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Treatment of Obese Adolescents with Sibutramine: A Randomized, Double-Blind, Controlled Study

Division of Nutrology and Metabolism, State Institute of Diabetes and Endocrinology, Catholic University of Rio de Janeiro (A.G.-M., L.C., A.V., J.O., E.P.G., L.M., C.R.), and Obesity and Eating Disorders Group, Institute of Psychiatry, Federal University of Rio de Janeiro/State Institute of Diabetes and Endocrinology, Catholic University of Rio de Janeiro (R.O.M., W.C., J.C.A.), 22271-090, Rio de Janeiro, Brazil

Address all correspondence and requests for reprints to: Dr. Amélio Godoy-Matos, Nutrology and Metabolism Department, Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione, Rua Visconde Silva, 52/704 Botafogo, 22271-090, Rio de Janeiro, Brazil. E-mail: godoymatos{at}openlink.com.br.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Adolescent obesity is becoming a health problem in both developed and developing countries. Antiobesity drug therapy is not currently indicated for the treatment of adolescent obesity and remains investigational at this time. The aim of this study was to determine the efficacy and safety of sibutramine in obese adolescents. A randomized, double-blind, placebo-controlled trial, enrolling 60 adolescents, aged 14–17 yr, for 6 months was conducted. In the first month, all patients received placebo and a hypocaloric diet plus exercise orientation. For the next 6 months, participants received either sibutramine or placebo. Patients assigned to sibutramine group lost an average of 10.3 ± 6.6 kg, and patients in placebo group lost 2.4 ± 2.5 kg (P < 0.001). The mean body mass index reduction was significantly greater in the sibutramine group (3.6 ± 2.5 kg/m²) than in the placebo group (0.9 ± 0.9 kg/m²; P < 0.001). No participant withdrew because of adverse events, and no difference in blood pressure or heart rate was noted between groups. There were no changes in echocardiographic parameters. In conclusion, sibutramine plus diet and exercise induced significantly more weight loss in obese adolescents.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ADOLESCENT OBESITY IS increasing in both developed and developing countries. Overweight prevalence in United States, defined as a body mass index (BMI) in the 95th percentile or higher for age and sex, increased from 5% to 11% between 1980 and 1994, reaching 15.5% in 2000 (1, 2). Brazil is an example of a developing country where obesity has become a serious health problem in the adult and adolescent/child populations (3). During the period from 1974/1975 through 1996/1997 in Brazil, the prevalence of overweight (defined by International Obesity Task Force standards) in children and adolescents increased from 4.1% to 13.9% (4).

Health implications for this epidemic cannot be neglected (5, 6, 7, 8, 9). The prevalence of the metabolic syndrome in the entire age group of 12- to 19-yr-olds included in the NHANES III population is 4.2% and increases to approximately 29% in those with a BMI above 95th percentile (7). Type 2 diabetes (DM2) and impaired glucose tolerance, typically adult metabolic diseases related to obesity, are becoming increasingly prevalent among children and adolescents (8, 9).

Behavior therapy is the preferred treatment approach in obese adolescents and children, but it has not been shown to produce clinically significant weight loss (10, 11). Although drug therapy for obesity in this young population is a frequent topic at congresses and symposia, there are very few published data (12). Berkowitz et al. (12) conducted a 6-month, double-blind, placebo-controlled study with sibutramine plus a structured behavior therapy (BT) program in obese adolescents. The double-blind period was followed by an open-label extension when all their patients received sibutramine. They concluded that the addition of sibutramine to BT induced significantly more weight loss than placebo and BT. They also suggested that more data would be necessary about the safety and efficacy of drug therapy in children and adolescents before conclusions can be made about its indication in this population.

Antiobesity drug therapy for adults is now widely accepted, although few medications are currently approved (see Refs.13 and 14 for reviews). Sibutramine has been shown to be an efficacious and safe antiobesity agent in adults (15, 16). Our clinical experience with sibutramine therapy in obese adults encouraged us to proceed with a randomized controlled trial in obese adolescents. The aim of this study was to determine whether sibutramine plus diet and exercise is safe, tolerable, and efficacious in a regular clinical setting.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study design

A single-blind, 4-wk, placebo run-in period was followed by a 6-month, randomized, double-blind, placebo-controlled period. This study was approved by the ethical committee of the Institute of Diabetes and Endocrinology of Rio de Janeiro and was conducted from January 2002 to April 2003 at the Department of Nutrology and Metabolism. All patients and one of their parents signed a written informed consent before recruitment.

Patient population

Candidates were boys and girls, aged 14–17 yr, with a BMI of 30–45 (BMI calculated as weight in kilograms divided by the square of height in meters). To avoid growth variation, all participants were required to have adult bone age, as determined by left hand radiography (Greulich-Pyle method).

Contraindications to enter the study included diabetes mellitus, endocrine diseases predisposing to obesity (e.g. Cushing syndrome), severe hyperlipidemia (total cholesterol >300 mg/dl or triglycerides >500 mg/dl), systemic or major psychiatric disorders, history of bulimia or anorexia, uncontrolled hypertension (diastolic blood pressure >110 mm Hg) or other cardiovascular diseases, weight loss of 3 kg or more within 2 months or use of weight loss or weight gain drugs within 3 months before recruitment, drug or alcohol abuse, recent tobacco cessation or intention to quit during study period, and pregnancy or lactation.

Interventions

All patients received dietary counseling to achieve an energy deficit of 500 kcal/d at the start of the run-in phase. No additional visits to the dietitian were allowed. The recommended diet composition was approximately 30% from fat, 20% from protein, and 50% from carbohydrates. Because this study was designed to reproduce a regular clinical setting practice, we did not use structured behavioral counseling. Physical activity instructions were delivered by the attendant doctor in a brief written protocol aimed to obtain mainly aerobic moderate exercises for at least 30 min/d.

Medication protocol

During the single-blind run-in period, all participants received a placebo capsule. Subjects who completed the run-in period and returned less than 25% of the prescribed capsules were randomized to receive sibutramine (10 mg/d) or matching placebo capsules without regard to weight loss during the run-in period. Subjects were instructed to take their capsule in the morning. Knoll Pharmaceutical, subsequently Abbott Laboratories (Chicago, IL), provided and manufactured both placebo and sibutramine capsules. Visits were scheduled for every 4 wk; subjects were attended by the same doctor throughout the study whenever possible.

Dependent measures

During the initiation visit (visit 1, wk –4) a complete clinical examination was performed. Weight and height were assessed, and BMI was calculated. Waist circumference was measured at the minimal circumference between iliac crest and last rib edge. Hip circumference was assessed at the greatest circumference through the major trochanters. Blood pressure and heart rate were assessed with the patient seated after 5 min of rest. The same procedures were used at each subsequent visit. A complete clinical examination was also performed during the last visit (visit 8, wk 24).

Routine blood tests were performed at visits 1, 2 (baseline, wk 0), 5 (wk 12), and 8 (wk 24). After a 12-h overnight fast, venous blood was sampled for measurement of lipids, serum glucose, and insulin. Plasma glucose was measured by a glucose oxidase method. Plasma total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides were assessed with standard enzymatic spectrophotometric techniques, and insulin was determined by RIA. Plasma low-density lipoprotein (LDL) cholesterol was calculated with the equation of Friedewald. Serum human chorionic gonadotropin-ß was measured by RIA in females at randomization (wk 0) and at the end of study (wk 24). A urinary human chorionic gonadotropin-ß test was performed at each visit after randomization to assess possible pregnancy. An electrocardiogram was obtained at visit 1 (wk –4).

A baseline echocardiogram was performed at visits 2 (wk 0) and 8 (wk 24) by an examiner who was blinded to group assignment. Exams were performed using a phased array, commercially available, ultrasound system (Acuson Sequoia 6.0 Siemens Medical Systems, Mountain View, CA) equipped with a 3.5-MHz phased array harmonic transducer. Cardiac dimensions and septal and posterior wall thicknesses were measured in accordance with the American Society of Echocardiography recommendations. At least five consecutive beats were recorded from the parasternal window to obtain left ventricle (LV) internal diameters and wall thickness, just below the anterior mitral leaflet from the short axis view. M-mode echocardiography was used to measure cardiac dimensions (left atrium diameter, diastolic LV diameter [LVDd], and systolic LV diameter [LVDs]) and septal and posterior wall thicknesses during diastole (SWD and PWD). LV ejection fraction (LVEF) was calculated as (LVDd³ – LVDs³) /LVDd³. Left ventricular mass (LVM) was calculated using the following formula: LVM (g) = 0.8 x 1.04 [(LVDd + SWD + PWD)³ – (LVDd)³] + 0.6, and was indexed for body surface area. LV diastolic function was evaluated by means of well standardized diagnostic criteria of mitral flow, pulmonary venous flow, and spectral tissue Doppler at the mitral annulus. Valvular morphology was assessed by bidimensional analysis, and the presence of valvular regurgitation was quantified using combined Doppler and color Doppler parameters and was graded as trace, mild, moderate, or severe.

Adverse events were assessed and recorded at each visit. Treatment compliance was assessed by counting prescribed vs. returned capsules. Those who returned more than 40% of the prescribed capsules (i.e. compliance <60%) were withdrawn from the study.

Data analysis

Baseline characteristics between groups were compared using a two-tailed, unpaired t test. The primary efficacy measures were the change in weight (kilograms) and BMI (kilograms per meter squared). Secondary efficacy measures were the change in waist, hip, and waist to hip ratio. First, an intent to treat analysis was used with the last observation carried forward as the end point. We analyzed the mean absolute change in weight, BMI, waist, hip, and waist to hip ratio from baseline (wk 0) to wk 24 and the percent change in BMI and weight from baseline (wk 0) to wk 4, 8, 12, 16, 20, and 24 using repeated measures ANOVA. In addition, a linear mixed model analysis was performed for weight and BMI using SAS PROC MIXED (SAS Institute, Cary, NC). This procedure is also considered an intent to treat analysis, including dropouts at all time points. A categorical analysis was performed to determine the proportion of subjects who lost 5% or more, 10% or more, or 15% or more of initial weight (wk 0) to wk 24 using Fischer’s exact test.

Laboratory variables were analyzed in those with completed data at baseline (visit 2, wk 0) and at wk 12 and 24 using ANOVA for comparison between sibutramine and placebo, and analysis of covariance for comparison between baseline and wk 24.

Echocardiography data were analyzed using SIAC software produced by Locus Medical Software (Rio de Janeiro, Brazil). Adverse events and secondary parameters were compared by ² or Fisher’s test. All statistical tests assumed a two-tail analysis with a significance level of 0.05.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study population

Sixty-eight patients were included in the run-in period. Eight subjects were not randomized. Five were lost during the run-in phase. One patient had a concomitant medical condition (i.e. repeated episodes of hypoglycemia) and was discontinued. Two patients returned for the baseline visit, but were not randomized because they refused to continue in the study. Therefore, no patient was withdrawn due to nonadherence.

Table 1 shows the baseline characteristics of the 60 obese adolescents who completed the run-in period and were randomized to sibutramine or placebo. There were 10 subjects who withdrew during the study, eight in placebo group and two in sibutramine group. The reasons for withdrawal in the placebo group were nonadherence to the protocol or loss of follow-up (6), consent withdrawal (1), and pregnancy (1). In the sibutramine group, one adolescent was discontinued because of a new job and another because a BMI of less than 25 kg/m² was attained. No participant in either group withdrew because of an adverse event. Additionally, Table 1 shows that during the run-in period (from wk –4 to wk 0), patients later assigned to sibutramine or placebo lost the same amount of weight.

Compared with wk 0, participants in the sibutramine group lost 10.3 ± 6.6 kg, and those in the placebo group lost 2.4 ± 2.5 kg (P < 0.001; Table 2). The mean BMI reduction was also significantly greater in the sibutramine group (3.6 ± 2.5 kg/m²) than in the placebo group (0.9 ± 0.9 kg/m²; P < 0.001). A statistically significant difference favoring sibutramine was also observed in mean waist and hip circumference. Differences in waist to hip ratio were not significant (Table 2). An additional approach using ANOVA demonstrated the superiority of sibutramine over placebo in efficacy measures. The mean difference in the percent change in BMI (Fig. 1) and weight (Fig. 2) from baseline to end point was statistically significant starting at wk 4 and remained so throughout the rest of the study (P < 0.05 in all weeks).

View larger version (22K): [in this window] [in a new window]   FIG. 1. Mean percent change in initial BMI for adolescents treated with sibutramine or placebo. *, P < 0.05 between groups at each point (by ANOVA).

View larger version (24K): [in this window] [in a new window]   FIG. 2. Mean percent change in body weight for adolescents treated with sibutramine or placebo. *, P < 0.05 between groups at each point (by ANOVA).

The percentage of patients later assigned to each treatment group who lost at least 5, 10, and 15% of initial body weight is shown in Table 3. More than five times as many adolescents assigned to the sibutramine group (n = 14; 46.6%) reduced their initial body weight by at least 10% compared with the placebo group (P < 0.001). Approximately 25% of adolescents assigned to the sibutramine group (n = 7) reduced their initial weight by at least 15% compared with 0% in the placebo group (P < 0 0.001; Table 3).

Table 4 shows that no statistical difference was observed between groups in cardiovascular parameters. It is also important to note that systolic and diastolic pressures as well as heart rate tended to decrease more in the placebo than in the sibutramine group.

Biochemical parameters

We analyzed seven biochemical variables, as shown in Table 5. No differences were found when the groups were compared at the different time points (baseline, wk 12, and wk 24). However, there was a significant decrease in tri-glycerides and very low density lipoprotein cholesterol levels at wk 24 in the sibutramine group compared with the baseline values. Also, the relation between total cholesterol/HDL cholesterol was calculated, and a trend toward significance was found between wk 24 and baseline in the sibutramine group (P = 0.07). There was no difference in any parameter in the placebo group.

Events that occurred in greater than 10% of the patients are shown in Table 6. The difference between groups was statistically significant only for constipation, which occurred in 40% of sibutramine-treated subjects and 13% of placebo-treated subjects (P = 0.039). No patient withdrew due to adverse events. No significant event (e.g. a serious adverse event or a rare event) was reported during the study.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Sibutramine is an efficacious drug in adults (15, 16). A dose-related study of sibutramine in adults conducted by Bray et al. (15) showed a mean 4.7% or 5.7-kg absolute weight loss from baseline to wk 24 in the sibutramine (10 mg) group. Thus, the present study suggests that obese adolescents may be even more responsive to sibutramine than obese adults.

This is, to the best of our knowledge, the second published study of sibutramine in the treatment of adolescent obesity. Berkowitz et al. (12) recently published an elegant study on the efficacy of sibutramine in combination with a well structured behavioral therapy program in obese adolescents. The researchers demonstrated a mean weight reduction of 7.8 kg in the sibutramine/behavioral therapy group compared with 3.2 kg in the placebo/behavioral therapy group after 6 months. Compared with Berkowitz’s study, our patients receiving sibutramine lost more weight (3 kg), and a greater proportion of them lost at least 5% of the initial body weight (10%). It is important to mention that our results were achieved even without any kind of behavioral intervention. Because the demographic characteristics of our patients at baseline do not seem to be different from those of Berkowitz’s group, differences in ethnicity may have influenced our results. Other possible reasons are: first, an "obesogenic" environment has been claimed to be responsible for the obesity epidemic worldwide. Therefore, cultural influences (e.g. food habits, physical activities, etc.) from developed and developing countries may vary and may have interfered with both studies. Second, differences in data analysis should also be considered. Berkowitz et al. (12) used a baseline carried forward analysis in contrast to the last observation forward analysis used in our study.

Sibutramine was well tolerated in adolescents. Constipation was the only adverse event that was significantly increased in the sibutramine treatment compared with placebo. No subject withdrew as a result of side effects. In contrast to Berkowitz et al. (12), we did not observe a clinically significant increase in blood pressure or heart rate. Differences observed between the two studies in these measures may be attributed to some characteristics of our study: a lower sibutramine dose, a greater reduction in BMI and body weight, and a smaller sample size. A recent meta-analysis of adult sibutramine trials demonstrated that the effect size on increases in mean systolic and diastolic blood pressures was significantly higher when initial body weight was 92 kg or more and age was less than 44 yr (17). However, in accordance with Berkowitz et al. (12), more controlled studies are needed in children and adolescents before we can conclude that sibutramine can be safely used in this obese age group.

Concerns about heart valves and other cardiac abnormalities had been raised with antiobesity drugs (18, 19). Therefore, we performed echocardiographic examination to evaluate sibutramine safety. This is, to the best of our knowledge, the first study to include echocardiographic assessment in obese adolescents treated with sibutramine. Our results demonstrated no modifications of individual or group variables. Regurgitation observed in a few patients at baseline and after treatment was judged physiological. More important, no morphological changes in valves were observed. Thus, it seems reasonable to conclude that in contrast to old appetite-suppressant drugs, short-term treatment with sibutramine does not seem to be associated with morphological valvular abnormalities.

Impaired glucose tolerance and silent DM2 in obese children and adolescents are highly prevalent (9). Moreover, an extremely high prevalence of metabolic syndrome was found recently in overweight Latino youth, raising concerns about future cardiovascular risk in this population (20). In this group, insulin resistance appeared to be crucial and independently correlated to an adverse lipid profile, blood pressure, and abdominal obesity (20). Considering this perspective, our results are quite interesting. Indeed, sibutramine showed additional positive effects in some important metabolic parameters. Although we did not find any significant differences favoring sibutramine in most biochemical parameters at different time points, the use of sibutramine was associated with a significant decrease in triglycerides and very low-density lipoprotein levels. Furthermore, HDL cholesterol increased nearly 15% in the sibutramine group. This might have contributed to a trend in reducing the total cholesterol/HDL cholesterol ratio (P = 0.07). Overall, the changes observed in lipid profile may have an important role in preventing development of the metabolic syndrome and future cardiovascular disease.

Weight loss has been demonstrated to prevent progression to DM2 (21, 22) in adults and may be extrapolated to high-risk obese adolescents. Vanhala et al. (23) found that the odds ratio for developing metabolic syndrome as an adult was higher among those who were obese since childhood compared with those who became obese as adults. These results raised the possibility that metabolic syndrome can be prevented if we succeed in treating obesity earlier in life. Accordingly, the primary prevention of atherosclerotic disease should begin in childhood (24).

In conclusion, sibutramine seems to be an efficient drug to treat obese adolescents. Conclusions regarding treatment group differences are somewhat limited by the small sample size and the fairly good weight reductions in the placebo group. Nevertheless, the better results seen in body weight and metabolic biochemical profile in the sibutramine group would suggest a positive effect in prevention of later metabolic and atherosclerotic complications. Although our results demonstrate that sibutramine seems to be safe in obese adolescents, larger placebo-controlled, randomized trials are necessary to confirm our data.

	Acknowledgments

 
We thank Dr. Monica Alcantara from Proecho-Rio de Janeiro for echocardiographic study.

	Footnotes

 
This work was supported by a grant from Abbott Laboratories.

First Published Online December 21, 2004

Abbreviations: BMI, Body mass index; BT, behavior therapy; DM2, type 2 diabetes mellitus; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LV, left ventricle; LVDd, diastolic left ventricle diameter; LVDs, systolic left ventricle diameter; LVEF, left ventricle ejection fraction; LVM, left ventricular mass.

Received March 2, 2004.

Accepted December 14, 2004.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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