#92020: Pediatric Obesity

In the dominant EBM, energy imbalance resulting in obesity is caused by overeating and insufficient exercise; we gain weight because we eat more calories than we burn [8]. If the uptake in calorie-dense food is greater than the energy expenditure, it is expected that the accumulation of fat will increase in direct proportion to this imbalance [42].

The EBM paradigm of the obesity epidemic has become conventional wisdom, but different lines of evidence challenge its validity, and EBM cannot explain or address the following.

Between 1999–2000 and 2017–2018 as adult obesity increased 28% and severe obesity increased 92%, caloric intake decreased, activity energy expenditure increased, and adults showed clear evidence of dietary improvement with increased healthy fats and plant sources of protein, and decreased sugar intake [8,43].

Between 1988 and 2006, despite weekly physical activity increasing 47% in men and 120% in women, BMI was up to 2.3 kg/m² higher in 2006 than in 1988 for an equivalent amount of energy intake or physical activity; in other words, BMI increased even when holding carbohydrate and fat intake and physical activity constant [44].

Between 1987 and 2017, changes in energy expenditure were examined in 4,800 adults. Activity energy expenditure includes exercise and non-exercise activity. Resting energy expenditure, or basal metabolic rate, is the minimum to maintain vital physiological functions. Total energy expenditure (in calories/day) is the sum of activity energy expenditure and resting energy expenditure [45,46]. During 1987–2017, total energy expenditure significantly declined, confirming its role in obesity epidemic. However, activity energy expenditure significantly increased. Declining basal metabolic rate, not reduced physical activity, accounted for lower total energy expenditure [47].

Additionally, numerous mammalian species (in the wild, near human populations, pets) have also exhibited increasing obesity over the past decades, including animals in research colonies where food intake is highly controlled, suggesting that something has changed within the environment in which humans and animals reside [42].

Furthermore, unless the average infant consumes more calories and exercises less than previous generations, EBM does not explain how prenatal factors and the in utero environment influence childhood obesity [8,42].

The obesity epidemic lacks clear explanation. Increased caloric intake and decreased activity do not adequately explain rising BMI and obesity and are unsupported by national data since 2000 [44,47]. The entrenched belief that overeating and inactivity already explain the epidemic perpetuates the inadequate attention and investment in understanding its root causes [8].

Instead, unrecognized factors seem to be modifying how energy intake and expenditure influence body weight over time through misleading signals about energy status, generated by the energy regulatory system, which alter normal energy metabolism and shift energy balance to promote adiposity, independent of overeating and sedentary lifestyle [42,44,47,48].

This accumulating evidence, and the limitations of EMB, have recently led to two related paradigms.

Obesogens alter energy metabolism by disrupting signaling pathways that regulate energy intake and expenditure, nutrient handling, and adipose biology. Obesogens can be naturally occurring (e.g., heavy metals, viruses), anthropogenic (e.g., plastics, household chemicals, personal care products, insecticides, prescription drugs), or food components (e.g., non-nutritive sweeteners, fructose, trans-fats, preservatives), any of which can increase adiposity via endocrine or nonendocrine mechanisms. Exposures can occur via food, air, water, and placental transmission [49].

As endocrine-disrupting chemicals, obesogens fundamentally contribute to the obesity epidemic by shifting energy balance to promote adipose accumulation and metabolic disease. This evidence led to the obesogen hypothesis, which states [50]:

In the pathogenesis of obesity, individual response to development-specific exposures is influenced by genetic predisposition. Cumulative environmental exposures in utero and throughout childhood can interact in programming disease expression, and frequently co-occur to result in additive, antagonistic, or potentiating effects. The burden of exposure is not uniformly distributed; some racial, ethnic, and low-income populations, who are more likely to live in poorly resourced communities, are highly burdened [40].

The development of childhood obesity is a complex multi-factorial process, with numerous interconnected pathways and clustering of risk factors that shift energy homeostasis to energy imbalance and excess weight gain. The exposome paradigm helps to disentangle how these environmental, biological and behavioral exposures interact at critical developmental windows to increase obesity and metabolic risks [40].

The in utero environment is a critical period for the origins of obesity and cardio-metabolic disease in childhood by increasing sensitivity or susceptibility to gain weight [9].

Birth weight shows a U-shaped association with obesity risk; both low and high birth weights increase risks of obesity and metabolic disease, often associated with early-life high-risk growth trajectories [9]. Pre-natal exposure to maternal obesity, smoking, and hyperglycemia doubles the odds of early post-natal high-risk BMI trajectories [40].

Small for gestational age newborns are typically hyperinsulinemic and insulin resistant at birth, exhibit rapid catch-up growth in infancy, and develop obesity in childhood with persistent insulin resistance and later development of metabolic syndrome [9]. Early rapid weight gain confers a nearly 4-fold greater risk for developing overweight or obesity from childhood to adulthood [40].

Large for gestational age babies are hyperinsulinemic at birth with double the prevalence of insulin resistance and metabolic syndrome. Maternal gestational diabetes and obesity are associated with greater adiposity and obesity in offspring [9].

Some aspect of prematurity alters developmental programming. Premature infants followed into early childhood demonstrate increased weight gain, insulin resistance, and compensatory insulin levels inappropriately high for their weight gain [9].

Prenatal stress may cause epigenetic changes in glucocorticoid receptor coding which alter neonatal stress reactivity. With chronic stress, high glucocorticoid levels may act as a feed-forward system, recruiting a major chronic stress response network that alters the normal output of autonomic, neuroendocrine and behavioral systems toward increased HPA-axis activity and fear-like behavior that increases ingestion of high energy–density food with subsequent increased fat stores and metabolic syndrome [9].

Maternal metabolic factors before and during pregnancy adversely affect offspring growth or adiposity in utero and after birth, increasing risk for cardiometabolic disease into adulthood. Maternal obesity and diabetes are associated with high birth weight and higher BMI during childhood, and excess adipose tissue accumulation [40].

High-risk growth patterns associated with maternal obesity begin in infancy. Women with obesity have a 4-fold increased risk for gestational diabetes, yet maternal gestational diabetes independent of BMI is associated with greater offspring body fat and adverse metabolic health [40].

Mechanisms involved in the developmental programming of offspring growth, adiposity and metabolic health include epigenetic modifications, altered placental function, and maternal and fetal inflammation, which affects appetite regulation, adipose tissue growth, and mitochondrial metabolism [40].

In breast milk analyses, maternal obesity is associated with increased fat content with altered appetite and satiety-regulating hormones, while maternal obesity and diabetes is characterized by chronic systemic low-grade inflammation with increased inflammatory cytokines and altered immunoglobulin concentrations [40].

Early-life synthetic chemical exposures contribute to risk for obesity, diabetes, and hypertension. Bisphenols are synthetic estrogens that reprogram mesenchymal cells away from bone to fat and antagonize adiponectin. Phthalates adversely influence receptors crucial to lipid and carbohydrate metabolism, are oxidative stressors, and have estrogenic and anti-androgenic effects. Multiple, rather than single, chemical exposures are prevalent during pregnancy [40].

Several adverse childhood health outcomes are consistently associated with intrauterine tobacco smoke exposure, including fetal growth retardation and obesity during childhood. Maternal smoking in pregnancy is associated with an elevated odds for childhood obesity. The effects of exposure through secondhand smoke alone are also substantial [40].

Growth dynamics in children with obesity substantially differ from children with normal weight. Children with obesity are often significantly taller in early childhood. Earlier puberty, blunted pubertal growth spurt, altered serum sex hormone profiles, and advanced bone age may explain subsequent normalization in height vs normal-weight children [41].

The Registered Nurses' Association of Ontario recommends assessing the family environment for factors (e.g., parenting/primary caregiver influences and sociocultural factors) that may increase children's risk of obesity.

(https://rnao.ca/sites/rnao-ca/files/Childhood_obesity_FINAL_19.12.2014.pdf Last Accessed: September 30, 2026)

Level of Evidence: IV (Evidence obtained from expert committee reports, opinions, and/or clinical experiences of respected authorities)

Executive functioning deficits and poor self-regulation highly associate with childhood obesity and underlie comorbid ADHD, and some early childhood obesities have features of a broader neurodevelopmental disorder [40,51,52]. Sleep and the circadian rhythm show inconsistent data [40].

Socioeconomic status is another important risk factor for pediatric obesity. In children with a low socioeconomic status, the odds ratio for obesity is more than two-fold higher than in children with higher status [41].

A number of pediatric medications can induce excessive weight gain and metabolic disorders, discussed later under clinical management.

Monogenic obesity involves single-gene defects in the leptin-melanocortin pathway, most commonly MC4R (>5%) and LEPR (3%) (likely underestimates) [41,58]. Most patients with monogenic obesities show rapid post-natal weight gain through the 12 months. LEP or LEPR prevents normal pubertal development due to hypogonadotropic hypogonadism. MC4R patients show less pronounced early weight gain, with severe obesity later in childhood and taller stature. Some clinical features are gene-specific. Cognitive development is usually normal. Motor development may seem delayed, but excess BMI at least partly explains this effect [41].

Unlike the more common monogenic obesities, syndromic obesities are rare pleiotropic syndromes that typically present with dysmorphic features and specific congenital alterations, neurodevelopmental disorders, and/or additional multisystem disease-specific phenotypes. Bardet-Biedl syndrome is the only genetic obesity diagnosed by clinical presentation [7,38,58].

The energy regulation system is centered in the hypothalamus. The ARC receives input signals from peripheral tissue (adipose tissue, liver, gut, pancreas) of satiety (anorexigenic) or hunger (orexigenic) which activate anorexigenic POMC neurons, or orexigenic neuropeptide Y and agouti-related peptide (NPY/AgRP) neurons, in the ARC. In response, the ARC directs pertinent brain areas to adjust food intake and energy expenditure, controlling energy and bodyweight through food-seeking behavior, gastric emptying, gut nutrient uptake, pancreatic release of insulin, and insulin effects in adipose tissue, liver, and skeletal muscle [5,59].

Circulating hormones (e.g., leptin, insulin, ghrelin, glucagon-like peptide 1 [GLP-1]), bind their receptors on POMC and NPY/AgRP neurons in the ARC [7]. To communicate short-term energy needs, the gut releases hormones in anticipation of food intake (ghrelin), in response to nutrient ingestion (GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and cholecystokinin [CCK]), or during nutrient deprivation (glucagon) [60].

The incretin hormones GLP-1 and GIP stimulate insulin secretion to regulate glucose homeostasis. GLP-1 also acts centrally to reduce appetite by activating satiety pathways, and in the stomach to delay gastric emptying [7]. Ghrelin, the only orexigenic gut hormone, signals the need for increased food intake [60].

After food intake, adipocytes release leptin, and pancreatic β-cells release insulin in response to elevated blood glucose. Both activate POMC to signal satiation and promote energy expenditure, important for resistance against diet-induced obesity, and both suppress orexigenic NPY/AgRP signaling [9,59].

Ghrelin and leptin have opposing actions aimed at increasing or decreasing adiposity. Caloric deficit increases ghrelin and reduces leptin levels, which reverse post-prandially and high leptin suppresses ghrelin release. Ghrelin activates NPY neurons to inhibit POMC signaling and increase food intake. Ghrelin and GLP-1 have opposite actions on eating behaviors and food reward, which ghrelin reinforces and GLP-1 attenuates [9].

Disruption of these regulatory circuits decreases satiety response and energy expenditure, increases appetite- and hunger-promoting processes, promoting excess weight gain and obesity [6,57,60].

As obesity develops, exposure to high insulin levels silences POMC neuron response to leptin. Hyperinsulinemia and CNS insulin resistance block leptin receptor signaling and promote leptin resistance, which increases food intake [9]. Other disruptions in the leptin-melanocortin network diminish satiety response and reduce energy expenditure, increasing appetite- and hunger-promoting processes and excessive adiposity [6,57,60].

Hypertension prevalence is more than 10% in school children with obesity, compared with 0.8% to 3.2% among normal-weight peers; severe obesity confers a four-fold greater risk of hypertension [14]. Hypertension is strongly associated with high BMI and is also linked to hyperinsulinemia [88].

Combined dyslipidemia, the dominant hyperlipidemic pattern in childhood, describes moderate to severe elevations in triglyceride and non-high-density lipoprotein cholesterol (non-HDL-C), with reduced HDL-C. In youth, combined dyslipidemia occurs almost exclusively with obesity and is seen in more than 50% of children with obesity and 30% to 60% of obese adolescents. The prevalence of combined dyslipidemia increases as obesity severity increases; its strong association with visceral adiposity, insulin resistance, NAFLD, and metabolic syndrome suggests an underlying, integrated pathophysiologic response to excessive fat mass [82,89].

The prevalence of youth-onset type 2 diabetes has increased dramatically since 2000 (tripling in adolescents), a result of the significant increase in pediatric obesity and severe obesity [15]. Among 8,942 children with type 2 diabetes, 77% had obesity at type 2 diabetes diagnosis. Obesity was twice as likely in boys than in girls, highest in White Americans (89%), and lowest in Asians (64%), who are known to develop type 2 diabetes at lower BMI levels. Type 2 diabetes rates are higher in African American and Hispanic than in White children, but rates of obesity with type 2 diabetes are similar [90].

Hyperinsulinemia and glucose dysregulation are key features of pediatric obesity. Type 2 diabetes is preceded by a progressive decline in β-cell function and an increase in insulin resistance. When the insulin release can no longer compensate for the insulin resistance, type 2 diabetes occurs [81].

Type 2 diabetes is a significant comorbidity of childhood obesity and an aggressive disease in children. The ≥20% decline in β-cell function per annum, nearly double the rate in adult type 2 diabetes, can progress, sometimes rapidly, to diabetic complications of NAFLD, dyslipidemia, PMOS, and nephropathy [90]. Pediatric type 2 diabetes is also highly treatment-resistant; the odds of disease progression despite intervention are more than 50% [15].

Metabolic syndrome, an adverse metabolic phenotype with hypertension, dyslipidemia, insulin resistance, and obesity, is directly linked to target organ damage, cardiovascular disease (CVD), and all-cause mortality in adults. Metabolic syndrome is increasingly common in children with obesity, with the same core elements as in adults [91]. The pathogenesis involves interactions between obesity, insulin resistance, and inflammation, along with hyperinsulinemia and oxidative stress [14,88].

Childhood obesity is associated with several markers of subclinical atherosclerosis and changes in cardiac function [89]. Children with obesity show altered hemodynamics, including subclinical left ventricular diastolic dysfunction in all obesity classes and disturbed systolic functions in early stages of obesity. Successful treatment of obesity in childhood could reduce the adult incidence of CVD and mortality [14].

Pediatric liver disease, a severe and increasingly common complication of childhood obesity, is a spectrum of fatty liver or NAFLD (steatosis >5% without hepatocellular injury), steatohepatitis or non-alcoholic steatohepatitis (NASH) (>5% steatosis plus hepatocyte inflammation with cell injury and death), cirrhosis, and hepatocellular carcinoma [19].

In childhood obesity, insulin resistance promotes, and is exacerbated by, hepatic fat accumulation [19]. Hyperinsulinemia significantly contributes to steatosis [88]. NAFLD is now the leading pediatric chronic liver disease, with a prevalence of 7.4% overall and up to 52.5% in children with obesity [92].

In 237 children (mean age: 4 years) with severe obesity, 35% had elevated alanine aminotransferase (ALT) (>30 U/L) consistent with NAFLD, which may precede other obesity-related morbidities [211]. In 408 children (age 9 to 17 years) with obesity, NAFLD was more common in boys (33%) than girls (25%) [93].

Among children with NASH, 83% have a BMI ≥97th percentile. Nearly 25% of children with NAFLD have NASH, and 7% to 10% may develop cirrhosis and end-stage liver disease [14,94]. The disease course in childhood is more severe than in adults, and pediatric NAFLD imposes a long-term cardiometabolic burden with increased morbidity and mortality in early adulthood [92]. Hepatocellular carcinoma and cardiovascular complications are life-threatening comorbidities of both NAFLD and NASH [95].

The nomenclature of fatty liver disease was revised in 2024. Metabolic dysfunction-associated steatotic liver disease (MASLD) replaced NAFLD; metabolic dysfunction-associated steatohepatitis (MASH) replaced NASH [96]. With the recency of this change, the older terminology is almost exclusively used in obesity-related research. The use of these acronyms in the remainder of this course will mirror their use in the referenced literature.

Childhood obesity is an increasing risk factor for CKD, a cardiometabolic comorbidity that develops from interactions between insulin resistance, obesity, and renal hemodynamics, leading to impaired kidney function and CKD [97]. Severe obesity, type 2 diabetes, and hypertension elevate the risk of CKD [89].

Polyendocrine metabolic ovarian syndrome (PMOS), previously referred to as polycystic ovary syndrome (PCOS), is a complex endocrine-metabolic syndrome characterized by ovarian dysfunction and reproductive abnormalities associated with dysregulation of multiple endocrine and metabolic pathways, including androgen excess and insulin resistance, resulting in reproductive, metabolic, and potentially long-term cardiometabolic consequences. Adolescent females with obesity are at increased risk of PMOS [19,92].

The pathophysiology of PMOS is strongly tied to insulin resistance and overlaps with obesity and NAFLD. Hyperinsulinemia increases ovarian androgen production and decreases sex hormone-binding globulin thus increasing androgen bioavailability and impairs ovarian follicle development [88]. Obesity exacerbates hyperinsulinemia, inflammation, and adipokine dysregulation typical of PMOS and NAFLD; abnormal glucose metabolism is frequent in all three [92].

The free androgen index, which reflects free androgen levels, can biochemically assess hyperandrogenism in PMOS. In patients with PMOS, every 10% weight loss associated with 18% decrease in free androgen index; variation in body weight explained 90% of variation in free androgen index, showing a linear association between weight loss and improved free androgen index [98].

Obstructive sleep apnea is deeply intertwined with obesity and hypertension. Obesity is the primary driver of adolescent obstructive sleep apnea and hypertension. Obstructive sleep apnea impairs sleep, thus increasing food consumption and weight gain. Increased obstructive sleep apnea severity is also associated with more frequent and severe hypertension [99]. Neurocognitive deficits and excessive daytime sleepiness are common in obese children with obstructive sleep apnea. Obstructive sleep apnea is diagnosed with polysomnography [89]. Obesity hypoventilation syndrome may represent a long-term consequence of obstructive sleep apnea and is associated with a high mortality rate. Aggressive therapy is warranted for obese children with this syndrome [88].

Obese children have a higher prevalence of asthma and asthma exacerbations. This link is mediated through inflammatory and oxidative stress, chest wall restriction with airway narrowing, and obesity-related morbidities such as obstructive sleep apnea and gastroesophageal reflux [88].

Idiopathic intracranial hypertension (IIH) is an uncommon disease of childhood and adolescence characterized by increased intracranial pressure without any identifiable cause. Nearly 50% of children who present with IIH are obese and are more symptomatic at onset. IIH presents with headache and may lead to severe visual impairment or blindness. The potential for visual impairment indicates the need for aggressive treatment of obesity in these patients [88].

Fractures, musculoskeletal discomfort, lower extremity malalignment such as Blount disease, and slipped capital femoral epiphyses are more common in children and adolescents with high BMI. Blount disease is a disorder of the proximal tibial growth plate, which results in progressive bowing of the tibia. Around 65% of Blount disease patients have obesity. Slipped capital femoral epiphysis occurs due to epiphyseal plate disruption and 30% to 50% of these patients have overweight/obesity [88].

A comprehensive evaluation of a child or adolescent with obesity should begin with a detailed medical history, including relevant prenatal, birth, growth, developmental, medical, psychosocial, and medication histories [100,103]. The birth history should assess for maternal diabetes and whether the patient was large or small for gestational age. Growth history is also important, particularly early-onset obesity occurring before 5 years of age with hyperphagia, which may suggest monogenic obesity, and a history of failure to thrive during infancy, which may be associated with Prader-Willi syndrome. The history should also identify previous CNS injury or hypothalamic tumors that may contribute to weight gain or obesity.

The assessment should include screening for depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD), as well as adverse childhood events and food insecurity, all of which may influence eating behaviors, physical activity, weight, and the ability to implement weight-management strategies. Current and previous medications should be reviewed for agents associated with weight gain or the development of obesity, including second-generation antipsychotic agents, corticosteroids, and other obesogenic medications.

The family history should assess for obesity and obesity-related conditions among first- and second-degree relatives [100,103]. Relevant conditions include type 2 diabetes, gestational diabetes, hypertension, fatty liver disease, dyslipidemia, other cardiovascular diseases, and PMOS. The evaluation should also explore a history of familial obesity, including weight-loss strategies previously attempted by family members, bariatric surgery, and associated obesity-related conditions.

The Academy of Nutrition and Dietetics recommends a registered dietitian nutritionist assess the frequency of fastfood intake of overweight or obese children and adolescents. Limited evidence in populations 8 to 16 years of age at baseline suggests that higher frequency of fast-food consumption, particularly more than twice a week, is associated with increased adiposity, body mass index, or risk of obesity during childhood, adolescence, and the transition from adolescence into adulthood.

(https://www.andeal.org/topic.cfm?menu=5296 Last Accessed: September 30, 2026)

Level of Evidence/Strength of Recommendation: Weak/Imperative (The recommendation is considered broadly applicable, but the quality of evidence that exists is suspect or well-done studies show little clear advantage to one approach versus another.)

Assessment of lifestyle factors should include a detailed review of dietary intake and eating behaviors [100,103]. This should address consumption of sugar-sweetened beverages and juice, habitual eating patterns, the locations where meals and snacks are consumed, the types of foods eaten, and typical portion sizes. Sedentary behaviors and physical activities should also be assessed, along with the patient's usual sleep routine. Previous and current strategies for weight loss should be discussed to identify approaches that have been attempted and potential barriers to successful weight management.

The review of systems should evaluate for underlying conditions that may contribute to obesity and for potential obesity-related complications [100,103]. Developmental delays may be associated with genetic syndromes. Neurologic symptoms, including headache and visual disturbances, may suggest pseudotumor cerebri. Respiratory symptoms such as shortness of breath, with or without wheezing, may reflect physical deconditioning or asthma. Snoring, daytime lethargy, and early morning headache may indicate obstructive sleep apnea.

Sleep-related symptoms should be assessed carefully, including snoring, witnessed apnea, nocturnal enuresis, daytime sleepiness, and symptoms of ADHD, as these may be associated with sleep apnea or poor-quality sleep. Gastrointestinal symptoms, particularly abdominal pain, may be related to constipation, gallbladder disease, liver disease, or gastroesophageal reflux disease (GERD). Endocrine symptoms may include irregular menses, which may suggest PMOS; polyuria, polydipsia, and nocturia, which may indicate type 2 diabetes; and signs of hypogonadism, which may be associated with a genetic syndrome. Musculoskeletal symptoms such as hip pain, with or without a limp, should prompt consideration of slipped capital femoral epiphysis. Psychological symptoms and eating behaviors, including binge eating, rapid weight loss or weight cycling, purging, depression, and anxiety, should also be assessed.

The physical examination should evaluate for obesity-related complications and findings that may suggest an underlying cause of obesity (Table 6) [6,100,103]. Blood pressure should be measured and interpreted using standards based on the patient's sex, age, and height. The examination should assess for dysmorphic features that may indicate a genetic syndrome and for papilledema, which may be associated with pseudotumor cerebri. Thyromegaly or goiter may suggest hypothyroidism.

Abdominal examination should assess for hepatomegaly, which may be associated with NAFLD, as well as abdominal pain following rapid weight loss, which may indicate gallstones. Examination of pubertal and reproductive development should include assessment for undescended testes or delayed puberty, which may suggest hypogonadism or an underlying genetic disorder.

The musculoskeletal examination should evaluate for bowed legs, which may be associated with Blount disease, and for a limp, which may indicate slipped capital femoral epiphysis. Skin findings may include acanthosis nigricans, a marker of insulin resistance, and hirsutism, severe acne, or both, which may suggest PMOS. Finally, overall mood and affect should be evaluated. A flat affect, chronic fatigue, and sleep problems may be associated with depression.

Several organizations have established clinical practice guidelines and recommendations related to the use of metabolic and bariatric surgery for the treatment of obesity in pediatric patients (Table 7).

American Academy of Pediatrics (AAP)

In 2023, the AAP published their first clinical practice guideline on the evaluation and treatment of pediatric obesity. Patients 13 years of age or older with severe obesity should be referred to multidisciplinary pediatric bariatric surgery centers for metabolic and bariatric surgery evaluation. However, the AAP also states that age should not be the sole determinant of eligibility for metabolic and bariatric surgery [11].

American Society of Metabolic and Bariatric Surgery (ASMBS)

Metabolic and bariatric surgery should be considered for children and adolescents with obesity and a major co-morbidity, or severe obesity, after evaluation in a multidisciplinary specialty center [113]. Given the lifelong, cumulative impact of untreated obesity, the ASMBS suggests that all children with severe obesity be referred for surgical evaluation, regardless of physiologic maturity as measured by linear growth or tanner stage [12].

International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO)

A survey of international experts in obesity management identified areas of consensus and non-consensus on metabolic and bariatric surgery in pediatric patients [114].

Expert Delphi Consensus

Following the 2023 metabolic and bariatric surgery guideline by ASMBS, an international panel of metabolic and bariatric surgery experts established consensus guidelines for selection of metabolic and bariatric surgery appropriate for Class I and II obesity [115].

Several landmark prospective and long-term studies support the efficacy and relative safety of metabolic and bariatric surgery for adolescents with severe obesity. The major studies, including Teen-LABS, FABS-5+, AMOS, AMOS-2, and the PCORnet Bariatric Study, demonstrate substantial and generally durable weight loss, marked improvement or remission of obesity-related comorbidities, and improvements in weight-related quality of life following Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). These studies have followed patients for up to 10 years or longer and have contributed to recommendations supporting expanded use of metabolic and bariatric surgery in appropriately selected adolescents [116].

In Teen-LABS, 242 adolescents with severe obesity were followed for up to 10 years after RYGB, SG, or laparoscopic adjustable gastric banding (LAGB) [117,118,119]. At three years, mean weight and BMI loss were similar with RYGB (28%) and SG (26%), and 26% of patients were no longer obese. At five years, modest weight regain had occurred, but substantial BMI reduction was maintained [119,120]. Both procedures also resulted in high rates of remission of type 2 diabetes, prediabetes, renal dysfunction, hypertension, and dyslipidemia. Weight-related quality of life improved significantly; however, nutritional deficiencies were common, particularly following RYGB, underscoring the importance of long-term nutritional monitoring and adherence to vitamin and mineral supplementation [119,120].

Long-term Teen-LABS analyses suggest that age alone should not preclude surgery. Adolescents undergoing RYGB or SG at 13 to 15 years of age had weight loss, remission of hypertension and dyslipidemia, nutritional outcomes, and quality-of-life improvements generally comparable to those treated at 16 to 19 years of age. Although type 2 diabetes remission was statistically greater among older adolescents, remission rates were high in both groups [22]. Similarly, compared with adults with juvenile-onset obesity undergoing RYGB, adolescents achieved comparable five-year weight loss but had significantly greater remission of type 2 diabetes and hypertension, suggesting greater potential for reversal of some obesity-related complications when treatment occurs during adolescence [121].

LAGB has demonstrated substantially less favorable long-term outcomes. In the small Teen-LABS cohort followed for up to 10 years, initial BMI reduction was followed by progressive weight regain, with average BMI exceeding baseline by year 10. LAGB had little long-term effect on weight loss, cardiometabolic risk factors, or micronutrient deficiencies, and initial improvements in weight-related quality of life returned to baseline with weight regain [117].

The FABS-5+ study further demonstrated the durability, but also variability, of long-term outcomes after RYGB. Approximately eight years after surgery, mean BMI reduction remained nearly 30%, compared with BMI gain among nonsurgical controls; however, 64% of surgical patients remained severely obese, and weight regain varied substantially [23,24]. Patients who maintained their initial weight loss had substantially better long-term BMI outcomes than those who regained weight. Type 2 diabetes, dyslipidemia, and hypertension declined markedly, but residual obesity remained strongly associated with cardiometabolic risk. Higher baseline BMI predicted higher long-term BMI, suggesting a potential advantage to considering surgery before severe obesity progresses further. The authors noted that earlier intervention during the accumulation of excess weight may permit more complete reversal of severe obesity and cardiometabolic risk [23]. Nutritional abnormalities, including mild anemia, hyperparathyroidism, and low vitamin B12 levels, were also common and support the need for continued long-term follow-up [23,24].

The Swedish AMOS study similarly found that adolescents undergoing RYGB achieved substantial five-year weight loss and significantly greater improvement in cardiometabolic risk factors than those receiving lifestyle modification therapy. RYGB resulted in major reductions in glucose dysregulation, dyslipidemia, hypertension, inflammation, and elevated liver enzymes, while quality of life and physical functioning generally improved. However, nutritional deficiencies remained frequent despite prescribed supplementation, and not all aspects of quality of life improved. Additional procedures, particularly those related to internal herniation and gallstones, also occurred, although subsequent advances in surgical techniques may reduce these risks [13].

AMOS-2 provided rare randomized evidence comparing RYGB with intensive lifestyle modification therapy. At two years, RYGB produced a mean BMI reduction of 29.3%, compared with essentially no sustained BMI reduction with intensive lifestyle therapy, despite the latter being more intensive than standard care [122]. RYGB also resulted in greater improvement in cardiovascular risk factors, uncontrolled eating, binge eating, physical functioning, and general health-related quality of life. Reduced bone mineral density was observed following RYGB, although nutritional markers and gastrointestinal symptoms did not differ between groups, and adverse events were few and generally mild [122].

As SG has become the predominant metabolic and bariatric procedure performed in U.S. adolescents, comparative evidence has become increasingly important. The PCORnet Bariatric Study of 544 adolescents found substantial BMI reductions after both RYGB and SG, whereas LAGB produced considerably less weight loss and showed no evidence of a meaningful long-term role in adolescent obesity treatment [123]. Although differences between RYGB and SG were not statistically significant at three years, RYGB produced somewhat greater BMI reduction and a higher proportion of patients achieving greater than 30% BMI loss. SG maintained substantial weight loss through five years but demonstrated gradual weight regain. SG may have lower risks of some nutritional deficiencies and complications, but its irreversibility and the possibility that RYGB may be more effective for patients with more severe obesity should be considered when selecting a procedure [123].

Single-institution and longer-term studies extend these findings. A Miami clinic study of patients evaluated approximately 14 years after adolescent bariatric surgery found sustained median weight loss of approximately 31%, with major reductions in obesity-related comorbidities. However, anemia was highly prevalent, and poor adherence to recommended supplementation was common, reinforcing the importance of lifelong nutritional surveillance [25].

Long-term SG data from the King Saud University cohort provide evidence in younger children as well as adolescents. Among more than 2,500 pediatric patients with extended follow-up, SG produced durable weight loss, substantial remission of type 2 diabetes, dyslipidemia, and hypertension, and no significant adverse effect on growth trajectory through as long as 10 years of follow-up. Adverse events were uncommon, and no procedure-related mortality was reported [26,124].

Emerging evidence also supports the safety and effectiveness of metabolic and bariatric surgery in selected preteens. Studies of patients younger than 13 years have reported substantial postoperative BMI reduction, improvement in metabolic comorbidities, and low rates of short-term complications when procedures are performed at specialized centers [125,126]. Additional data identify factors associated with increased postoperative risk, including chronic corticosteroid use and a history of GERD, highlighting the importance of individualized preoperative risk assessment [127]. Overall, these findings suggest that chronological age alone may not be an appropriate determinant of surgical eligibility when severe obesity and appropriate medical indications are present.

The European Society of Endocrinology and the Pediatric Endocrine Society suggest that FDA-approved pharmacotherapy for obesity be administered to children and/or adolescents only with a concomitant lifestyle modification program of the highest intensity available and only by clinicians who are experienced in the use of anti-obesity agents and are aware of the potential for adverse reactions.

(https://academic.oup.com/jcem/article/102/3/709/2965084 Last Accessed: September 30, 2026)

Level of Evidence/Strength of Recommendation: 2|⊕○○○ (Suggestion based on very-low-quality evidence)

The history, physical, and laboratory screening lay the groundwork for pharmacotherapy selection based on presenting symptoms and co-occurring diseases. From there, a three-tiered approach is beneficial for clinicians: review of existing pharmacotherapy to identify weight-promoting medications, treatment of comorbid disorders, and initiation of pharmacotherapy [15,16,19,128,129].

Clinicians should review past and present medications for weight-promoting medications, which can be the primary cause of obesity; second-generation antipsychotic drugs require particular attention. Adding a medication to mitigate weight-promoting medication effects may be considered.

Children with obesity frequently present with obesity-related diseases that can be treated using medications that both promote weight loss and address the specific co-occurring disorder. Attention-deficit hyperactivity disorder (ADHD) and binge eating disorder (BED) are prominent examples.

All pediatric obesity phenotypes benefit from an anti-obesity medication trial. Newer glucagon-like peptide-1 receptor agonists (GLP-1RA) are safe and effective. However, given the pathophysiologic complexity of pediatric obesity and variable responses to all obesity therapies, multiple mechanisms of action by combining anti-obesity medications can be needed to improve outcomes, even GLP-1RAs. There are no standard discontinuation rules for pharmacotherapy, but if BMI has not decreased after three to four months on full-dose or if troublesome adverse effects persist, most clinicians switch to an alternative agent.

This approach allows the clinician to fully assess disease status and formulate a comprehensive treatment strategy which may require combinations of anti-obesity medications and weight-mitigating medications [15,16].

Importantly, this area of study is rapidly evolving with new, practice-changing findings. For example, semaglutide (a GLP-1RA) recently demonstrated the least heterogeneity (i.e., greatest uniformity) in treatment response of any pediatric obesity therapy [18,130].

This section will discuss pharmacotherapies, including anti-obesity medications with pediatric and adult approval and medications approved for comorbidities (Table 8), clinically used in children and adolescents with obesity to target the chronic disease of obesity by decreasing adiposity, to improve weight and metabolic health in comorbidities (e.g., metformin in PMOS), to mitigate weight-promoting medication effects (metformin and topiramate), and to simultaneously treat ADHD and/or BED in pediatric obesity (lisdexamfetamine). Monotherapy, combination therapy, and off-label prescribing will be examined.

In the studies, all pediatric participants received lifestyle modification therapy plus active drug, or placebo when randomized to the control arm of a randomized controlled trial. In placebo-controlled trials, placebo-subtracted or -corrected change in BMI or weight refers to the difference in treatment effect between the active drug and placebo [130].

Setmelanotide is approved for chronic weight management in all patients 6 years of age or older with monogenic obesity or syndromic obesity due to POMC, PCSK1, or LEPR deficiency; or Bardet-Biedl syndrome [134].

Setmelanotide can be used for patients with variants in POMC, PCSK1, LEPR, or Bardet-Biedl syndrome genes considered pathogenic, likely pathogenic, or of uncertain significance, but is not indicated in other causes of obesity, polygenic obesity (i.e., common obesity) or benign variants of the gene mutations [16].

Setmelanotide, a melanocortin 4 receptor (MC4R) agonist, stimulates the leptin-melanocortin pathway upstream of the genetic defect that causes disruption in this pathway; the reestablished MC4R activity restores satiety signaling, reducing hyperphagia and decreasing weight [16,134]. Over 52 weeks, setmelanotide led to median weight loss of 26.7% (in POMC or PCSK1) and 9.8% (in LEPR), and BMI loss of 8.8% (in Bardet-Biedl syndrome) [134].

Adverse effects are most commonly skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous erections in men [16].

Hypothalamic obesity may affect melanocortin signaling. Setmelanotide (3 mg) in 18 teens with hypothalamic obesity (mean BMI: 38 kg/m²) decreased BMI 15% after 16 weeks, and by 26% in 12 patients who completed ≥52 weeks of treatment. adverse effects were consistent with other trials. Setmelanotide efficacy in hypothalamic obesity is supported [135].

Setmelanotide is administered by subcutaneous injection once-daily starting at 1 mg (6 to 11 years of age) or 2 mg (12 years of age or older) with a target dose of 3 mg daily [134].

Metreleptin is a recombinant human leptin analog, approved for lipodystrophy in 2014 and used for congenital leptin deficiency. Metreleptin may be used in patients with dysfunctional LEP gene variants, which impair leptin receptor binding. Although effective and safe in multiple pediatric studies, antibodies against metreleptin can develop that reduce efficacy. To ensure tailored treatment for leptin deficiency, it is advised to categorize leptin variants based on molecular and functional characteristics [105].

Metreleptin is administered subcutaneously once-daily, starting at 0.06 mg/kg (in patients ≤40 kg), 2.5-mg in men >40 kg and 5-mg in women >40 kg [136].

A 16-week trial evaluated the effects of liraglutide and naltrexone/bupropion in patients with melanocortin-4 receptor pathway-related genetic obesity and hypothalamic obesity syndrome-related genetic obesity. The study included 29 patients with melanocortin-4 receptor pathway-related genetic obesity (mean age: 23 years; mean BMI: 42 kg/m²) and 81 patients with hypothalamic obesity syndrome-related genetic obesity (mean age: 34 years; mean BMI: 44 kg/m²), with a mean age of obesity onset of 6 years in both groups [131]. Liraglutide produced median weight reductions of 4.7% in patients with melanocortin-4 receptor pathway-related genetic obesity and 5.2% in those with hypothalamic obesity syndrome-related genetic obesity and improved appetite, fat mass, fasting glucose, and HbA1c in both groups. Among patients with hypothalamic obesity syndrome-related genetic obesity, liraglutide also improved eating behaviors and quality-of-life domains. Naltrexone/bupropion produced median weight reductions of 5.2% and 4.4% in the melanocortin-4 receptor pathway-related genetic obesity and hypothalamic obesity syndrome-related genetic obesity groups, respectively, and significantly reduced appetite, fat mass, and waist circumference in both groups. Obesity-related comorbidities also improved in significant proportions of patients treated with either liraglutide or naltrexone/bupropion [131].

Both medications were associated with gastrointestinal adverse effects, including nausea, constipation, diarrhea, and dyspepsia. However, naltrexone/bupropion was associated with higher rates of headache (24% vs 8%), dizziness (19% vs 5%), and discontinuation because of adverse effects (14.6% vs 6%) compared with liraglutide [131]. These findings suggest that patients with a clinical phenotype of genetic obesity, with or without a definitive genetic diagnosis, may benefit from access to a broader range of treatment options when FDA-approved therapies are ineffective, unavailable, or poorly tolerated. The short-term improvements in appetite and weight observed with liraglutide and naltrexone/bupropion are therefore encouraging [131]. In addition, a recent review concluded that semaglutide and retatrutide, which remains in late-stage clinical trials, may have the potential to prevent progression of metabolic abnormalities and improve outcomes in patients with rare and severe forms of obesity [137].

A 52-week randomized controlled trial examined liraglutide (3.0 mg) in 31 adolescents and 24 children with Prader-Willi syndrome and obesity. Neither age group showed significant differences in BMI vs placebo at weeks 16 and 52. Changes in other weight-related parameters were nonsignificant. Liraglutide seems ineffective in Prader-Willi syndrome [138].

GLP-1RAs were first developed and approved for type 2 diabetes treatment with exenatide in 2005, followed by liraglutide (2009), lixisenatide, albiglutide, and dulaglutide (2013–14), semaglutide (2017), and tirzepatide (2022) [139]. Unexpected weight loss in adult type 2 diabetes patients was confirmed in clinical trials, leading to FDA-approvals as long-term obesity treatment for liraglutide and semaglutide (in 12 years of age and older), and tirzepatide (18 years or older, pediatric trials in progress) [140,141].

Endogenous glucagon-like peptide 1 (GLP-1) is an incretin hormone with multifactorial direct and indirect effects on energy and glucose metabolism. GLP-1 promotes insulin secretion from pancreatic β-cells and reduces glucagon secretion from pancreatic β-cells, improving insulin sensitivity and suppressing hepatic glucose production. GLP-1 also inhibits postprandial gastric emptying and duodenal peristalsis, thereby reducing appetite and food intake [142].

GLP-1RAs are mimetics of GLP-1, chemically modified to resist breakdown by dipeptidyl peptidase-4 for longer half-life than endogenous GLP-1. GLP-1RAs primarily act on hypothalamic GLP-1 receptors to reduce appetite, delay gastric emptying, and prolong satiety, and on mid-brain receptors to decrease reward-driven eating behaviors. GLP-1RA's peripheral and CNS actions decrease energy intake and promote weight loss in polygenic obesity and monogenic obesities involving MC4R mutation [142,143].

Second-generation GLP-1RAs have greater weight loss efficacy than liraglutide and a longer half-life permitting weekly instead of daily dosing [144]. Although speculative, the molecular configuration of semaglutide may mediate its substantial anti-obesity effect by facilitating greater brain penetration and interaction with GLP-1R [139,145].

The success of semaglutide sparked the development of new GLP-1RA-based molecular entities that combine GLP-1RA with activity at other incretin receptors, such as glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon [146].

Tirzepatide is a dual GLP-1R and GIP-R agonist. GIP regulates energy balance through cell-surface signaling in adipose and brain tissue. This dual receptor activation synergistically promotes greater weight loss and glycemic control, and in theory decreases side effects [16]. Retatrutide, an anti-obesity medication in phase III trials, goes even further as a triple GLP-1, GIP, and glucagon receptor agonist. In obese adults, retatrutide (12mg) led to an impressive 24.2% average weight loss after 48 weeks [147].

GLP-1RAs are administered subcutaneously once-daily (liraglutide) or once-weekly (semaglutide, tirzepatide) [142]. All GLP-1RA trials randomized patients to lifestyle modification therapy plus active (drug) or inert (placebo) subcutaneous injections.

Liraglutide (3-mg) Efficacy

In 251 teens with obesity (mean age: 14.5 years, mean BMI: 35.5 kg/m²), from baseline to 56 weeks, liraglutide was superior to placebo in BMI change (-4.64% vs 0%), subjects with BMI loss ≥5% (43.3% vs 18.7%) and ≥10% (26% vs 8%). Changes in glycemic and cardiometabolic variables or in weight-related quality of life did not substantially differ between groups [148]. Early response to liraglutide (i.e., weight or BMI reduction ≥4% after 12 weeks) predicted greater weight loss at week 56 compared with early non-responders [149].

These results in adolescents were recently replicated in 82 children 6 to 11 years of age with obesity. From baseline to 56 weeks, liraglutide was superior to placebo in BMI change (-5.8% vs +1.6%, a difference of -7.4%), weight change (+1.6% vs +10%), and BMI decrease ≥5% (46% vs 9%). Liraglutide (vs placebo) led to more frequent GI adverse effects (80% vs 54%) and similar serious adverse effects (12% vs 8%) [150]. These findings that liraglutide was effective and generally tolerated in children with obesity over 56 weeks are important because no anti-obesity medication is currently approved for polygenic obesity in children younger than 12 years of age [150].

In a 2023 meta-analysis, liraglutide modestly reduced mean weight (-2.13 kg) and BMI (-1.56) over placebo, improved fasting plasma glucose, and HbA1c control in type 2 diabetes, did not differ from placebo in fasting serum insulin, lipids, or blood pressure [151].

A "real-world" efficacy study of liraglutide is noteworthy: 10 of 22 patients (mean age: 15 years, mean BMI: 41 kg/m²) stopped liraglutide due to GI adverse effects; those completing the 72-week study showed no statistically significant changes in weight parameters from baseline. High dropout from adverse effects was a significant drawback, suggesting poor tolerability which may impact liraglutide effectiveness in adolescent obesity [152].

Semaglutide (2.4-mg) Efficacy

The landmark STEP Teens trial randomized 201 adolescents 12 to 17 years of age (mean BMI: 37 kg/m²) to semaglutide or placebo for 68 weeks [130]. Semaglutide (vs placebo) led to superior change in BMI (-16.1% vs +0.6%), weight (-16.3% vs +2.6%), and subjects with weight loss ≥10% (62% vs 8%), ≥15% (53% vs 5%), and ≥20% (37% vs 3%). The primary endpoint, BMI change, showed a treatment effect of -16.7%.

Semaglutide (vs placebo) significantly decreased cardiometabolic risk factors of HbA1c (–0.4% vs –0.1%), total C (–8.3% vs –1.3%), LDL-C (–10.2% vs –3.4%), triglyceride (–28.4% vs +2.6%), and ALT (–18.3% vs –4.9%).

Semaglutide (vs placebo) led to greater GI adverse effects (62% vs 42%) and cholelithiasis (4% vs 0%), similar dropout from adverse effects (5% vs 4%) and serious adverse effects (11% vs 9%), and fewer psychiatric adverse effects (7% vs 15%) [130]. Of note, semaglutide was equally or more effective in this trial than shown in adults [16,153].

Also examined was how BMI decrease from baseline to week 68 translated to changes in BMI category (e.g., normal-weight, overweight [BMI <30 kg/m²], and obesity class 1–3) [154]. Semaglutide (vs placebo) was superior in reducing BMI by ≥1 category (74% vs 19%), by ≥2 categories (44.9% vs 3.4%), and below obesity threshold (45% vs 12%). Subjects in obesity class 3 decreased on semaglutide (37.3% to 13.6%) but increased on placebo (19% to 22.4%).

Subjects with BMI decrease ≥2 categories in obesity class 1 (57%), obesity class 2 (51.4%), and obesity class 3 (29.5%), were greater in those with less severe obesity. Those decreasing ≥2 categories (vs <2) showed greater improvement across all evaluated parameters (ALT, LDL-C, triglycerides, waist circumference, blood pressure) except HbA1c.

Semaglutide decreased weight and BMI across the obesity spectrum, regardless of participant factors. Almost half (45%) were no longer obese, which can potentially change the natural history of obesity and its complications [154,155].

Tirzepatide Efficacy

Tirzepatide is approved for obesity in patients 18 years of age and older. In the pivotal SURMOUNT-1 trial, tirzepatide 15-mg led to mean weight loss of 21% and weight loss ≥25% in 36% of subjects [156,157].

Comparative Efficacy

A meta-analysis compared GLP-1RAs in pediatric obesity. Against placebo, semaglutide exhibited significantly greater weight, BMI, and BMI z-score reductions; exenatide showed notable weight loss; dulaglutide was more effective in A1c reduction; and liraglutide led to lower fasting glucose. Semaglutide showed greater weight loss, BMI z-score reduction, and BMI decrease than exenatide; and greater weight loss and BMI z-score reduction than liraglutide and dulaglutide. Semaglutide was first-ranked in reducing weight, BMI, BMI z-score, and waist circumference [145].

Safety

Gastrointestinal adverse effects are class-wide with GLP-1RAs, especially in the initial four to eight weeks of dose escalation. Common adverse effects (30% to 60% of patients) are mild-to-moderate vomiting, nausea, dyspepsia, diarrhea, constipation, and abdominal pain; others include headache and fatigue. These are generally transient, usually resolve within one to two weeks of dose titration or reduction, and mitigated by reducing meal sizes, avoiding fatty meals and high-sugar foods, and avoiding lying down after eating [104,149]. Short-term symptomatic treatments, including ondansetron, polyethylene glycol or other laxatives, and loperamide, can also be considered [96].

GLP-1RAs may vary in tolerability. Liraglutide had greater association with adverse effects and injection-site reactions than other GLP-1RAs in children with obesity [145]. In pivotal randomized controlled trials, dropout due to adverse effects with semaglutide did not separate from placebo but was significantly higher with liraglutide [130,148]. Increased resting heart rate by 6 to 10 beats per minute is a side effect of GLP-1RAs and heart rate should be monitored, particularly in patients with underlying cardiovascular disease [96].

Serious side effects are rare, but like any other pharmacologic intervention, the benefits of GLP-1RAs do not outweigh the risks in a small number of individuals [153]. Based on preclinical studies and some postmarketing case reports, GLP-1RAs are contraindicated in patients with a personal or family history of medullary thyroid carcinoma, and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2) [16,158].

A 2022 meta-analysis found no evidence of increased thyroid disorders, while FDA Adverse Event Reporting System (FAERS) data associated GLP-1RAs with a 10-fold increase in thyroid neoplasm and hyperplasia vs sodium-glucose cotransporter-2 (SGLT-2) inhibitors in adult patients with type 2 diabetes [159]. This retrospective reporting does not establish causality, but the safety signal may be clinically relevant [158]. Other adult type 2 diabetes data associated one to three years of GLP-1RA exposure with increased risk of all thyroid carcinomas (58%) and medullary thyroid cancer (78%) [160]. On the other hand, recent meta-analyses of GLP-1RA use in type 2 diabetes found no evidence of increased risk of digestive system cancers, no evidence of elevated risk of acute pancreatitis or pancreatic cancer in cardiovascular outcomes trials, and no increase in thyroid cancer risk with exenatide over 10 years [96].

Importantly, the side effect profile should be viewed in the broader context of the substantial risk of cardiometabolic complications and premature mortality with pediatric obesity. In this light, GLP-1RA benefits outweigh risks for most patients [153].

Notably, previously unreported side effects will emerge with increasing use. For example, several case reports attributed aspiration during anesthesia in patients taking GLP-1RA for obesity to their effects on gastric emptying [153]. In 20 patients on semaglutide after an eight-hour fast, most showed residual gastric contents on ultrasound evaluation [161]. Withholding GLP-1RAs for three or more half-lives before a procedure is recommended [153].

However, newer evidence suggests GLP-1RA adverse event and aspiration rates do not appear elevated [162]. Thus, a more individualized approach should be considered. As gastric emptying delay from GLP1-RAs diminishes over time, treatment longer than three months may not pose a higher risk of aspiration pneumonia. A strict liquid diet the day before endoscopy may decrease gastric remnants and aspiration risk and may be preferred to GLP-1RA interruption by patients [96].

Larger patient datasets have also alleviated previous safety concerns (e.g., suicidality risk with GLP-1RA treatment of adolescent obesity). Comparing matched adolescent cohorts prescribed GLP-1RAs or lifestyle modification therapy (controls) for obesity, teens prescribed GLP-1RAs had a 33% reduced incidence of suicidal ideation or attempts vs controls (1.45% vs 2.26%) over 12 months of follow-up, suggesting a favorable psychiatric safety profile of GLP-1RAs. Of note, as this study used data from clinical health care, the results reflect community practice rather than highly controlled research trials [163].

Phentermine/topiramate extended release (ER) is an anti-obesity medication approved as Qsymia. These agents remain important off-label considerations. Phentermine was approved in 1959 as short-term (≤12 weeks) obesity treatment in patients older than 16 years of age before obesity was understood as a chronic disease requiring long-term treatment. Phentermine has been among the most widely prescribed anti-obesity medication in adults for decades. Its efficacy, minimal side effects, and low-cost accessibility have also made phentermine the most widely prescribed anti-obesity medication (off-label) in patients 16 years of age or younger or longer than 12 weeks [19,164].

Phentermine, a sympathomimetic norepinephrine re-uptake inhibitor with weak dopaminergic activity, increases hypothalamic norepinephrine which activates POMC and increased satiety; and weakly stimulates DA release in the prefrontal cortex, which improves inhibitory control and decreases food intake [142,164].

Phentermine may cause insomnia, headache, dry mouth, GI complaints, nervousness, and a mild increase in blood pressure; patients should be monitored for blood pressure, heart rate, and side effects every six to eight weeks. No serious adverse effects have been observed in studies that included children and adolescents. Phentermine taken in the morning decreases insomnia risk [19].

While phentermine is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs), with cardiovascular disease, or uncontrolled hypertension, observational studies of phentermine in adults and adolescents have not found adverse changes in blood pressure; 13,972 adults prescribed phentermine showed a slight transient increase in heart rate, and no relationship between duration of phentermine use (up to three years) and risk of cardiovascular events or fatalities [129,142].

Topiramate is FDA-approved for seizure control in patients 2 years of age and older, and migraine prophylaxis in patients 12 years of age and older. Topiramate monotherapy is not approved for weight loss in any age [16].

Topiramate may promote weight loss through appetite suppression and satiety enhancement, and control food cravings, via mechanisms that block neuronal voltage-dependent sodium channels, enhance gamma-aminobutyric acid type A (GABA-A) activity, antagonize glutamate receptors, and/or inhibit carbonic anhydrase [16].

Topiramate can produce dose-related peripheral (paresthesia) and CNS (e.g., difficulty concentrating, memory impairment) adverse effects, dizziness, dry mouth and GI symptoms [128]. Clinicians should monitor patients for suicidal ideation [16].

Topiramate use during pregnancy is linked to a significantly increased risk of birth defects affecting orofacial, cardiac and urogenital development. Topiramate can also render oral contraceptives less effective. The teratogenic potential of topiramate makes pregnancy or high risk for pregnancy a contraindication and requires that females of reproductive age use a reliable form of birth control or refrain from sexual intercourse [128,129].

Other contraindications include hyperthyroidism, glaucoma, and MAOI use [16]. Patients should be weaned off topiramate slowly, because abrupt cessation may precipitate seizures [19,129].

After epilepsy patients unexpectedly showed weight loss during topiramate treatment, its development as an anti-obesity medication began. Although halted by adverse effects, obesity clinicians in private practice observed that phentermine mitigated topiramate adverse effects and synergistically increased weight loss. Clinical trials confirmed the efficacy, with fewer safety concerns, of once-daily, low-dose phentermine and topiramate ER combination [142,165].

Efficacy

In 2022, phentermine/topiramate ER was approved for chronic weight management in adolescents 12 to 17 years of age, based on two randomized controlled trials evaluating fixed-dose 7.5 mg/46 mg (mid-dose) and 15 mg/92 mg (top-dose) phentermine/topiramate tablets in adolescents 12 to 16 years of age with obesity [166,167,168]. In the larger trial, which included 277 adolescents and continued for 56 weeks, both doses produced substantially greater reductions in BMI and body weight than placebo. Mean BMI changed by -7.1% with the top dose and -4.8% with the mid-dose, compared with an increase of 3.3% with placebo; the treatment difference between the top-dose and placebo groups was -10.4%. Mean weight changed by -9.2 kg and -5.5 kg with the top and mid doses, respectively, compared with a gain of 6.6 kg with placebo, representing a top-dose versus placebo difference of -15.8 kg [167].

Clinically meaningful BMI reductions were also more common among patients receiving phentermine/topiramate. A BMI reduction of at least 10% was achieved by 42.5% of adolescents receiving the top dose and 31.5% receiving the mid-dose, compared with no participants receiving placebo. Similarly, BMI reductions of at least 15% were achieved by 28% and 13% of patients receiving the top and mid doses, respectively, compared with 0% of the placebo group. Both treatment doses also reduced waist circumference, with mean changes of -9.3 cm with the top dose and -7.4 cm with the mid-dose, compared with an increase of 0.3 cm with placebo. In addition to these weight-related benefits, both treatment groups experienced significant improvements in triglycerides, which decreased by 21%, and HDL-C, which increased by 10%, compared with placebo [167].

Safety/Contraindications

Incidence of any adverse effect with placebo (51.8%), mid-dose (37%) and top-dose (52.2%) and respective dropout from adverse effects (2%, 2%, 1.8%) were similar. Serious adverse effects were bile-duct stones on top-dose and depression and suicidal ideation on mid-dose. Patients should be monitored for the emergence or worsening of depressed mood [104,167].

This combination anti-obesity medication allows decreased dose of both drugs to reduce adverse effects. Phentermine/topiramate ER dose-dependently increases weight-loss, and adverse effects including dry mouth, constipation, paresthesia, sedation, mood disturbance, and visual disturbance [18].

Contraindications for phentermine/topiramate ER follow those of phentermine and topiramate monotherapies [128]. Patients should avoid alcohol use. Phentermine/topiramate ER has a black-box warning for worsening of depression in patients 18 to 24 years of age [16].

Phentermine/topiramate led to greater BMI decreases than shown in adolescent trials of lifestyle modification therapy, orlistat and liraglutide. The improvements in lipid profile are particularly important; excluding semaglutide, phentermine/topiramate is currently the only anti-obesity medication for adolescents to demonstrate weight loss sufficient for reducing cardiometabolic risk factors [167].

Orlistat inhibits pancreatic and gastric lipase, blocking triglyceride hydrolysis and free fatty acid breakdown which prevents 30% of dietary fat absorption at the recommended 120-mg thrice/daily dose. Orlistat, the only anti-obesity medication without CNS activity, acts locally in the GI tract. Weight loss is usually small (~3%) and diet-dependent [16,169,170].

Orlistat's 2003 approval for patients 12 years of age and older followed a randomized controlled trial in 539 teens, with orlistat (vs placebo) superior in BMI change (-0.55 vs +0.31 kg/m²) and ≥5% BMI reduction (26.5% vs 15.7%) [171]. Weight loss ≥5% by 12-weeks predicted a favorable BMI outcome at 52 weeks and was twice as likely with orlistat [172].

Other trials in adolescents showed varying weight loss effects [142]. In a meta-analysis of pediatric data, orlistat had significant effects on waist circumference and serum insulin, but no effect on weight, BMI, lipid profile, or serum glucose [173].

A study of prescription data in children and adolescents found 45% of patients discontinued orlistat within one month and 90% within six months, suggesting poor tolerability and/or efficacy [174].

Orlistat is rendered uniquely unappealing among available anti-obesity medications by GI side effects of oily rectal leakage, abdominal pain, flatulence with discharge, bowel urgency, fecal incontinence, and steatorrhea [140]. Orlistat is contraindicated with chronic malabsorption, cholestasis, and during pregnancy or breastfeeding [16,149].

Phentermine is not an amphetamine but has a similar chemical structure and is a Schedule IV controlled substance (CS IV) based on theoretical abuse potential, despite no evidence that adults develop phentermine abuse or addiction during long-term monotherapy [128]. Physicians should investigate local and state regulations and laws before prescribing phentermine off-label [79]. Phentermine/topiramate ER, although CS IV, is approved for long-term use in younger adolescents.

Although CS II status prohibits lisdexamfetamine use off-label for weight loss, randomized controlled trials are evaluating its weight loss effects in youth 8 to 13 years of age with ADHD and loss-of-control eating, and 6 to 12 years of age with severe obesity [107].

A range of weight-loss promoting medications can be considered when patients cannot access pediatric anti-obesity medications, have suboptimal response or weight-promoting comorbidities, or require weight-promoting medications (and mitigation).

Phentermine is widely prescribed in youth 16 years of age or younger and/or longer than 12 weeks and is the most affordable of any anti-obesity medication [168]. Phentermine's safety combined with topiramate, naltrexone, bupropion, zonisamide (an antiepileptic agent), and other agents for additive weight loss make it especially versatile in obesity [79].

Topiramate has highly versatile off-label drug use for weight loss across diverse pediatric obesity phenotypes and should also be considered for idiopathic intracranial hypertension or severe non-verbal autism [96].

Bupropion is a norepinephrine-dopamine reuptake inhibitor approved for adult depression and smoking cessation. In adult obesity, bupropion can induce modest weight loss of 5.1% with 400 mg/day after 48 weeks [182]. Its off-label drug use, often combined with phentermine, had been common [79]. Adverse effects include nausea, headache, constipation, insomnia, dry mouth, and dizziness. Uncontrolled hypertension, seizure, and eating disorders are contraindications [168].

Naltrexone/bupropion (Contrave), an adult anti-obesity medication, includes naltrexone, an opioid receptor antagonist approved for alcohol and opioid use disorder. In adults, weight loss over placebo is 4.8% to 6.0%. Naltrexone is contraindicated in pregnancy, severe hepatic dysfunction, and patients taking MAO inhibitors, opioids, and medications for alcohol or opioid use disorder [168].

Lisdexamfetamine is FDA-approved for ADHD in patients 6 years of age and older and for BED in patients 18 years of age and older. This drug hydrolyzes to slowly release the active drug, D-amphetamine, which inhibits reuptake and enhances release of dopamine and norepinephrine [16]. Lisdexamfetamine is well-tolerated with generally manageable side effects of dry mouth, restlessness, insomnia, and GI upset [183]. It is used off label in younger children with obesity and weight-promoting morbidities of ADHD, BED, or impulsive eating. Caution is advised in patients with cardiovascular disease and anxiety [96].

Metformin, exenatide, and dulaglutide, approved for type 2 diabetes in patients 10 years of age or older (18 years of age or older for dulaglutide), have been used off-label to promote weight loss. Metformin decreases hunger by increasing sensitivity to insulin and leptin, is useful in mitigating weight-promoting medication effects, treating PMOS, and might benefit patients with obesity and prediabetes. BMI reduction is similar to orlistat (~3%) [28]. Youth with PMOS should receive 1,000 mg twice-daily, if tolerated, to leverage the appetite-decreasing effect. Dose titration and ER formulations reduce initial GI upset. With long-term use, monitor for vitamin B12 deficiency [16]. Lactic acidosis is a rare but potentially fatal adverse effect; renal dysfunction and metabolic acidosis are contraindications [18]. Counselling on increased fertility on metformin is important. Metformin may mask the onset of type 2 diabetes and make diagnosis challenging [28].

Exenatide and dulaglutide are GLP-1RAs. A small randomized controlled trial of adolescents with severe obesity showed exenatide 10 mcg twice daily reduced BMI 4%; greater weight loss may require higher doses for longer periods. In patients with obesity on dulaglutide (4.5 mg), roughly 50% experienced ≥5% weight loss [16,18].

By combining medications with different mechanism of action, more significant improvements are achievable [16,128]. A child may achieve 8% to 11% BMI percentile reduction with phentermine/topiramate but glycemic dysregulation persists; adding semaglutide can improve glucose metrics and further decrease BMI by 7% to 16% [19].

GLP-1RAs and tirzepatide act on the MC4R pathway, and can increase setmelanotide efficacy in obesity from genetically-impaired MC4R signaling [184]. In two patients (BMI 77 and 41) with Bardet-Biedl syndrome discovered during evaluation for metabolic and bariatric surgery, tirzepatide plus setmelanotide led to 26% weight loss and no adverse effects after 34 to 45 weeks [185]. In 59 patients with Bardet-Biedl syndrome prescribed setmelanotide with or without additional treatments, metabolic and bariatric surgery plus GLP-1RAs or tirzepatide led to more BMI loss than metabolic and bariatric surgery or GLP-1RA/tirzepatide alone. Setmelanotide increased BMI loss in all three conditions [184].

A randomized controlled trial evaluated phentermine plus canagliflozin (a SGLT-2 inhibitor approved for type 2 diabetes) in 335 obese adults without type 2 diabetes. After 26 weeks, mean weight loss with placebo (1.1%), canagliflozin 300 mg (2.6%), phentermine 15 mg (4.6%), and canagliflozin plus phentermine (8.1%) demonstrated synergistic effects that continued through week 26 without plateau, and greater improvements in blood pressure and heart rate, with phentermine/canagliflozin combination [186].

Phentermine plus topiramate remains a cost-effective alternative to approved anti-obesity medications. Out-of-pocket costs of this agent rise with escalating dosage. Given the per-month cost of phentermine 15 mg ($15), topiramate ($40), and phentermine/topiramate ER (up to $300), many clinicians choose to prescribe both agents separately [128].

Of note, topiramate for three or more months in 32 children with obesity and MASLD significantly improved mean ALT (76 U/L vs 50 U/L), which normalized or decreased >50% in 43% of patients, and was well-tolerated [187]. Phentermine plus topiramate can be selected in patients with MASLD and strong hunger with frequent snacking, poor satiation, binge eating, or migraine headaches [96].

Psychological treatment should begin with a comprehensive assessment of factors that may affect eating, physical activity, sleep, weight-related behaviors, and the family's ability to participate in treatment. Relevant areas include depression, anxiety, ADHD, adverse childhood experiences, trauma, food insecurity, family stress and conflict, weight stigma, bullying, body image concerns, and social isolation. Clinicians should also assess for maladaptive eating patterns and eating disorders, including binge eating, loss-of-control eating, purging, severe dietary restriction, and recurrent weight cycling. These conditions may require specific mental health treatment and should be addressed concurrently with obesity treatment rather than delaying or separating treatment unnecessarily.

Assessment should also consider the developmental stage of the child or adolescent. For younger children, intervention is directed primarily toward parents and caregivers, who control much of the home food environment, routines, opportunities for physical activity, and behavioral reinforcement. As children mature, treatment should increasingly incorporate the patient's autonomy, preferences, motivation, self-image, and capacity for independent behavior change. Adolescents should be active participants in establishing treatment goals and selecting behavioral targets [11].

Treatment goals should be individualized and collaborative. Although improvement in BMI or attenuation of excessive weight gain may be appropriate outcomes, psychological treatment should also emphasize broader goals, such as improved eating patterns, physical activity, sleep, emotional well-being, self-esteem, social functioning, and obesity-related comorbidities. Focusing exclusively on a number on the scale may undermine engagement and can obscure meaningful improvements in health and quality of life. The AAP recommends collaborative goals that are not limited to BMI reduction and that address the individual needs and circumstances of the child and family [11].

Family involvement is central to effective psychological and behavioral treatment of pediatric obesity. As noted, children generally have limited control over food purchasing, meal preparation, household routines, transportation, and opportunities for physical activity. Parents and caregivers therefore play an essential role in creating a home environment that supports healthy behaviors. Effective interventions engage the family rather than identifying the child as the sole target of treatment or assigning blame to parents or caregivers.

Family-based treatment may address parenting skills, role modeling, monitoring, consistent limit-setting, positive reinforcement, problem-solving, and modification of the home environment. Families can work together to establish regular meals, improve the availability of nutritious foods, reduce reliance on sugar-sweetened beverages, limit eating in response to environmental cues or screen use, and develop regular opportunities for enjoyable physical activity. Parents and caregivers should be encouraged to model the behaviors they are asking their children to adopt. Behavioral health specialists can support this process by addressing parenting practices, family conflict, and the use of consistent reinforcement strategies [11].

Treatment should avoid approaches that shame the child or family or characterize obesity as evidence of poor parenting or a lack of willpower. Families may face substantial barriers, including financial limitations, food insecurity, limited access to safe activity spaces, competing medical or family responsibilities, and other social drivers of health. These factors should be identified and incorporated into treatment planning. A psychologically informed approach recognizes these barriers and helps families develop realistic strategies within their particular circumstances [11].

Behavioral interventions focus on identifying modifiable patterns and helping children and families develop sustainable alternatives. Treatment may include self-monitoring, stimulus control, goal setting, problem-solving, positive reinforcement, and relapse-prevention strategies. Rather than attempting to change all behaviors simultaneously, clinicians can help families select specific, achievable targets and evaluate progress over time.

Common targets may include establishing more regular meal and snack patterns, reducing sugar-sweetened beverages, modifying portion sizes, decreasing eating in response to boredom or emotional distress, increasing family meals, improving sleep routines, reducing sedentary behaviors, and increasing participation in enjoyable physical activities. Interventions should be tailored to the child's developmental abilities, learning style, family culture, and available resources. Programs for younger children may emphasize parental skills and modification of the home environment, whereas interventions for adolescents should increasingly address autonomy, preferences, self-management, and self-image [11].

Positive reinforcement is generally preferable to punishment or criticism. Families can identify non-food rewards for accomplishing behavioral goals and focus on reinforcing effort and specific behaviors rather than weight alone. Setbacks and lapses should be expected and addressed as opportunities for problem-solving rather than as treatment failure. Because obesity is a chronic condition, behavior change requires ongoing support, and treatment should emphasize maintenance and long-term adaptation rather than a short-term "diet" or rapid weight-loss approach [11].

Motivational interviewing is a patient-centered, collaborative counseling approach that can help engage children, adolescents, and families in behavior change. Rather than prescribing goals, clinicians work with the patient and family to identify behaviors they consider important and achievable. Motivational interviewing is particularly useful when families are ambivalent about treatment or when external barriers and competing priorities make obesity treatment difficult.

The AAP identifies motivational interviewing as a core component of comprehensive obesity treatment. The process includes engaging the patient and family, focusing on potential targets for change, eliciting their own motivations and reasons for change, and collaboratively developing a plan. For younger children, the primary focus may be on caregiver motivation [11].

Motivational interviewing can be applied to a wide range of behavioral targets. For example, a family might choose to reduce sugar-sweetened beverages, increase participation in a preferred physical activity, establish regular family meals, or improve sleep hygiene. Success is defined by meaningful progress toward the selected behavior rather than by imposing a predetermined weight goal. This approach may improve engagement by respecting the family's priorities and capacity for change [11].

Psychological treatment should address the relationship between emotions and health behaviors. Some children and adolescents may eat in response to stress, boredom, anxiety, sadness, or other emotional states. Others may use food restriction or compensatory behaviors in response to body dissatisfaction or concerns about weight. Clinicians can help patients identify triggers, recognize connections among thoughts, feelings, and behaviors, and develop alternative coping strategies.

Cognitive-behavioral strategies may be useful for identifying maladaptive thoughts and behavioral patterns that interfere with treatment. Depending on the patient's needs, intervention may focus on emotional regulation, coping with stress, problem-solving, self-monitoring, challenging unhelpful beliefs, and developing alternative responses to eating or inactivity triggers. Co-occurring depression, anxiety, ADHD, trauma-related symptoms, or other psychiatric conditions should be appropriately evaluated and treated because these conditions may affect treatment participation and long-term outcomes.

Treatment should also address body image, self-esteem, and weight-related stigma. Children and adolescents with obesity may experience teasing, bullying, discrimination, or internalized negative attitudes about weight. Psychological care should provide a safe, supportive environment in which these experiences can be discussed and addressed. Clinicians should use person-first, nonstigmatizing language and avoid framing body size as a moral or personal failure. AAP guidance emphasizes approaches that honor the unique qualities of each child and family and recognize the social and structural contributors to obesity [11].

Obesity and disordered eating can coexist, and psychological assessment should not assume that a patient with a higher weight is free of an eating disorder. Clinicians should assess for BED, LOC-ED, purging, restrictive eating, rapid or recurrent weight loss, and other concerning behaviors. The presence of these symptoms may require specialized treatment and coordination with clinicians experienced in eating disorders.

Importantly, structured, professionally delivered pediatric obesity treatment is not inherently associated with increased eating disorder risk. The AAP notes that professionally managed obesity interventions that emphasize healthy eating, enjoyable physical activity, and improvements in self-esteem and self-concept may be associated with reductions in eating disorder prevalence, risk, and symptoms. Nevertheless, clinicians should continue to monitor for emerging or worsening disordered eating throughout treatment and avoid unnecessarily restrictive or stigmatizing approaches [11].