Introduction

Pediatric obesity is not only a concern in our country but also a global trend [1-3]. This trend was exacerbated by lifestyle changes resulting from social isolation during the coronavirus disease 2019 pandemic [4,5]. Pediatric obesity can lead to adult obesity and trigger various complications such as pediatric type 2 diabetes, hypertension, hyperlipidemia, fatty liver disease, sleep apnea, and polycystic ovary syndrome (PCOS) [6-10]. Therefore, the prevention and treatment of pediatric obesity are essential.

In pediatric and adolescent age groups, obesity treatment has traditionally focused on lifestyle modifications, including dietary adjustments, exercise, and behavioral changes [11]. While some children and adolescents have successfully overcome obesity through these measures, many continue to struggle with obesity-related complications for various social, economic, and personal reasons. Consequently, ample research has been conducted on the use of anti-obesity medications (AOMs) in the pediatric population. Although AOM use has been somewhat cautious, the American Academy of Pediatrics guidelines released in 2023 recommend the active consideration of AOMs and surgical interventions as adjuncts to intensive health behavior and lifestyle treatment (IHBLT) for cases of severe obesity [12]. Even in South Korea, where severe childhood obesity was relatively uncommon a decade ago, there has been a noticeable increase in the number of children who are severely obese presenting with related complications [13]. Although dietary therapy, exercise, and behavioral interventions have been effective in many studies, it is essential to consider additional treatments for children who require further assistance. In this manuscript, we describe medications relevant to pediatric obesity, including metformin, orlistat, glucagon-like peptide 1 (GLP-1) agonists, phentermine, and phentermine/topiramate combination therapies.

Anti-obesity medication for pediatric and adolescent obesity: indications and decision to continue or discontinue

Pediatric and adolescent obesity is a significant public health concern that requires effective treatment strategies. The primary therapeutic approach involves lifestyle modifications that emphasize the correction of habits and behaviors. IHBLT is a foundational approach for reducing body mass or attenuating excess weight gain in children. This involves visits of sufficient frequency and intensity to facilitate sustained healthy eating and physical activity habits [14].

However, when lifestyle interventions alone do not yield successful outcomes, consideration of AOMs becomes relevant. Indications for AOM treatment in pediatric and adolescent obesity include individuals aged 10 years and above with a body mass index (BMI) at or above the 95th percentile, accompanied by weight-related comorbidities, or those with a BMI exceeding 120% of the 95th percentile without responding to lifestyle modifications [11,15]. Continuation of the medication is recommended if there is a ≥5% BMI reduction from baseline at 12 weeks on the optimal dose or if arrest or significant slowdown in weight gain is a reasonable clinical outcome, especially as linear growth occurs in adolescence [15]. Discontinuation of AOM is recommended if <5% weight loss/BMI reduction from baseline is achieved within 12 weeks at the maximum appropriate dose [11,16,17]. The medication should also be discontinued if it is not tolerated by the patient or if dangerous side effects occur or persist despite dose titration.

Considerations before choosing anti-obesity medication for treatment of obesity in children

A comprehensive review of the patient’s medical background, including prior and current medication use and obesity-associated comorbidities, is pivotal to ascertaining the optimal selection of AOMs. Medications can cause unintended weight gain, the extent of which may not be fully recognized by healthcare providers [18,19]. In such cases, providers should consider substituting weight-neutral medications or incorporating additional medications to offset the weight-promoting effects (Table 1 [20-22]) [19]. Specifically, factors related to satiety, satiation, emotional triggers of food intake, and reduced energy expenditure serve as essential guidelines for tailoring AOM selection to address the most prevalent symptomatology [23]. The questions used to assist in determining obesity phenotypes are listed in Table 2 [18]. In a recent study, four main obesity phenotype domains were identified based on dominant symptoms and screening tools: hungry brain (abnormal satiation), emotional hunger (hedonic eating), hungry gut (abnormal satiety), and slow burn (decreased metabolic rate) [23]. The recommended AOMs are phentermine/topiramate extended-release for hungry brain, oral naltrexone/bupropion sustained-release (not approved by the U.S. Food and Drug Administration [FDA] for use in pediatric cases) for emotional hunger, liraglutide for hungry gut, and phentermine plus increased resistance training for slow burn. After 12 months of treatment, the mean weight loss was –15.9% in the phenotype-guided group compared with –9.0% in the non-phenotype-guided group [23]. Screening tools should also be used before selecting AOM aids to identify personalized treatment approaches and achieve optimal outcomes.

Anti-obesity medications for pediatric and adolescent obesity

1. Metformin

Metformin, an insulin sensitizer, is primarily used as a therapeutic agent for type 2 diabetes in children and adolescents aged 10 years and above. Off-label indications for metformin include prediabetes, PCOS, and weight gain due to atypical antipsychotic medications [24]. In addition, metformin may be considered in cases of severe insulin resistance resulting from obesity. However, its use in obesity treatment is restricted because it falls outside the approval range set by regulatory authorities owing to ongoing debates and uncertainties surrounding its effectiveness.

Metformin is a biguanide that inhibits hepatic glucose production, reduces intestinal glucose absorption, and enhances insulin sensitivity to lower blood glucose levels. Although there have been reports suggesting that metformin reduces appetite, it has not been approved as an anti-obesity drug. A meta-analysis conducted in 2017 among pediatric and adolescent populations demonstrated a modest weight loss associated with metformin. Specifically, patients taking metformin showed lowered BMI z-scores (mean difference in change from baseline, –0.10; 95% confidence interval [CI], –0.17 to –0.03) and reduced overall BMI (mean difference in change from baseline, –0.86; 95% CI, –1.44 to –0.29) than controls [25]. In a randomized controlled trial involving children and adolescents who were severely obese (mean BMI, 34.6 kg/m²) aged 6 to 12 years, metformin (1,000 mg twice daily) combined with lifestyle modification therapy resulted in an approximately 1 kg/m² reduction in BMI over 6 months [26]. Despite these findings, the effects of metformin on weight loss remain limited, and metformin is not classified as a primary anti-obesity treatment. Common side effects include abdominal bloating, nausea, vomiting, and diarrhea. Severe adverse effects such as lactic acidosis, which are common in the adult population, are rare in pediatric and adolescent populations [24].

2. Orlistat

Orlistat, a gastrointestinal lipase inhibitor, is approved for use as an AOM in individuals aged 12 years and older. By inhibiting pancreatic and gastric lipases, orlistat reduces fat absorption by approximately 30%. Studies have indicated that orlistat-treated groups experienced a decrease in BMI compared with that of placebo groups. Notably, a multicenter randomized controlled trial involving 539 adolescents aged 12 to 16 years with a BMI at or above the 95th percentile demonstrated a BMI reduction of 0.55 kg/m² in the orlistat group over 54 weeks, while the placebo group showed an increase of 0.31 kg/m² [27]. In a meta-analysis of 779 adolescents aged 12 to 17 years (baseline BMI, 37.4 kg/m²) conducted in 2017, the change in BMI was –0.94 (95% CI, –1.58 to –0.30) for the orlistat group and –0.50 (95% CI, –7.62 to 6.62) for the placebo group. Absolute weight changes ranged from +1 lb to –12 lb [25].

The most common side effects of orlistat are gastrointestinal and include steatorrhea, fecal urgency, and flatulence [27]. Side effects may lead to early treatment discontinuation [27,28]. The recommended dose is 120 mg, up to three times daily. Since orlistat impairs the absorption of fat-soluble vitamins (A, D, and E), vitamin supplementation may be necessary.

3. Glucagon-like peptide 1 receptor agonists

GLP-1 receptor agonists (GLP-1 RAs) are a class of medications that mimic the effects of GLP-1, an incretin hormone involved in glucose regulation. These agents enhance glucose-dependent insulin secretion, slow gastric emptying, and reduce postprandial glucagon levels. GLP-1 RAs do not typically cause hypoglycemia unless combined with other therapies that do.

In pediatric and adolescent obesity, long-acting GLP-1 RAs, such as liraglutide, are approved for use in combination with lifestyle modification therapies. Eligible patients are aged 12 years or older, with an initial BMI exceeding 30 kg/m² (adult equivalent) or body weight exceeding 60 kg [29]. Regular assessments of treatment responses are necessary after initiating treatment. If a minimum of 4% reduction in BMI or BMI z-score is not achieved after 12 weeks of treatment, discontinuation and reevaluation are recommended.

Clinical trials involving exenatide, another GLP-1 RA, have demonstrated significant weight loss after 3 months of treatment in adolescents who were severely obese [30,31]. A 6-month randomized controlled trial using exenatide in youths who were severely obese showed improvements in BMI, blood glucose, and cholesterol levels [32]. A recent study confirmed the effectiveness of liraglutide in children and adolescents who were obese and not responsive to lifestyle therapy [33]. Over 54 weeks, patients treated with liraglutide exhibited a weight difference of approximately 4.5 kg compared to placebo, with a BMI reduction of approximately 5% and a standardized BMI reduction of approximately 0.22. The recommended starting dose of liraglutide is 0.6 mg subcutaneously once daily, which is gradually titrated up to a maximum of 3.0 mg daily. Common side effects include nausea and vomiting, and caution is advised in patients with a family history of multiple endocrine neoplasia as they may be at increased risk of medullary thyroid cancer [33].

Recently, once-weekly semaglutide has been approved by the FDA for the treatment of obesity in individuals over 12 years of age [34]. Semaglutide is a new GLP-1 RA that is structurally similar to liraglutide, with a longer half-life of 165 hours [35,36]. A 68-week randomized, placebo-controlled trial using a once-weekly, 2.4-mg dose of subcutaneous semaglutide in adolescents (12–17 years of age) who were obese or overweight and had at least one weight-related coexisting condition showed a mean BMI reduction from baseline of 16.1% (placebo, 0.6% BMI change; estimated difference, –16.7%; 95% CI, –20.3 to –13.2; p<0.001) [34]. The recommended starting dose of semaglutide for obesity is 0.25 mg once weekly for 4 weeks, followed by up-titration every 4 weeks to 0.5, 1.0, 1.7, and 2.4 mg once weekly. Adverse reactions among adolescents were consistent with those observed in adults and with those of the GLP-1 RA drug class in general [37]. Gastrointestinal events were the most common adverse events reported [34].

4. Phentermine

Phentermine, a central nervous system agent, inhibits the reuptake of norepinephrine, serotonin, and dopamine, thereby extending their durations of action and reducing appetite. Introduced as an anti-obesity drug in 1959, phentermine is approved by the FDA and Korean Ministry of Food and Drug Safety for short-term treatment (within 12 weeks) in conjunction with lifestyle modification therapy for individuals aged 16 years and older. A retrospective chart review of adolescents with obesity treated with phentermine plus lifestyle modification therapy indicated that phentermine use was associated with a greater percent change in BMI at 1 month (–1.6%; 95% CI, –2.6% to –0.6%; p=0.001), 3 months (–2.9%; 95% CI, –4.5% to –1.4%; p<0.001), and 6 months (–4.1%; 95% CI, –7.1% to –1.0%; p=0.009) than lifestyle modification alone [38]. The recommended doses are 7.5, 15, 30, and 37.5 mg, which can be adjusted based on the treatment response. If satisfactory weight loss (a reduction of at least 1.8 kg or an amount agreed upon by both the doctor and patient) is achieved within 4 weeks, the treatment can be continued. Common side effects include increased blood pressure, dizziness, headache, trembling, dry mouth, and abdominal pain, which are dose-dependent but do not directly correlate with increased dosage [38].

5. Phentermine/topiramate combination

One combination drug therapy uses phentermine to suppress appetite and extended-release topiramate as an antiepileptic agent with appetite-modulating effects. Approved for weight control in adults, this combination medication was tested in a randomized controlled trial in adolescents aged 12 to 17 years who were obese and failed to achieve weight control through lifestyle modifications. After 56 weeks of treatment, the group taking 15-mg phentermine/92-mg topiramate exhibited a BMI reduction of approximately 7.1%, while the group taking 7.5-mg phentermine/46-mg topiramate showed a BMI reduction of approximately 4.8%. In contrast, the placebo group experienced a BMI increase of approximately 3.3%. Treatment also led to improvements in high-density lipoprotein cholesterol and triglyceride levels [39]. In a recent study, phentermine/topiramate was reported to be the most cost-effective AOM among the four currently approved for pediatric use [40]. Common adverse effects include depression, dizziness, and joint pain. Additionally, caution is advised because of the potential risks associated with an increased heart rate, suicidal impulses, suicide attempts, and growth impairment. In South Korea, this medication is only prescribed for individuals aged 18 years and older and necessitates careful consideration.

6. Others

Naltrexone/bupropion is a combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. Naltrexone/bupropion achieved FDA approval for the treatment of adults with a BMI ≥30 kg/m² or ≥27 kg/m² in the presence of at least one weight-related comorbidity. Nevertheless, the safety and efficacy of naltrexone/bupropion in individuals aged <18 years have not been established; thus, the use of this medication is not recommended for pediatric patients [41]. Setmelanotide is a melanocortin-4 receptor agonist indicated for chronic weight management in adult and pediatric patients 6 years of age and older with proopiomelanocortin (POMC), leptin receptor (LEPR), or proprotein convertase subtilisin/kexin type 1 deficiency, as well as patients with Bardet-Biedl syndrome [42]. Setmelanotide suppresses appetite and increases resting energy expenditure in both obese animals and humans with obesity [43,44]. Single-arm, open-label, multicenter, phase 3 trials with participants aged 6 years or older with obesity due to POMC or LEPR deficiency received open-label setmelanotide for 12 weeks. Participants who had a weight loss of ≥5 kg then entered an 8-week placebo-controlled withdrawal sequence followed by 32 additional weeks of open-label treatment [45]. Eight participants (80%) in the POMC trial and five participants (45%) in the LEPR trial achieved at least 10% weight loss at approximately 1 year [45]. The most common adverse reactions to setmelanotide included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection [45]. The FDA recently approved tirzepatide for chronic weight management in adults with obesity. Tirzepatide activates the receptors of hormones secreted from the intestine (GLP-1) and glucose-dependent insulinotropic polypeptides to reduce appetite and food intake [46]. A clinical trial investigating the use of tirzepatide in pediatric participants with obesity is currently in progress (LY3298176).

Limitations of drug therapy for pediatric and adolescent obesity

Research has been conducted on the efficacy and side effects of anti-obesity drugs available to children and adolescents, but no study has examined their long-term use. In addition, there is a dearth of research on the effects of these drugs on overall growth, including puberty and height. Because of the limited information and experience with AOMs, caution is necessary when using them. Furthermore, challenges include insurance coverage difficulties, potential side effects, unrealistic expectations regarding efficacy, and related financial burden [47]. Before initiating treatment, a thorough discussion with both the adolescent and his/her guardians regarding these aspects is crucial.

Conclusion

AOMs may be considered for the treatment of pediatric and adolescent patients who are obese and have not achieved successful outcomes with lifestyle modification therapy alone. Currently, the FDA-approved anti-obesity drugs for this population include orlistat, liraglutide, phentermine, and a combination of topiramate and phentermine. These medications are suitable for individuals aged ≥12 years who are obese. In South Korea, the domestically approved anti-obesity drugs for pediatric and adolescent use are orlistat and liraglutide (Table 3).

Prior to initiating pharmacological treatments for obesity, it is essential to prioritize comprehensive lifestyle modification therapies. If weight continues to increase or metabolic complications related to obesity persist despite lifestyle modifications, the concurrent use of AOMs can be considered. It is advisable to reserve medications for adolescents who are severely obese and have completed their growth and pubertal development. Additionally, a thorough assessment of pubertal development and growth should accompany AOM use.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

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