Obesity Medication in Children and Adolescent

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Author(s):

	Marie-Laure Frelut
	Marie-Laure Frelut is a Pediatrician. She became involved in the field of childhood obesity in the 1990s when she had to run an inpatient unit for severely obese adolescents.
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	Daniel Weghuber
	Assoc. Professor (Priv. Doz.) of Pediatrics Department of Pediatrics
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Obesity in children and adolescents represents a complex chronic pathology, the comprehension of which has undergone significant advancements in recent years, owing to the identification of genetic factors and an exponential growth in biological knowledge. Obesity is nowadays largely considered as the consequence of dysregulation of the regulatory centres of appetite and associated behaviours of the brain (1).  On the other side, the adipose tissue, functioning as an endocrine organ, engages in constant communication with various regulatory centres, including the cerebral appetite control centres and the neuroendocrine signalling of the digestive tract (2). When facing a child or adolescent living with obesity, a meticulous analysis of the trajectory of their pathology, potential anomalies, and associated clinical complications and the assessment of the social environment as well as the nutrition, eating, physical activity and psychosocial behaviour becomes imperative. The earlier the obesity, the most likely multiples health and psychosocial consequences are likely to be severe leading to increased and earlier morbidity and mortality rates especially from metabolic and cardiovascular disease and cancers. In 2024, an estimated number of 44,000 lives could be saved in adults in the US by expanding access to the new generation of weight loss drugs (3).  In adolescents, conclusions about cost effectiveness should be drawn careful since old drugs are obviously likely to be cheaper and remain so for a while (4). Price only should never be the single reason why to promote a treatment the quality of which relies on the combination of its efficacy and short- and long-term safety.

Collaborating with paediatric reference centres and genetic research facilities enables the identification of associated mutations and allows for the consideration of specific and effective treatment in cases that may be rare but likely underdiagnosed. Recently, two randomized trials demonstrated the significant beneficial effects of Glucagon-like peptide 1 (GLP-1) receptor analogue, a pivotal molecule in the regulation of appetite originating from the intestine. Although additional studies and real world registries are needed to assess long-term results and potential adverse events, the obtained and promising findings, i.e. effects filling the gap between those of health behaviour and lifestyle treatment and metabolic and bariatric surgery (MBS) prompt a re-evaluation of existing obesity management options and concepts (5, 6).

While prioritizing prevention remains crucial, ongoing investigations are exploring various molecules and therapeutic avenues for the most prevalent metabolic and chronic disorder in childhood. This overview addresses the evolving landscape of understanding and treating paediatric and adolescent obesity, acknowledging that health behaviours and lifestyle treatment remain cornerstones of a successful management.

1. REGULATION OF APPETITE BY PERIPHERAL ORGANS AND THE BRAIN

The complex mechanisms that regulate appetite and the reciprocal interactions between the brain and peripheral organs represent a pivotal area of focus for therapeutic molecules and the foundation of their respective indications (1).

The regulation of appetite and satiety is achieved through continuous bidirectional exchanges between the cerebral appetite-regulating centres and peripheral organs. The digestive tract, pancreas, and adipose tissue act in coordination, particularly with the hypothalamus. The transmission of information between peripheral organs and the brain occurs is facilitated by two distinct mechanisms: the bloodstream and the nerves. The latter is characterized by the presence of afferent fibres within the vagus nerve which acts as conduits for this transmission. The action of intestinal hormones in the regulation of appetite regulation can be categorized into two distinct classifications: short-term and long-term. The secretion of short-term hormones, such as ghrelin, cholecystokinin (CCK), peptide tyrosine tyrosine (PYY), glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM),occurs in anticipation, response or deprivation.  Glucagon and fibroblast growth factor 21 (FGF21) are notable exceptions, as they are secreted in response to nutrient deprivation. The long-term effects of regulatory hormones on the brain are indicated by the signals they send regarding the proportion of stored lipids in the body (leptin, insulin, amylin). it is evident that both hunger and satiety are also influenced hedonically by environmental factors. The cerebral areas involved are adjacent to the hypothalamus and brainstem and include the mesolimbic reward centres, hippocampus, and cortical regions.

The hypothalamic melanocortin system is a critical integration area for the homeostasis of food control, comprising orexigenic neurons which co-express neuropeptide Y (NPY) and agouti-related peptide (AgRP). These neurons stimulate food intake by blocking the melanocortin receptor 4 (MC4R). Anorexigenic neurons co-express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). The activation of NPY/AgRP neurons has been demonstrated to induce the secretion of AgRP, which in turn stimulates food intake by blocking MC4R. Activation of POMC/CART neurons has been demonstrated to trigger the secretion of α-melanocyte-stimulating hormone (α-MSH), which in turn activates MC4R, thereby inhibiting food consumption.

In the periphery, ghrelin, secreted by the stomach, reaches the hypothalamus where it stimulates food intake through the activation of NPY/AgRP neurons. Initially, insulin was recognised for its hypoglycaemic action; however, it is now understood that in pair with amylin, it is co-secreted by the pancreas, thereby reducing food intake via the central nervous system (CNS). FGF21, a hormone secreted by the fasting liver has been shown to increase energy expenditure through both central and peripheral mechanisms.

CCK, secreted by intestinal cells, appears to act primarily via the vagus nerve in response to a fatty meal. PYY is co-secreted with GLP-1 by small intestine cells. GLP-1 has been demonstrated to reduces food intake via the CNS by acting directly on POMC/CART neurons and pathways involved in hedonism. OXM, anorexigenic, binds to GLP-1 receptors (GLP-1R).

Glucagon has been demonstrated to induce weight loss through multiple mechanisms, including the stimulation of lipolysis, energy expenditure, and the inhibition of food intake. Figure 1 summarizes the interactions between the periphery and the nuclei of the hypothalamus.

Figure 1

Appetite regulation: peripheral hormones are integrated into central regulation of homeostasis and hedonic eating behaviours (from (1)). 

Abbreviations: αMSH α-melanocyte stimulating hormone; AgRP agouti related peptide; ARC arcuate nucleus; POMC pro-opiomelanocortin; CART cocaine and amphetamine regulated transcript; CCK cholecystokinin; CPF prefrontal cortex; FGF21 fibroblast growth factor 21; GIP glucose dependent insulinotropic peptide; GLP-1 glucagon like peptide; MC4R melanocortin 4 receptor; NPY neuropeptide Y; NTS nucleus of the solitary tract; OXM oxyntomodulin; PCSK1 proprotein convertase subtilisin/kexin type 1; PYY peptide tyrosine tyrosine; YR1 neuropeptide Y type 1 receptor.

2. OBESITY OF GENETIC ORIGIN

The discourse pertaining to the relative contribution of genetics versus environmental factors to obesity has evolved from an initial focus on twin and population studies to a more nuanced consideration of biological genetic studies. In the early stage of genetic analysis, the application of genetic techniques  was limited to the identification of mutations present in a small number of individuals. The power of whole-genome analyses, coupled with metabolic studies (omics), has been essential in unravelling the biological significance of numerous polymorphisms and opening therapeutic avenues (7).

Bi-allelic mutations are estimated to be causal in approximately 5 to 10% of cases presenting with severe obesity early, typically during infancy or toddlerhood. Syndromic obesities, which involve neurodevelopmental abnormalities (cognitive impairment, autism spectrum disorder, etc.) along with dysmorphic features or organic malformations, is not discussed here. Non-syndromic monogenic obesities is characterized by disruptions in the leptin-melanocortin pathway (refer to Table 1). The role of heterozygous mutations in this pathway has recently been elucidated, involving either simple heterozygotes or compound heterozygotes (2 mutations). The expression of this phenomenon may range from the same severity as homozygous mutations to a milder degree. This accounts for 7% of patients in a French cohort, and in another study, 1 in 1000 patients carried a pathogenic variant in the LEP/LEPR gene, encoding leptin or its receptor, respectively. The inadequate exploration of these mutations is of particular significance, given that specific treatments are beginning to emerge (8, 9).

Genome wide polygenic score of obesity (GPS) based on the analysis by computational algorithms of genome wide association studies (GWAS) of the effect over 2 million of genetic variants on BMI, is a powerful tool that allow to predict early risk level of polygenic obesity, starting in early childhood and further diverging into adulthood. High risk profiles have been shown to face obesity risk level close to monogenic mutation carriers. GPS may become a tool to better decide which subject need to undergo drug treatment (10). Recently, Smit et al. (11) showed that BMI GPSs can be used for prediction of adult obesity throughout the life course, particularly in early life, and for severe obesity. The newly developed GPS was shown to be a substantial improvement compared to previous scores and may help to identify individual at high risk to allow for timely prevention or treatment of obesity., such as integration in a broader predictive framework jointly modelling genetic and environmental risk.

Table 1

Main genes implicated in severe and early onset obesity (from (7)).

3. PHARMACOLOGICAL TREATMENTS FOR OBESITY

The adverse events observed with the first generation obesity medication (see table 2) which were frequently severe, prompted the development and use of MBS as an effective treatment option (12), although access remained limited due to challenges including social vulnerability and lack of insurance coverage (3). However, recent advancements in new medications have significantly altered this landscape (13). All such medications undergo approval processes, with the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in Europe, though their assessments often diverge (12, 14).

Most historical treatments were initially utilized exclusively in adults. The utilisation of randomized controlled trials versus placebos as a standard practice were not initially implemented, consequently resulting in the identification of some serious adverse effects. The rigorous methodologies employed have facilitated the detection of immediate, medium-term, and long-term adverse effects, resulting in the withdrawal of several compounds (15).

The treatment of severe obesity, including in children and adolescents, have now been revolutionized by metreleptin, setmelanotide and incretin-based medications, GLP-1 agonists for the treatment of severe obesity. The more thoroughly understood role of metformin, an antidiabetic agent, further solidifies its place among adjunctive medications in the management of obesity (13).

Table 2: Generations of medications against obesity

3.1 Historical Compounds

The identification of serious adverse events exhibited by a large range of initial medications, including amphetamines and their derivatives, thyroid hormones, dinitrophenol, and various combinations, resulted in the subsequent withdrawal of approval. Nevertheless, the prescription of these medications for indications not included in the approved ones persisted, a practice that was also observed in France (16).

3.1.1. Sympathomimetics

This category includes methamphetamine, fenfluramine and dexfenfluramine, sibutramine, and phentermine. These medications were not officially used in adolescents under the age of 15. The mechanisms of action of these obesity medications are briefly summarized as follows:

Amphetamine stimulates serotonin release and serotonin reuptake inhibition, fenfluramine and dexfenfluramine inhibit serotonin reuptake, sibutramine causes serotonin and norepinephrine reuptake inhibition, and pipradolol causes serotonin and dopamine reuptake inhibition. Despite the fact that these medications produced modest weight reduction effects ranging from 2 to 5%, adverse effects led to their successive withdrawals: addiction and suicidal ideation, cardiovascular complications, including hypertension, stroke, tachycardia, and for fenfluramine and dexfenfluramine, valvular lesions and pulmonary hypertension, leading to notable legal cases and fatalities. Phentermine alone (15-30 mg) is not authorized before the age of 16 and only for brief periods (often interpreted as 3 months) by the FDA only (https://www.accessdata.fda.gov/drugsatfda.docs ) (13).

3.1.2. Topiramate and Phentermine-Topiramate Combination

Topiramate, an antiepileptic and antimigraine agent with a long-standing presence in paediatric medicine, exerts its neuronal action through GABAergic mechanisms and weak carbonic anhydrase inhibition. The utilisation of this agent in the treatment of obesity was predicated on the observation of a pronounced anorexigenic effect in a subset of paediatric subjects. Whilst favourable results have been reported in adults living with obesity, its application in children and adolescents within strict protocols has not been successful. This is evidenced by a high number of inclusion refusals and dropouts due to concerns about side effects such as depression and suicidal risk (Tobi Protocol NCT02273804).

The FDA-approved combination of phentermine and topiramate, permitted from the age of 12, is not authorized in Europe. The doses of each molecule in the combination are lower than when taken alone (3.75/23 mg, 7.5/46 mg, 11.25/69 mg, 15/92 mg). A 56-week double blind multicentre trial demonstrated a significant effect on BMI. Mean age was 14 ± 1.4 years (12-17-), mean BMI 37.8±7.1 kg/m². Participants (54.3 % girls) were randomly assigned to either mid dose PHEN/TPM (7.5/46 mg, n = 56 or top-dose (15/92 mg, n = 113) or placebo (n= 56).  The percent change in BMI was -10,44 percentage points (95% CI -13,89 to- 6.99; p<0.001) and -8.11 (95%CI -11.92 to -4.31; p<0.001) for the top and mid doses of PHEN/TPM, respectively. The incidence of participants reporting at least one adverse effect was 51.8%, 37.0% and 52.2% in the placebo, mid-dose and top-dose groups, respectively. Events related to psychiatric disorders occurred in 4 participants in the mid dose group and 10 participants in the top-dose group. Two patients reported depression and suicidal ideation in the top-dose group. In 2022, it was approved by the FDA for adolescents with a BMI in the 95th percentile or above, aged 12 and over (17).

3.1.3. An Endocannabinoid Receptor 1 (CB1) Antagonist

Rimonabant, an antagonist of the endocannabinoid receptor type 1 (CB1), was rapidly withdrawn from clinical use due to its association with depression and suicide in adults. However, the combined effect of peripheral activation of CB1 is to promote appetite and energy storage and preservation leading to weight gain and maintenance. Therefore, a new generation of CB1 antagonists and indirect modulators of the endocannabinoid system is currently developed and at the stage of clinical trials. The action of these new generation of CB1 antagonists is restricted to the periphery and has no action on the brain. Their interest may go beyond treating obesity and its associated metabolic complications. Conversely, CB1 agonists are tested in the treatment of cancer anorexia and pain (18).

3.1.4. Opioid Receptor Antagonists and Dopamine/Norepinephrine Reuptake Inhibitors

The combination of naltrexone/bupropion (32 mg/360 mg) is available in Europe and the USA, but not approved for the paediatric age group. The primary concern associated with this combination pertains to the potential for an increased propensity towards suicidal tendencies.

3.1.5. Lipase Inhibitors

Orlistat is an inhibitor of gastrointestinal and pancreatic lipases, thereby reducing the rate of intestinal absorption of lipids. It has been determined that approximately one-third of dietary fatty acids are not absorbed. The prescription of this medication should be accompanied by the recommendation of a low-fat diet, with the objective of achieving a daily caloric reduction of 200 to 300 kilocalories. The resultant steatorrhea is estimated to be in the range of 20 to 30 grams per day. The primary adverse effect is of a digestive nature, with symptoms including discomfort. However, adherence to the prescribed dietary measures is known to minimise the occurrence of such symptoms. It is imperative to monitor the levels of fat-soluble vitamins A, D, E, and K. Gallstones have been reported in association with this condition. In adults, the use of this substance has been demonstrated to reduce the risk of developing diabetes, particularly in individuals with prediabetes, by 35%. Another lipase inhibitor with similar effects, cetilistat, is available in Japan. Despite the fact that it is utilised in adolescents aged 12 and older in the USA, it is not approved in Europe (12, 15). Recently, the Canadian evidence-based clinical practice guideline derived a recommendation against the use of orlistat, as data on adverse events outweighed the limited effects on relevant outcomes, such as BMI or cardiometabolic outcomes (19).

3.1.6. Serotonin Receptor Agonists

Lorcaserin 10 mg, which was approved in the United States but not in Europe, is a high-affinity serotonin receptor subtype 5-HT2C agonist with lower affinity for 5-HT2B receptors located on cardiac valves. An elevated probability of developing cancer has been documented. As demonstrated by the findings of published studies, significant weight loss has been observed, along with a concomitant decrease in the risk of diabetes in adults.

As a consequence, The European Medicines Agency (EMA) did not approve the drug due to concerns regarding psychiatric risks and valvopathies and FDA withdrew it from the market in the USA in 2020.

3.2. Results of Initial Interventions in Children and Adolescents

In 2008, the first systematic review and meta-analysis of randomised trials on the pharmacological treatment of childhood obesity was published, encompassing 61 studies. Patients with obesity associated with eating behaviour disorders were excluded from the study. Ten per cent of the articles (23 out of 263) were focused on pharmacotherapy and were included in the analysis. The pharmaceutical agents included in this study were sibutramine, orlistat, and metformin. Sibutramine was the only substance to result in substantial weight reduction, with a mean decrease of -2.4 kg/m², accompanied by elevated blood pressure and heart rate. In terms of BMI, these results were found to be superior to those of health behaviour and lifestyle interventions only. The occurrence of fatal pulmonary hypertension in adults administered amphetamine derivatives resulted in the subsequent rejection of this molecule in paediatric populations (20, 21). In 2016, a Cochrane study selected 21 randomised trials (11 ongoing trials were excluded) involving 2,484 treated children and adolescents over 12 to 48 weeks, with follow-ups ranging from 6 months to 100 weeks. The medications included in the study were metformin (10 studies), orlistat (4 studies), sibutramine (6 studies), and the metformin-fluoxetine combination (1 study). The study’s quality was judged to be substandard, primarily due to a high rate of attrition. The intervention’s impact was an additional average weight loss of 3.9 kg in the treated group (21).

In an updated meta-analysis by Torbahn et al. (13), based on 35 randomised controlled trials (RCTs) with a minimum duration of six months and involving 4,331 subjects under the age of 19, the following obesity medications were included: metformin, sibutramine, orlistat, topiramate, exenatide, liraglutide, phentermine/topiramate, lorcaserin, fluoxetine and semaglutide. The analysis of moderate certainty evidence revealed a BMI reduction of -1.71 (95% confidence interval : -2.27 to -1.14) units. Semaglutide produced the most significant reduction of -5.88 kg/m² (95% CI -6.99 to -4.77, n=201). The analysis revealed that the drug type accounted for approximately 44% of the observed heterogeneity. The occurrence of serious adverse effects and the incidence of study discontinuation did not differ between the drug and comparator groups. However, medication dose adjustments were higher in the treatment groups than in the placebo groups (10.6% vs. 1.7%, RR 3.74 ). The prevalence of serious adverse events was found to be 1% among the adolescent population. Evidence gaps were reported to exist for children, psychosocial outcomes, comorbidities and weight loss maintenance.

The long pipeline of ongoing and planned clinical trials assessing new substances in different patient groups will likely change the therapeutic options and our knowledge substantially, but will also raise new questions.

3.3. Therapeutic Advances in Phase III or IV

3.3.1. Leptin

The use of injectable recombinant leptin, metreleptin, enabled, for the first time in 1999, the treatment of a severe genetic form of childhood obesity caused by a homozygous mutation in the LEP gene but not in its receptor (LEPR) gene (8). Metreleptin’s inferred action from its metabolomic profile includes lipolysis and fatty acid oxidation associated with low protein catabolism, contrary to calorie reduction. The emergence of anti-metreleptin antibodies has been reported. The indication is limited to obesities caused by LEP mutations. In common polygenic obesities, the elevation of circulating leptin levels, proportional to fat mass, reflects resistance to the hormone’s action. Metreleptin is ineffective and contraindicated in such cases (22, 23) (see chapter on Obesity of Genetic Origin).

3.3.2. MC4R Agonists, including Setmelanotide

Setmelanotide is an MC4R agonist that substitutes for the absent endogenous ligand (α and/or β MSH). It is approved for the treatment of patients with deficiencies in the leptin-melanocortin signalling pathway in the hypothalamus (see above and Fig. 1) due to deficiencies in POMC, PCSK1, and LEPR. These rare mutations (which may be underdiagnosed) result in insatiable hyperphagia and early-onset obesity. The initial generation of MC4R agonists exhibited the efficacy of this approach in vitro and subsequently in paediatric subjects. However, this was accompanied by adverse effects. The findings of two phase III studies encompassing 17 patients (POMC, n=8, PCSK1, n=1, LEPR, n=8) over a one-year observation period demonstrated that all patients, who had previously exhibited treatment resistance, exhibited a substantial decrease in BMI. In children and adolescents, the findings indicated that height growth and pubertal development were within normal parameters (9, 20). Setmelanotide was recently also approved for the treatment of patients with Bardet-Biedl syndrome (see chapter on Obesity of Genetic Origin for further details).

3.3.3. GLP-1 and GIP Analogues

• Mechanism of action

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have become central in managing obesity and type 2 diabetes, primarily through appetite suppression and metabolic regulation. GLP-1 is an incretin, a molecule secreted by intestinal L cells, which maintains physiological blood glucose levels regardless of the quantity of ingested carbohydrate by stimulating beta cells and alpha cells in the pancreas that carry GLP-1 receptors (GLP-1-R). It has been demonstrated that both GLP-1 and GIP, another incretin, are capable of stimulating insulin secretion, even in individuals diagnosed with type 2 diabetes. In addition, GLP-1 has been shown to inhibit glucagon secretion, a finding that has contributed to the development of analogues used in the treatment of type 2 diabetes.

GLP-1R expression has been observed in most tissues of the body including the brain, kidneys, pancreas, stomach and heart, as well as in adipocytes and skeletal muscle with no expression observed in the liver. In the periphery, GLP-1 (but not GIP) has been shown to inhibit gastrointestinal motility and gastric secretions by inhibiting vagal activity, stimulating the solitary tract nucleus, and then the hypothalamus. It is hypothesised that hepatic GLP-1-RAs would act via the portal system. The plethora of cerebral sites expressing GLP-1-R demonstrates the redundancy of mechanisms through which appetite could be inhibited. The administration of GLP-1 through peripheral routes has been demonstrated to act directly on the central nervous system (1).

In the context of obesity complications, the presence of GLP-1-R in the walls of blood vessels, the heart, and the immune system leads to a decrease in blood pressure in hypertensive subjects, a reduction in postprandial chylomicron secretion, and a decrease in inflammation in the heart and blood vessels. GIP-Rs have also been identified in the human heart, specifically in atrial and ventricular cardiomyocytes, pericytes, and adipocytes.

As demonstrated in figure 1, the extensive distribution of GLP-1-R instigates a plethora of metabolic effects, concomitant with the facilitation of metabolic improvements in the treatment of the metabolic consequences of obesity and type 2 diabetes (T2D).

Figure 2: Main metabolic effects per organ of GLP-1 (from (1))

• GLP-1 analogues

The first line trials, focusing mainly on T2D, were based on a single molecule use of short action. These medications include exenatide, lixisenatide receptor agonist, liraglutide, dulaglutide, albiglutide, and semaglutide receptor agonist.

In recent times, the development of long-acting versions of certain molecules has enabled a transition from daily to once-weekly injections. Semaglutide, for instance, possesses a half-life of approximately 160 hours. In addition, higher doses of liraglutide and semaglutide have been shown to be effective in the treatment of weight reduction.

• Therapeutic Trials of GLP-1 analogues

Several GLP-1 receptor analogues, either in isolation or as dual and triple incretin-based co-agonists (including combinations with GIP, amylin, glucagon and other molecules), have been developed.

• Trials on polyagonists: GLP-1-GIP1 compound analogues

These compounds have only been tested on adults thus far, and consist of a combination of GLP-1 and GIP1 analogues. The GIP agonist has been shown to counteract the emetic effects of GLP-1. Tirzepatide is a compound that is currently undergoing phase III trials, and preliminary findings suggest that it may hold significant potential in addressing obesity in adults diagnosed with T2D. This observation pertains to both the components of obesity and T2D. Further trials are underway, with the objective of investigating the efficacy of long-term weight loss as a treatment for obesity in the absence of concomitant diabetes (24).

• GLP-1 receptor agonists in adolescents

The publication by Weghuber et al. on the effect of semaglutide in adolescents living with obesity (the STEP TEENS study) radically changes therapeutic perspectives in this population (5). This multicentre study (37 sites) was conducted from October 2019 to March 2022 over a period of 68 weeks in a double-blind manner. A total of 201 adolescents aged 12 to 18 years were included in the study, of whom 180 completed it. In the present study, the efficacy of subcutaneous semaglutide at a dose of 2.4 mg/week was compared to that of a placebo, with both groups receiving lifestyle intervention. The mean decrease in BMI was -16.1% in the treated group in comparison to 0.6% in the placebo group (95% CI: -20.3 to -13.3, p<0.001). The study demonstrated that a weight reduction of 5% or more was attained in 73% of the treated group, in comparison to 18% of the control group (estimated odds ratio: 14.0; 95% CI: 6.3 to 31.0). Furthermore, the analysis revealed that a minimum of 15% weight reduction was achieved in 53% of the treated group, as opposed to 5% of the control group, and a minimum of 20% weight reduction was achieved in 37% of the treated group, in contrast to 3% of the control group. The nadir of weight loss was reached in both groups at 60 weeks. The investigation revealed that cardiometabolic risk factors (HbA1c, total cholesterol, LDL and VLDL cholesterol, triglycerides, and ALT) exhibited a greater decrease in response to semaglutide. The investigation revealed no significant differences in blood pressure or HDL cholesterol levels between the groups. Gastrointestinal adverse effects were reported in 62% of cases in comparison to 42% in the placebo group, with a peak observed around the 16th week, and gallstones were present in 5% of cases in comparison to 0% in the placebo group. No psychiatric adverse effects were reported. A more extensive research study is required to provide a more robust set of findings. However, the preliminary results obtained from this therapeutic class have already begun to challenge the established indications for bariatric surgery (13).

• GLP-1 in children 6 to less than 12 years old

Fox et al. (6) administered liraglutide in a RCT in children aged between six and under 12 years. The duration of the treatment period was 56 weeks, with a subsequent 26-week period of follow-up. In the course of the study, 82 participants were divided into two groups: 56 were assigned to the liraglutide group, while 26 were assigned to the placebo group. In week 56, the mean BMI had decreased by 5.8% with liraglutide and 1.6% with placebo (95% CI: -11.6 to -3.2, p <0.001). The mean percentage change in body weight was 1.6% with liraglutide and 10% with placebo (95% CI: -13.4 to -3.3, p = 0.001). A decrease in BMI of a minimum of 5% was observed in 46% of subjects in the liraglutide group, in comparison to 9% in the placebo group. Utilising an adjusted odds ratio, the study yielded a result of 6.3 (95% CI: 1.4 to 28.8, p = 0.02). The occurrence of adverse events was recorded in 89% and 88% of the treatment and placebo groups, respectively. The occurrence of gastrointestinal adverse events was found to be higher in the liraglutide group than in the comparator group (80% vs. 54%), as was the incidence of serious adverse events (12% vs. 8%). The equal number of overall adverse events emphasises the necessity of taking the psychological background into account and providing psychological support in this pathology.

• Ongoing trials in children and adolescents

A number of clinical trials on the treatment of severe obesity in children and adolescents are currently underway. Some of them use medications in a RCT procedure and are registered on the National Clinical Trials (NCT) website of the USA, https://clinicaltrials.gov/  (See table 2).

Table 2 : RCTs on obesity in children and adolescents using medications and listed on the NCT website in July 2025

3.4 Metformin

Metformin, a biguanide that has been in existence since the 1920s, was prescribed as an antidiabetic agent as early as 1957 and has been commercially available in France since 1959 at a low cost. The earliest publications on its use in the treatment of adolescent obesity appear to date back to 2009. The precise mechanism by which it exerts its effects remains to be fully elucidated. The primary action of this substance in reducing blood glucose appears to be intestinal, inducing an increase in basolateral glucose passage. The increase in portal blood glucose in hyperglycaemic conditions has been demonstrated to trigger hepatic counter-regulation, thereby reducing hepatic glucose production (25).

In the context of adolescent obesity, a condition which is rarely associated with diabetes in Europe but more often with insulin resistance without hyperglycaemia, metformin is prescribed in cases where there is suspected insulin resistance-related pathology (e.g. polycystic ovaries with oligomenorrhea and hyperandrogenism) or strong resistance, as assessed by simultaneous measurements of insulin and blood glucose, which is usually associated with acanthosis nigricans. A moderate effect on overweight subjects has been observed in such cases. The aforementioned meta-analysis of randomised trials included 38 studies with a total of 2,199 participants. The reduction in BMI was 1.07 kg/m² (95% CI -1.43 to -0.72), and weight reduction was -2.51 kg (95% CI -3.14 to -1.81) (25). Whilst the use of metformin for the treatment of obesity is off-label in a number of countries, the role of metformin must be redefined in light of the arrival of incretin analogues. This is to ensure that children and adolescents are offered a range of treatment options. For instance, the utilisation of biguanides – in conjunction with Health Behavior and Lifestyle Treatment (HBLT) – was proposed by the most recent Canadian Paediatric Clinical Practice Guideline for children and adolescents living with obesity (26).

4. THE FUTURE: GREAT HOPES BUT PENDING SERIOUS QUESTIONS

Despite the apparent efficacy of incretin-based obesity medications that act on the brain-gut axis, there are several issues that require further attention, particularly in the context of young subjects: the temporal parameters surrounding the initiation of pharmacotherapy and its duration are pivotal considerations. The investigation into the potential adverse consequences of the treatment extends to the inquiry of its long-term implications. The question therefore arises as to whether the genetic background in fact plays a detrimental or protective role. The following question must be posed: how should mid- and long-term management be handled?  The question therefore arises as to how such diets should be adapted. The final issue to be addressed is that of the overall positive versus negative balance.

A number of research directions are currently being pursued, driven at a rapid pace by the field of artificial intelligence (27). These include the synthesis of new agonists specific to known neurotransmitters, such as amylin, PYY, and ghrelin. Furthermore, molecules that act on mitochondria are also being studied, since increased uncoupling of oxidative phosphorylation could lead to increased heat production at the expense of ATP. The challenge lies in the toxicity of most of these molecules and the need for highly targeted ionophoric action. Inhibitors of cytokines represent a further promising avenue of research.

The intestinal microbiota differs between individuals with normal weight and living with obesity. The role of the microbiota in the genesis of obesity, especially polygenic obesity, is well established. This is evidenced by the increase in intestinal permeability to fatty acids caused by certain flora profiles, and the contribution of these profiles to the flow of neurotransmitters. Modifications to the microbiota have been identified as potential therapeutic targets; however, investigating such modifications is an extraordinarily complex process and no medication is yet available.

The management of obesity in children and adolescents is experiencing unprecedented therapeutic improvements and developments. Whilst prevention remains of crucial importance, the benefits for patients require physicians to adopt a fresh perspective on this pathology and to promote collaboration between specialities. According to the most recent ethical information, the prescription should be retained by reference centres and administered only to patients for whom adherence to long-term follow-up can be reasonably expected (11). It is imperative that guidelines evolve in order to incorporate publications with expanded qualitative evaluation.

Whilst clinical-practice guidelines advocate the utilisation of obesity medications in conjunction with HBLT, the function and composition of HBLT remain to be elucidated. This is due to the paucity of data concerning the content of HBLT interventions and the absence of evaluations of their impact on behavioural outcomes, including adherence, nutrition, eating behaviour and physical activity.

Altogether, several challenges are still faced in the management of child and adolescent obesity while research gaps have to be fulfilled such as the assessment of long-term effects of anti-obesity medications (AOM), of rare adverse events in large cohorts of patients, the introduction of the phenotype in order to guide the choice of the medication. AOM development and prescription are nowadays, especially in children and adolescents, at the crossroad between individually based medicine and ethical prescription to groups of patients with or without identified genetic background.  Therefore, beyond the role of the regulatory agencies, the implication of National Health Care Systems into AOM regulation and accessibility is required.

While clinical-practice guidelines recommend the use of obesity medications in addition to HBLT (19), the role and content of HBLT remains currently unclear as the data on the content of HBLT-interventions were barely reported and effects on behavioural outcomes, such as adherence, nutrition or eating behaviour and physical activity have not been evaluated (13).

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