise mechanisms by which sibutramine and possibly weight loss are acting to alter blood pressure in overweight adolescents. We should be careful, however, not to overstate the apparent differences between adults and adolescents as shown in this study, and in the absence of direct comparative studies, these findings should be considered as suggestive only. In addition, it must be appreciated that these study results cannot be generalized to include overweight adolescents with hypertension or tachycardia, because subjects with these conditions were excluded from entry. At this time, the Food and Drug Administration has not approved sibutramine use in adolescents who are <16 years of age.

Increases in obesity-related morbidity and mortality carry over to adulthood from adolescence.30–32 In the Harvard Growth Study, adolescents at risk of overweight (BMI >75th percentile) were significantly more prone to adult morbidity and mortality from coronary heart disease and mortality from all causes, independent of adult weight status.30 In the Boyd Orr cohort, all- cause and cardiovascular mortality was increased among adults who were in the ≥75th BMI percentile as children and adolescents.31 The adverse effects of adolescent overweight on cardiovascular risk factors have been evaluated in the Bogalusa Heart Study.33,34 Adverse levels of lipids, fasting insulin, and blood pressure were more common in adolescents with a BMI >95th percentile compared with those with a BMI <85th percentile.34 Clustering of ≥2 adverse risk factors occurred in 50% of the high-BMI group. Follow-up investigations revealed that elevated BMI and adverse risk factor clustering persisted from adolescence into young adulthood. Furthermore, increased BMI was associated with asymptomatic atherosclerosis in the aorta and coronary arteries.35

Nearly 30% of adolescents with BMI >95th percentile are estimated to have metabolic syndrome according to the National Cholesterol Program compared with ~7% with a BMI between the 85th and <95th percentile. In adolescents with a BMI <85th percentile, the rate is only 0.1%.36 There are no definitive guidelines for assessing clinically significant changes in weight status and related comorbidities in adolescents and no long-term outcome studies that demonstrate the positive effects of weight reduction in this population.37 Substantial evidence from the treatment of overweight and obese adults corroborates that moderate weight loss (≥5% to 10%) is associated with improvements in obesity-related comorbidities, delay of onset of type 2 diabetes, and reduced mortality because of obesity.38–40 It is reasonable, therefore, to propose that the positive effects of weight loss in obese adults are applicable to weight loss in overweight adolescents. Thus, the observed effects of sibutramine treatment on surrogate markers for the development of cardiovascular disease, type 2 diabetes, and increased mortality because of obesity in obese adolescents should be considered clinically significant.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Overweight poses a major health problem for the pediatric population with limited treatment options. First-line therapy for overweight adolescents should be the same as that for overweight and obese adults, that is, a calorie-controlled diet, increased physical activity, and behavior modification. Pharmacotherapy should be used as adjunctive therapy only to lifestyle modification. In a pediatric population where the individuals are still actively growing, even small losses in BMI or, in fact, maintenance of BMI are important outcomes that will impact related comorbidities.

This study has demonstrated that sibutramine treatment effectively promotes weight loss in obese adolescents with concomitant improvements in blood pressure and heart rate. Sibutramine treatment seems to have minimal cardiovascular effects and to be well tolerated in this population.


   ACKNOWLEDGMENTS
 
The study was supported by Abbott Laboratories.

The work of the staff in the participating centers and the assistance of all of the study subjects are gratefully acknowledged.


   FOOTNOTES
 
Accepted Dec 12, 2006.

Address correspondence to Stephen R. Daniels, MD, PhD, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital, 1056 E 19th Ave, Denver, CO 80218. E-mail: daniels.stephen{at}tchden.org

Financial Disclosure: Dr Daniels has received research grants and honoraria from Abbott Laboratories. Dr Long received a research grant and expenses to present a poster from Abbott Laboratories. Ms Walch is a clinical project manager, Ms Jaskinsky is an associate director of clinical research, Ms Cwik is a senior clinical research associate, Ms Hewkin is a clinical statistician, and Dr Blakesley is a medical director at Abbott Laboratories.

This trial has been registered at www.ClinicalTrials.gov (identifier: NCT00261911).


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord. 1998;22 :39 –47[CrossRef][ISI][Medline]
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  3. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Circulation. 2006;113 :898 –918[Abstract/Free Full Text]
  4. National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. NIH publication 98–4083. Bethesda, MD: National Heart, Lung, and Blood Institute; 1998
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