The prevalence of obesity is children in the Netherlands is 3-4%. Obesity leads to physical and mental complaints, a high morbidity due to complications and reduced life expectancy. The basis of treatment is combined lifestyle intervention (CLI). CLI has an average effect of 5% on BMI reduction which is often insufficient to reduce the weight related health risk. Since 2020, EMA approved anti-obesity pharmacotherapy, has become available for children/adolescents (Hample, 2023; Ball, 2025). Internationally and nationally, pharmacotherapy is being implemented in the care for children with obesity. Now, Dutch guideline recommendations are needed for its indications.

Metformin

1. Risk of Bias: serious. Lack of details on allocation concealment, Frequent or large difference between study groups in loss to follow-up.; Imprecision: serious. Wide confidence intervals;
2. Risk of Bias: serious. Frequent or large difference between study groups in loss to follow-up.; Imprecision: serious. Wide confidence intervals; Only data from one study.
3. Risk of Bias: serious. Lack of details on allocation concealment, Frequent or large difference between study groups in loss to follow-up.; Imprecision: serious. Wide confidence intervals; Only data from one study.
4. Risk of Bias: serious. Lack of details on allocation concealment, Frequent or large difference between study groups in loss to follow-up.; Imprecision: serious. Wide confidence intervals; Only data from one study.
5. Risk of Bias: serious. Lack of details on allocation concealment, Frequent or large difference between study groups in loss to follow-up.; Imprecision: serious. Wide confidence intervals; Only data from one study.
6. Risk of Bias: serious. Lack of details on allocation concealment.; Imprecision: serious. Only data from one study.

GLP-1 agonist

1. Risk of Bias: serious. Usually commercially funded studies.; Imprecision: very serious. Wide confidence intervals;
2. Risk of Bias: serious. Usually commercially funded studies.; Imprecision: very serious. Wide confidence intervals;
3. Risk of Bias: serious. Usually commercially funded studies.; Inconsistency: serious. Inconsistent results; Imprecision: very serious. Wide confidence intervals;
4. Risk of Bias: serious. Usually commercially funded studies.;
5. Risk of Bias: serious. Usually commercially funded studies.; Imprecision: serious. Wide confidence intervals;
6. Risk of Bias: serious. Usually commercially funded studies.;

Description of studies

A total of five studies were included in the analysis of the literature. Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).

Torbahn (2024) conducted a Cochrane systematic review and meta-analyses. The systematic review included studies published from 1 January 2016 to 17 March 2023. All studies included in de previous Cochrane review (Mead, 2016) were carried forward. The review included RCTs of children and adolescents with obesity aged <19 years. Interventions included any antiobesity medication, which aimed to treat paediatric obesity. The intervention had to be ≥ 12-weeks with a minimum of 6 months follow-up from baseline. Comparators could be placebo, usual care and/or other therapies including surgical interventions. Torbahn (2024) included 35 trials, of which we selected six studies that met our PICO and follow-up length of at least 12 months.

Kelly (2023) conducted a post hoc analysis of the double-blind, phase 3a randomized controlled Semaglutide Treatment Effect in People with obesity (STEP) TEENS trial. The study was conducted at 37 sites across eight countries, and included adolescents aged 12 to <18 years, with BMI ≥95th percentile or with BMI ≥85th percentile with at least one weight-related comorbidity.

Babakir (2025) conducted a retrospective cohort study at a specialized children’s hospital in Saudi Arabia. Inclusion criteria were children and adolescents aged 12 – 14 years with simple obesity who were evaluated in the pediatric endocrinology clinics from January 2019 to December 2022.

Ruiz Pons (2025) conducted a retrospective observational study in adolescent patients aged 12 – 18 years with obesity (BMI ≥ P95) at the nutrition and metabolic disease unit of a tertiary care hospital in Spain between February 2022 and January 2024.

Fox (2025) conducted a phase 3a randomized controlled trial (the SCALE kids trial). The study was conducted at 23 sites across nine countries, and included children aged 6 to <12 years with obesity (age-adjusted and sex-adjusted BMI in the 95th percentile or higher).

Table 2. Characteristics of included studies

*For further details, see risk of bias table in the appendix

Results

In total, four studies reported on the effects of metformin and six studies reported on the effects of GLP-1 agonists, of which two studies reported on the effects of semaglutide and four studies reported on the effects of liraglutide. Eight of these studies were RCTs and two studies were observational studies. None of the included studies reported on the effects of tirzepatide or naltrexon bupropion.

BMI

All included studies reported the effect of pharmacotherapy on BMI (Fox, 2025; Kelly, 2020; Ruiz Pons, 2025; Weghuber, 2022; Van der Aa, 2016; Kelly, 2023, Clarson, 2014; Bassols, 2019; Babakir, 2025; Warnakulasuriya, 2018). Four studies reported the percentage change of BMI (Fox, 2025; Kelly, 2020; Ruiz Pons, 2025; Weghuber, 2022), one study reported the median (interquartile range) BMI-SDS (Van der Aa, 2016), one study reported the proportion of children achieving a normal weight (Kelly, 2023), one study reported change in BMI (Babakir, 2025) and three studies reported change in BMI z score (Clarson, 2014; Bassols, 2019; Warnakulasuriya, 2018).

Metformin

Three studies reported on the effect of metformin on BMI (Clarson, 2014; Bassols, 2019; Warnakulasuriya, 2018). The pooled data shows a mean difference (MD) of -0.21 (95% CI: -0.63 to 0.21) change in BMI-SDS, in favor of the metformin group (figure 1). This difference is considered clinically relevant.

In addition, Van der Aa (2016) reported a median change in BMI SDS of -0.12 (-0.50 to 0.08) in the metformin group, compared to a median change of 0.04 (-0.24 to 0.10) in the control group.

Figure 1. Forest plot of pooled analysis of the effect of metformin on change in BMI-SDS

Liraglutide

Three studies, of which two RCTs (Kelly, 2020; Fox, 2025) and one observational study (Ruiz Pons, 2025), reported on the effect of liraglutide on BMI (Kelly, 2020; Fox, 2025; Ruiz Pons, 2025).

The two RCTs showed a mean difference of -5.20% (95% CI: -19.26% to 8.87%) change in BMI, in favor of the liraglutide group (figure 2). The SMD is -2.99% (95%CI: -30.65% to 24.67%). This difference is considered clinically relevant.

The observational study showed a mean difference of -6,89% (95% CI: - 8.85 to -4.93%) change in BMI, in favor of the liraglutide group (figure 2). The SMD is -2.12% (95%CI: -2.89% to -1.35%). This difference is considered clinically relevant.

Figure 2. Forest plot of pooled analysis of the effect of liraglutide on change in BMI

Semaglutide

Three studies, of which two RCTs (Weghuber, 2022; Kelly, 2023) and one observational study (Babakir, 2025), reported on the effect of semaglutide on BMI. Weghuber (2022) reported a mean difference of -16.70% (-20.3% to -13.2%), in favor of the semaglutide group. The SMD is -1.37 (-1.70 to -1.05). This difference is considered clinically relevant.

In addition, Kelly (2023) reported that in the semaglutide group, 44.9% of the children achieved a normal weight or overweight, compared to 12.1% in the control group.

The observational study (Babakir, 2025) reported a mean difference of -1.10 (-3.75 to 1.55) for T3 versus baseline in the semaglutide group compared to a mean difference of -0.14 (-2.82 to 2.54) in the control group. This difference was not considered clinically relevant.

Waist circumference

Four studies reported the effect of pharmacotherapy on waist circumference (Kelly, 2020; Weghuber, 2022; Ruiz Pons, 2025; Fox, 2025).

Metformin

Warnakulasuriya (2018) reported on the effect of metformin on waist circumference. The mean difference was -1.93 (-3.14 to -0.70) cm, in favor of the metformin group. This difference was considered clinically relevant.

Liraglutide

Three studies, of which two RCTs (Kelly, 2020; Fox, 2025) and one observational study (Ruiz Pons, 2025), reported on the effect of liraglutide on waist circumference. The two RCTs showed a mean change in waist circumference of -2.93 (95% CI: -3.10 to -2.76) cm, in favor of the liraglutide group (figure 3). This difference is considered clinically relevant.

The observational study showed a mean change in waist circumference of -4.81 (95% CI: - 6.68 to -2.76%) cm, in favor of the liraglutide group (figure 3). This difference is considered clinically relevant.

Semaglutide

Weghuber (2022) reported on the effect of semaglutide on waist circumference. The mean difference was -12.10 (-15.6 to -8.6) cm, in favor of the semaglutide group. This difference was considered clinically relevant.

Figure 3. Forest plot of pooled analysis of the effect of liraglutide on change in waist circumference

Cardiometabolic risk factors

Blood pressure

Four studies reported the effect of pharmacotherapy on blood pressure (diastolic and systolic) (Clarson, 2014; Kelly, 2020; Weghuber, 2022; Fox, 2025).

Metformin

Clarson (2014) reported on the effect of metformin on blood pressure. The mean difference was in diastolic blood pressure was -0.20 (-0.55 to 0.15) mm HG, in favor of the metformin group. The SMD was -0.27 (-0.75 to 0.20). This difference was not considered clinically relevant.

The mean difference in systolic blood pressure was -0.07 (-0.37 to 0.23) mm HG, in favor of the metformin group. The SMD was -0.11 (-0.59 to 0.36). This difference was not considered clinically relevant.

Liraglutide

Two studies on the effect of liraglutide on diastolic blood pressure (Kelly, 2020; Fox, 2025). The mean difference in diastolic blood pressure was -1.06 (-35.15 to 11.01) mm Hg, in favor of the liraglutide group (figure 4). The SMD is 0.67 (-13.55 to 14.88). This difference was considered clinically relevant.

The mean difference in systolic blood pressure was -2.06 (-3.16 to -0.95) mm Hg, in favor of the liraglutide group (figure 5). The SMD is -1.37 (-2.59 to -1.95). This difference was considered clinically relevant.

Figure 4. Forest plot of pooled analysis of the effect of liraglutide on change in diastolic blood pressure

Figure 5. Forest plot of pooled analysis of the effect of liraglutide on change in systolic blood pressure

Semaglutide

Weghuber (2022) reported on the effect of semaglutide on diastolic blood pressure. The mean difference was -0.60 (-3.00 to 1.80) mm Hg, in favor of the semaglutide group. The SMD is -0.07 (-0.37 to 0.22). This difference was not considered clinically relevant.

The mean difference in systolic blood pressure was -1.90 (-4.95 to 1.15) mm Hg, in favor of the semaglutide group. The SMD is -0.18 (-0.48 to 0.11). This difference was not considered clinically relevant.

Quality of life (generic or weight related)

Three studies reported the effect of pharmacotherapy on quality of life (Kelly, 2020; Weghuber, 2022; Van der Aa, 2016), all using the Impact of Weight on Quality of Life – Kids (IWQOL-Kids) questionnaire.

Metformin

Van der Aa (2016) reported a median change in total IWQOL-score of 2.6 (0.2 to 5.7) in the metformin group, compared to a median change of 5.2 (-2.2 to 9.6) in the control group. This difference is not considered clinically relevant.

Liraglutide

Kelly (2020) reported a mean difference of 1.31 (−1.57 to 4.20) between the liraglutide group and the placebo group. This difference is not considered clinically relevant.

Semaglutide

Weghuber (2022) reported a mean difference of 4.3 (0.2 to 8.3) between the semaglutide group and the placebo group. This difference is not considered clinically relevant.

Adverse events or side effects

Four studies reported on the outcome measure adverse events (Clarson, 2014; Weghuber, 2022; Fox, 2025; Ruiz Pons, 2025).

Metformin

Clarson (2014) reported no severe medication related adverse events.

Liraglutide

One RCT (Fox, 2025) reported 50/56 (89%) adverse events in the liraglutide group compared to 23/26 (88%) in the control group. The RR is 1.01 (0.86 to 1.19). One observational study (Ruiz Pons, 2025) reported that the most frequent adverse events were gastrointestinal, especially abdominal pain, however no numbers were provided in the article. These differences are not considered clinically relevant.

Semaglutide

Weghuber (2022) reported that 105/131 (79%) in the semaglutide group compared to 55/67 (82%) in the control group experience an adverse event. The RR is 0.98 (0.85 to 1.12). This difference is not considered clinically relevant.

Discontinuation rates (or medication adherence/treatment adherence)

Four studies reported discontinuation rates (Van der Aa, 2016; Kelly, 2023; Ruiz Pons, 2025; Foz, 2025).

Metformin

Van der Aa (2016) reported two participants (8.7%) in the metformin group who discontinued the study due to adverse effects: one due to severe nausea despite dose reduction, and one due to abdominal pain. No participants in the control group discontinued due to adverse events.

Liraglutide

One RCT (Fox, 2025) reported that six participants (11%) in the liraglutide group discontinued the study because of adverse events. No discontinuations due to adverse events occurred in the

control group.

One observational study (Ruiz Pons, 2025) reported that five participants (16%) in the liraglutide group discontinued the study. In addition, eleven patients reported difficulties with adhering to treatment consistently due to shortages in pharmacies and/or the financial cost to the family.

Semaglutide

Kelly (2023) reported 14 participants in the semaglutide group (10.5%) who discontinued the study: six due to adverse events, two due to protocol violation, one due to pregnancy, one due to withdrawal of consent and four due to other reasons. In the control group, seven participants (10.4%) discontinued the study: four due to adverse events, one due to protocol violation, one due to withdrawal of consent and one other reason. 

A systematic review of the literature was performed to answer the following question(s):

What is the effect of pharmacotherapy in children and adolescents with obesity on health outcomes?

Table 1. PICO

Relevant outcome measures

The guideline panel considered BMI, quality of life, cardiometabolic risk factors and adverse events as critical outcomes measure for decision making; and waist circumference and discontinuation rates as important outcomes measure for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies.

The guideline panel defined the following as a minimal clinically (patient) important differences:

• BMI z-score or BMI-SDS ³ 0.2 SD.
• Quality of life:
  • ∆PedsQL ³ 4.4.
  • ∆IWQoL ³ 4.8;
• Waist circumference:
  • change ³ 1 cm;
  • z-score ³ 0,1 SD.

For all other outcomes, a difference of 25% (RR < 0.75 or > 1.25) for dichotomous outcomes or -0.5 < SMD > 0.5 for continuous outcomes was used as a minimal clinical difference.

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 2015 to the 24th of Juli 2025 for systematic reviews, RCTs and observational studies. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from three primary search concepts: (1) obesity; (2) children; (3) medication. Duplicates were removed using EndNote software. After deduplication a total of 1246 records were imported for title/abstract screening. Titles and abstracts were screened using the ASReview software. The settings ELAS u4 (TF-IDF and SVM) were used. Weghuber (2022) was used as prior knowledge for inclusion. The articles were screened by the guideline methodologist, using the following stopping rule: stop after 10% of the total set subsequent exclusions. Based on title and abstract, 60 articles were initially selected, and 1186 studies were excluded. After screening the full-text articles, one systematic review and four additional studies were included, and 55 studies were excluded (see the table with reasons for exclusion under the tab Methods).

1. Babiker A, Alfaraidi H, Aljarallah G, Albaraki J, Alharbi R, Alsomali N, Alkhalaf A, Yenugadhati N, Al Juraibah F, Al Alwan I. The metabolic effect of combined liraglutide treatment and lifestyle modification on obese adolescents in a tertiary center, Riyadh. Front Endocrinol (Lausanne). 2025 Apr 15;16:1573109. doi: 10.3389/fendo.2025.1573109. PMID: 40303643; PMCID: PMC12037372.
2. Ball GDC, Merdad R, Birken CS, Cohen TR, Goodman B, Hadjiyannakis S, Hamilton J, Henderson M, Lammey J, Morrison KM, Moore SA, Mushquash AR, Patton I, Pearce N, Ramjist JK, Lebel TR, Timmons BW, Buchholz A, Cantwell J, Cooper J, Erdstein J, Fitzpatrick-Lewis D, Hatanaka D, Lindsay P, Sajwani T, Sebastianski M, Sherifali D, Pierre JS, Ali MU, Wijesundera J, Alberga AS, Ausman C, Baluyot TC, Burke E, Dadgostar K, Delacruz B, Dettmer E, Dymarski M, Esmaeilinezhad Z, Hale I, Harnois-Leblanc S, Ho J, Gehring ND, Kucera M, Langer JC, McPherson AC, Naji L, Oei K, O'Malley G, Rigsby AM, Wahi G, Zenlea IS, Johnston BC. Managing obesity in children: a clinical practice guideline. CMAJ. 2025 Apr 13;197(14):E372-E389. doi: 10.1503/cmaj.241456. Erratum in: CMAJ. 2025 Jul 1;197(24):E697. doi: 10.1503/cmaj.250898. PMID: 40228835; PMCID: PMC12007946.
3. Bassols J, Martínez-Calcerrada JM, Osiniri I, Díaz-Roldán F, Xargay-Torrent S, Mas-Parés B, Dorado-Ceballos E, Prats-Puig A, Carreras-Badosa G, de Zegher F, Ibáñez L, López-Bermejo A. Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: A pilot study. PLoS One. 2019 Dec 10;14(12):e0226303. doi: 10.1371/journal.pone.0226303. PMID: 31821361; PMCID: PMC6903728.
4. Clarson CL, Brown HK, De Jesus S, Jackman M, Mahmud FH, Prapavessis H, Robinson T, Shoemaker JK, Watson M, Dowd AJ, Hill DJ. Effects of a Comprehensive, Intensive Lifestyle Intervention Combined with Metformin Extended Release in Obese Adolescents. Int Sch Res Notices. 2014 Nov 10;2014:659410. doi: 10.1155/2014/659410. PMID: 27433488; PMCID: PMC4897295.
5. Fox CK, Barrientos-Pérez M, Bomberg EM, Dcruz J, Gies I, Harder-Lauridsen NM, Jalaludin MY, Sahu K, Weimers P, Zueger T, Arslanian S; SCALE Kids Trial Group. Liraglutide for Children 6 to <12 Years of Age with Obesity - A Randomized Trial. N Engl J Med. 2025 Feb 6;392(6):555-565. doi: 10.1056/NEJMoa2407379. Epub 2024 Sep 10. PMID: 39258838.
6. Hampl SE, Hassink SG, Skinner AC, Armstrong SC, Barlow SE, Bolling CF, Avila Edwards KC, Eneli I, Hamre R, Joseph MM, Lunsford D, Mendonca E, Michalsky MP, Mirza N, Ochoa ER, Sharifi M, Staiano AE, Weedn AE, Flinn SK, Lindros J, Okechukwu K. Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity. Pediatrics. 2023 Feb 1;151(2):e2022060640. doi: 10.1542/peds.2022-060640. Erratum in: Pediatrics. 2024 Jan 1;153(1):e2023064612. doi: 10.1542/peds.2023-064612. PMID: 36622115.
7. Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, Hale PM, Marcus C, Mastrandrea LD, Prabhu N, Arslanian S; NN8022-4180 Trial Investigators. A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N Engl J Med. 2020 May 28;382(22):2117-2128. doi: 10.1056/NEJMoa1916038. Epub 2020 Mar 31. PMID: 32233338.
8. Kelly AS, Arslanian S, Hesse D, Iversen AT, Körner A, Schmidt S, Sørrig R, Weghuber D, Jastreboff AM. Reducing BMI below the obesity threshold in adolescents treated with once-weekly subcutaneous semaglutide 2.4 mg. Obesity (Silver Spring). 2023 Aug;31(8):2139-2149. doi: 10.1002/oby.23808. Epub 2023 Jul 9. PMID: 37196421.
9. McGowan B, Ciudin A, Baker JL, Busetto L, Dicker D, Frühbeck G, Goossens GH, Monami M, Sbraccia P, Martinez-Tellez B, Woodward E, Yumuk V. Framework for the pharmacological treatment of obesity and its complications from the European Association for the Study of Obesity (EASO). Nat Med. 2025 Oct;31(10):3229-3232. doi: 10.1038/s41591-025-03765-w. PMID: 41039115.
10. Ruiz Pons M, Gutiérrez Vilar M, García Zurita C, Fuentes Ferrer ME, Pérez Rodríguez A, Rosado Alonso C. Effectiveness of liraglutide in the treatment of adolescent obesity. An Pediatr (Engl Ed). 2025 Jul;103(1):503856. doi: 10.1016/j.anpede.2025.503856. Epub 2025 Jul 10. PMID: 40645873.
11. Torbahn G, Jones A, Griffiths A, Matu J, Metzendorf MI, Ells LJ, Gartlehner G, Kelly AS, Weghuber D, Brown T. Pharmacological interventions for the management of children and adolescents living with obesity-An update of a Cochrane systematic review with meta-analyses. Pediatr Obes. 2024 May;19(5):e13113. doi: 10.1111/ijpo.13113. Epub 2024 Mar 7. PMID: 38454737.
12. van der Aa MP, Elst MA, van de Garde EM, van Mil EG, Knibbe CA, van der Vorst MM. Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial. Nutr Diabetes. 2016 Aug 29;6(8):e228. doi: 10.1038/nutd.2016.37. PMID: 27571249; PMCID: PMC5022149.
13. Warnakulasuriya LS, Fernando MMA, Adikaram AVN, Thawfeek ARM, Anurasiri WL, Silva RR, Sirasa MSF, Rytter E, Forslund AH, Samaranayake DL, Wickramasinghe VP. Metformin in the Management of Childhood Obesity: A Randomized Control Trial. Child Obes. 2018 Nov/Dec;14(8):553-565. doi: 10.1089/chi.2018.0043. Epub 2018 Aug 2. PMID: 30070925.
14. Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, Kelly AS, Mastrandrea LD, Sørrig R, Arslanian S; STEP TEENS Investigators. Once-Weekly Semaglutide in Adolescents with Obesity. N Engl J Med. 2022 Dec 15;387(24):2245-2257. doi: 10.1056/NEJMoa2208601. Epub 2022 Nov 2. PMID: 36322838; PMCID: PMC9997064.