Pharmacotherapy for childhood obesity

August 2005

As obesity in the pediatric population increases, discussion of prevention and treatment strategies also increases.

A definition of overweight and obesity in the pediatric population (2 to 19 years of age) includes a body mass index (BMI) of more than 85% for age and more than 95% for age, respectively. Using this definition, recent epidemiologic data show that at least 15% of the U.S. pediatric population is overweight. Dietary and lifestyle strategies (eg, exercise) are essential components of a treatment regimen for obesity. Several agents are available for the pharmacotherapy of obesity, and although most data from their use come from studies involving adults, several trials evaluating adolescents have been published.

Anorectic agents

Most medications approved for use in treating obesity are classified as anorectic agents (appetite suppressants). These drugs suppress caloric intake and, pharmacologically, they have noradrenergic, serotonergic or dopaminergic actions, by inhibiting neuronal uptake of anorexigenic neurotransmitters – norepinephrine, serotonin or dopamine. The anorectic agents include benzphetamine (Didrex, Pfizer), diethylpropion, phendimetrazine, phentermine and sibutramine (Meridia, Abbott). All of the medications are classified as controlled substances, as their use entails an increased risk of abuse. Only sibutramine is labeled for use in the pediatric population (16 and older). With the exception of sibutramine, these drugs are labeled for short-term use only (ie, up to 12 weeks). Weight loss in adult studies of these medications typically ranges from four to 22 pounds. Phentermine may be recognizable by its past association as a combination of fenfluramine (Phen-fen). Phentermine use alone, however, has not been considered a risk factor for valvular heart disease.

Of the above agents, only sibutramine has been evaluated for use in adolescents. Two controlled trials of sibutramine use in adolescents (13 to 17) have been published, although sibutramine is labeled for use only at ages 16 and above. Amelio Godoy-Matox, MD, and colleagues evaluated sibutramine (10 mg daily) in 60 obese Brazilian adolescents in a double-blind, randomized, placebo-controlled manner for six months. Enrollment criteria for this study included a BMI of 30 to 45 kg/m², without concomitant diabetes mellitus or severe hyperlipidemia.

All patients were initially counseled to maintain a hypocaloric diet and a moderate exercise program. Behavioral counseling was not used, and data on dietary and exercise program maintenance throughout the study were not given. At study conclusion, adolescents receiving sibutramine lost an average 10.3 kg, as compared with a 2.4 kg weight loss in adolescents receiving placebo (P <.05). BMI was reduced by 3.6 kg/m² in patients receiving sibutramine as compared with a 0.9 kg/m² reduction in patients receiving placebo (P <.05). Other than a higher incidence of constipation in patients receiving sibutramine, there were no differences in adverse effects among the treatment groups, including changes in heart rate, blood pressure or echocardiographic alterations. This study is limited by a small number of enrolled subjects and limited data on dietary and exercise therapy.

Robert I. Berkowitz, MD, and his colleagues evaluated sibutramine and placebo in 82 obese (32 to 44 kg/m²) adolescents (13 to 17) in a randomized, double-blind manner. This trial incorporated an intensive family-based behavioral weight control program for all patients and monitored dietary and activity logs. Sibutramine and placebo were administered for six months, with an additional six-month open-label extension for everyone enrolled. Adolescents enrolled could not have a concomitant diagnosis of cardiovascular disease or diabetes mellitus. Sibutramine was titrated up to 15 mg daily, if tolerated. After six months of treatment, subjects receiving sibutramine lost a mean of 7.8 kg (8.5% reduction in BMI) as compared with a 3.2 kg weight loss (4% reduction in BMI) in adolescents receiving placebo (P <.05). BMI was reduced by 10% to 15% in more than twice as many adolescents receiving sibutramine as compared with placebo. In the six-month open label extension, patients initially receiving sibutramine gained 0.8 kg (0.2% reduction in BMI) as compared with an additional 1.3 kg weight loss (2.4% reduction in BMI) in adolescents who had initially received placebo. Adolescents receiving sibutramine also reported significantly greater reductions in hunger. No changes among the groups were noted in blood lipids, triglycerides or insulin resistance. Sibutramine doses were reduced or discontinued in 19 of the 43 patients during the first six months because of increases in blood pressure or heart rate. Mean increases in blood pressure and heart rate in these 19 patients were 8.6 mm Hg and 14.3 beats per minute, respectively.

Reducing nutrient absorption

Orlistat (Xenical, Roche) is a pancreatic lipase inhibitor and functions to inhibit the absorption of dietary fats. Orlistat binds to gastrointestinal lipases and prevents hydrolysis of triglycerides into absorbable free fatty acids. It is labeled for use in children and adolescents 12 and older. Published data documenting the efficacy and safety of orlistat in the pediatric population are limited. A published open-label three-month trial of 20 obese adolescents found orlistat to effectively reduce weight and BMI (4.4 kg and 1.9 kg/m²) when combined with dietary, exercise and behavioral control programs. Beneficial changes were also noted in total cholesterol and insulin sensitivity. Gastrointestinal adverse effects were relatively common – increased defecation, fatty or oily stools, oily spotting on clothes and increased flatus. Package labeling for orlistat includes additional data from a 54-week double-blind, placebo-controlled study of 539 obese adolescents. Subjects receiving orlistat had an average reduction in BMI of 0.55 kg/m². Orlistat may reduce gastrointestinal absorption of fat-soluble vitamins, and the manufacturer recommends that a multivitamin containing vitamins A, D, E, K and beta carotene also be administered (separated by two hours from orlistat).

Role of pharmacotherapy

Data from the above studies indicate that sibutramine and orlistat may provide moderate beneficial effects to obese adolescents. However, these data are limited to short-term evaluations. While supportive data for longer-term use (up to two years) exist for adults, it is unknown if adolescents would similarly benefit. In one study described above, weight loss from sibutramine appeared to plateau after six months of therapy. Because obesity can be a chronic condition, the long-term effects of drug therapy are important to assess. As a comparison, it has been shown that intensive, family-based behavioral treatment programs have demonstrated beneficial effects upon children’s weight for up to 10 years. Which children should receive sibutramine or orlistat? Recently published recommendations and commentaries by experts suggest not to routinely employ pharmacotherapy in the pediatric population, and to limit these medications for now to adolescents enrolled in controlled studies, until additional data from larger trials become available. Clinicians contemplating prescribing these medications should consider their potential for significant adverse effects and, if possible, a referral to a subspecialist for further evaluation.

For more information:

• Berkowitz RI, Wadden TA, Tershakovec AM, et al. Behavior therapy and sibutramine for the treatment of adolescent obesity. JAMA. 2003;289(14):1805-1812.
• Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year follow-up of behavioral, family-based treatment for obese children. JAMA. 1990;264(19):2519-2551.
• Godoy-Matos A. Treatment of obese adolescents with sibutramine: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. 2005;90(3):1460-1465.
• McDuffie JR, Calis KA, Uwaifo GI, et al. Three-month tolerability of orlistat in adolescents with obesity-related comorbid conditions. Obes Res. 2002;10(7):642-650.
• Speiser PW, Rudolf MC, Anhalt H, et al. Consensus statement: childhood obesity. Journal Clin Endocrin and Metab. 2005;90(3):1871-1887.
• Yanovski JA, Yanovski SZ. Treatment of pediatric and adolescent obesity. JAMA. 2003;289(14):1851-1853.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.