Recent approvals by the Brazilian Health Regulatory Agency (Anvisa, acronym in Portuguese) of treatment drugs that simulate the actions of the GLP-1 peptide in the body (liraglutide and semaglutide) for weight loss in adolescents (12 years of age and older) brings questions about the relevance and risks of using these drugs to treat childhood obesity. This argument is founded on five considerations: (1) the expansion of these treatment drugs for use in adolescents was based only on randomized clinical studies developed by the pharmaceutical industry that markets them; (2) the severity of side effects; (3) the absence of studies that evaluate long-term impacts; (4) the strategies to combat obesity in Brazil and internationally, and (5) alternatives to medicalization by investments in social justice.

Use of GLP-1 agonists for treating adolescent obesity in Brazil began with the approval for liraglutide administration in August 2020, followed by the expanded use of semaglutide in September 2023. Such approval is founded on the publication of two randomized clinical studies developed by the pharmaceutical company Novo Nordisk, the first with liraglutide ¹1. Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, Hale PM, Marcus C, et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N Engl J Med 2020; 382:2117-28. and second with semaglutide ²2. Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 2022; 387:2245-57.. However, it is widely known that several scientific studies are needed before gathering sufficient evidence to support public recommendations or guidelines. Approval of these two drugs in Brazil for treating obesity in adolescents (12 years of age and older) has no robust evidence of efficacy, no study of effectiveness and a complete lack of knowledge regarding long-term effects, as well as presents conflict of interest. For example, the study on semaglutide ²2. Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 2022; 387:2245-57. for adolescents was based on a methodology used for adults ³3. Wilding JP, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384:989-1002.. However, the study with adults concluded with 81% of the initial sample of 1,961 participants after 68 weeks, whereas the study with adolescents concluded with 196 participants from the initial 201 after 68 weeks. Thus, this second research included a population group of lesser representativeness and greater biological vulnerability, involving different pubertal stages and peculiarities between sexes. Additionally, the results registered on the ClinicalTrials platform (https://clinicaltrials.gov/) revealed that about 36% of body weight loss in adults ³3. Wilding JP, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384:989-1002. was due to the loss of muscle mass; not such data is available for the adolescent sample ²2. Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 2022; 387:2245-57.. Conducting studies with children and adolescents poses a huge challenge for researchers as metabolic diversity and intense changes in biology and body composition limit the research results. Hence the following questions: what are the metabolic consequences of muscle mass loss in growing individuals? What are the emotional and psychological consequences for children and adolescents of aggressive treatments such as the use of medication?

A recent review ⁴4. Alorfi NM, Alshehri FS. Usage of glucagon-like peptide-1 for obesity in children; updated review of Clinicaltrials.gov. J Multidiscip Healthc 2023; 16:2179-87. on the common adverse effects of GLP-1 receptor agonists in children and adolescents revealed events of vomiting, nausea, diarrhea, constipation, abdominal distension, abdominal pain, headache, dizziness, fatigue, dyspepsia, eructation, hypoglycemia in patients with type 2 diabetes mellitus, gastroenteritis, flatulence, gastroesophageal reflux disease, thyroid C-cell tumors, acute pancreatitis, sudden gallbladder disease, hypoglycemia, sudden kidney injury, diabetic retinopathy in individuals with type 2 diabetes mellitus, and suicidal ideation and behavior. Another publication highlights concerns regarding the late impact on child growth and development, medication abuse among patients with eating disorders or in certain sports practices, excessive or insufficient medical prescription in populations with a high prevalence of obesity and low physical fitness ⁵5. Cooper DM, Rothstein MA, Amin A, Hirsch JD, Cooper E. Unintended consequences of glucagon-like peptide-1 receptor agonists medications in children and adolescents: a call to action. J Clin Transl Sci 2023; 7:e184..

Importantly, the use of drug therapies that simulate the role of incretins in metabolism was primarily developed for treating type 2 diabetes mellitus, whose clinical conditions have serious consequences for patients’ general health and a high risk of mortality. However, we must evaluate the cost-benefit of its widespread use for weight loss. Wilding et al. ⁶6. Wilding JP, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 2022; 24:1553-64. observed that patients regained two-thirds of the weight lost after stopping taking the medication, subliminally suggesting that use of this drug should be continuous and probably lifelong since obesity is a chronic disease and therefore requires chronic treatment ⁶6. Wilding JP, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 2022; 24:1553-64..

GLP-1 is a hormone released in the intestine during food digestion that acts on pancreatic beta cells by increasing insulin production, inhibiting glucagon secretion, delaying gastric emptying and decreasing appetite. Another potential action found in a study was the increase and proliferation of pancreatic beta cells in young animals, but not adults, suggesting a difference in physiological impact in growing individuals ⁷7. Kedees MH, Grigoryan M, Guz Y, Teitelman G. Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic alpha and beta cells in two models of alpha cell hyperplasia. Mol Cell Endocrinol 2009; 311:69-76.. Additionally, GLP-1 receptors are present in other tissues including the thyroid, exocrine pancreas, meninges, renal tubules, bones, and their activation promote changes unrelated to glucose homeostasis. Hence the enormous concern about the widespread use of its agonists for weight loss in adolescents. Endogenous GLP-1 has a short half-life (< 2 minutes), is transiently taken up by its receptors and strongly regulated under healthy physiological conditions; however, these treatment drugs abruptly alter normal physiology, extending the time of action of GLP-1 receptors (approximately one week). Besides, there is insufficient evidence on long-term health damage. Interestingly, Butler et al. ⁸8. Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care 2013; 36:2118-25. state that the biggest issue would not be pancreatitis, which has been identified in the use of GLP-1 agonist medications such as liraglutide, but rather the probable proliferation of pancreatic ducts, acinar metaplasia and subclinical pancreatitis. Clinical pancreatitis is only the tip of the iceberg. Periductal alpha cell hyperplasia can cause obstruction and evolve to neuroendocrine neoplasia.

Another systematic review ⁹9. Wang J-Y, Kang J-W, Wu C-Y, Peng T-R, Liao L-M, Lee M-C, et al. The effects of incretin-based therapies on weight reduction and metabolic parameters in children with obesity: a systematic review and meta-analysis. Obes Rev 2024; 25:e13686. concluded that the use of GLP-1 agonist drugs was effective, safe and acceptable for weight reduction and glucose control in children and adolescents with obesity. However, great caution is needed in considering this systematic review as a reliable evidence parameter. It included six clinical trials with liraglutide, five of which had conflict of interest (funded by Novo Nordisk) and one study did not disclose the presence or absence of a conflict of interest. As for semaglutide, the only clinical trial reviewed was developed by Novo Nordisk. We therefore consider it premature to conduct systematic reviews to evaluate the efficacy of these medications in children and adolescents before we have studies without conflict of interest and researchers without ties to the pharmaceutical industry.

The World Health Organization ¹⁰10. World Health Organization. Report of the commission on ending childhood obesity. Geneva: World Health Organization; 2016. included childhood obesity as one of its priorities to establish strategies to combat it, considering that 41 million children under 5 are overweight. In Brazil, national data from the Brazilian Household Budgets Survey (POF, acronym in Portuguese) of 2008-2009 ¹¹11. Instituto Brasileiro de Geografia e Estatística. Pesquisa de Orçamentos Familiares 2008-2009. Antropometria e estado nutricional de crianças, adolescentes e adultos no Brasil. Rio de Janeiro: Instituto Brasileiro de Geografia e Estatística; 2010. showed an overweight prevalence of 33.5% in children aged 5-9 years, in line with Brazilian National Survey on Child Nutrition (ENANI, acronym in Portuguese) data from 2019 ¹²12. Universidade Federal do Rio de Janeiro. Estado nutricional antropométrico da criança e da mãe: prevalência de indicadores antropométrico de crianças brasileiras menores de 5 anos de idade e suas mães biológicas - ENANI 2019. https://enani.nutricao.ufrj.br/index.php/relatorios/ (accessed on 02/Feb/2024).
https://enani.nutricao.ufrj.br/index.php... which showed an overweight (body mass index > 1 Z-score) prevalence of 28.3% in children under 5 years of age. In a longitudinal analysis, data from the Pelotas cohort revealed an 88% increase in the prevalence of children with overweight aged 12 months between 1982 and 2015 ¹³13. Gonçalves H, Barros FC, Buffarini R, Horta BL, Menezes AM, Barros AJ, et al. Infant nutrition and growth: trends and inequalities in four population-based birth cohorts in Pelotas, Brazil, 1982-2015. Int J Epidemiol 2019; 48 Suppl 1:i80-8.. These numbers show that childhood obesity has intensified in Brazil and is occurring at an increasingly early age. Effective strategies should therefore be established to prevent the occurrence of obesity during the window of opportunity that is the first 1,000 days of life ¹⁴14. Baidal JAW, Locks LM, Cheng ER, Blake-Lamb TL, Perkins ME, Taveras EM. Risk factors for childhood obesity in the first 1,000 days: a systematic review. Am J Prev Med 2016; 50:761-79..

Recently, a successful experience in implementing actions to promote healthy eating in the first two years of life has shown a relevant impact on reducing childhood adiposity at 6 years of age in Southern Brazil ¹⁵15. Sangalli CN, Leffa PS, Valmórbida JL, Lumey LH, Vitolo MR. Impact of promoting healthy infant feeding practices on energy intake and anthropometric measures of children up to 6 years of age: a randomised controlled trial. J Hum Nutr Diet 2021; 34:771-83.. At the national level, since 2021 the Strategy for Prevention and Care of Childhood Obesity (Proteja, acronym in Portuguese), aims to halt the advance of childhood obesity and improve children’s health and nutrition by actions such as food and nutrition surveillance, health promotion in schools, continuous training of professionals involved in child care and intersectoral articulations for promoting healthy environments within cities.

Also, the American Academy of Pediatrics published guidelines for the clinical practice of childhood obesity treatment which emphasized the use of medications and bariatric surgery and paid little attention to behavioral changes such as diet and exercise ¹⁶16. Hampl SE, Hassink SG, Skinner AC, Armstrong SC, Barlow SE, Bolling CF, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics 2023; 151:e2022060640.. In response to this new paradigm, Ludwig & Holst ¹⁷17. Ludwig DS, Holst JJ. Childhood obesity at the crossroads of science and social justice. JAMA 2023; 329:1909-10. published an opinion against the medicalization of childhood obesity, advocating greater investment in effective strategies related to diets and lifestyle - which they called social justice. The authors argue that focusing on weight loss, as is the case with the use of these medications, does not necessarily improve the health of children and adolescents who, with lower weight but still engaging in unhealthy eating habits and sedentary lifestyle, will not be protected from cardiovascular diseases, cancer and other chronic diseases.

In time, we must add the high treatment cost in Brazil to the disadvantages and risks of using injectable medications for treating obesity in children and adolescents. Currently, the price of injectable treatment drugs can vary between Brazilian pharmacies as long as they do not exceed the Maximum Consumer Price (PMC, acronym in Portuguese) established by Anvisa. In practice, a single dose of injectables can equal the value of a minimum wage for a month’s formal work, which makes access to the medicine unviable for the most vulnerable populations and too costly for the federal government to subsidize.

In conclusion, the use of GLP-1 receptor agonists such as semaglutide, liraglutide and, in the future, tirzepatide (recently registered with Anvisa) in light of current evidence, lead to proven side effects that compromise quality of life during treatment and later, due to the unknown long-term effects of these innovative drug therapies on the physiological and clinical conditions of this vulnerable population group.

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