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Anti-obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long-term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end-points, secondary end-points, eligibility criteria, trial run-in and follow-up phases, use of active comparators and guidelines for down-titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end-points, emphasis was placed on moving away from BMI z-score as a primary outcome, incorporating multiple alternative BMI-related outcomes and measuring adiposity/body fat as a prominent secondary end-point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run-in phases was discussed. It was also underscored that designing trials with extended follow-up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo-controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down-titration to avoid excessive weight reduction when applicable., (© 2024 The Author(s). Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Importance: The effectiveness of anti-obesity medications for children and adolescents is unclear., Objective: To update the evidence on the benefits and harms of anti-obesity medication., Data Sources: Cochrane CENTRAL, MEDLINE, ClinicalTrials.gov and WHO ICTRP (1/1/16-17/3/23)., Study Selection: Randomized controlled trials ≥6 months in people <19 years living with obesity., Data Extraction and Synthesis: Screening, data extraction and quality assessment conducted in duplicate, independently., Main Outcomes and Measures: Body mass index (BMI): 95th percentile BMI, adverse events and quality of life., Results: Thirty-five trials (N = 4331), follow-up: 6-24 months; age: 8.8-16.3 years; BMI: 26.2-41.7 kg/m 2 . Moderate certainty evidence demonstrated a -1.71 (95% confidence interval [CI]: -2.27 to -1.14)-unit BMI reduction, ranging from -0.8 to -5.9 units between individual drugs with semaglutide producing the largest reduction of -5.88 kg/m 2 (95% CI: -6.99 to -4.77, N = 201). Drug type explained ~44% of heterogeneity. Low certainty evidence demonstrated reduction in 95th percentile BMI: -11.88 percentage points (95% CI: -18.43 to -5.30, N = 668). Serious adverse events and study discontinuation due to adverse events did not differ between medications and comparators, but medication dose adjustments were higher compared to comparator (10.6% vs 1.7%; RR = 3.74 [95% CI: 1.51 to 9.26], I 2  = 15%), regardless of approval status. There was a trend towards improved quality of life. Evidence gaps exist for children, psychosocial outcomes, comorbidities and weight loss maintenance., Conclusions and Relevance: Anti-obesity medications in addition to behaviour change improve BMI but may require dose adjustment, with 1 in 100 adolescents experiencing a serious adverse event., (© 2024 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Objectives: Associations between body mass index (BMI)- standard deviation score (SDS)/waist-to-height ratio (WHtR) were studied with (i) serum uric acid (sUA)/gamma-glutamyl-transferase (GGT) and (ii) cardiometabolic risk markers in children with obesity, considering sex, pubertal development, and degree of weight loss/type of patient care., Methods: 102 936 children from the Adiposity-Follow-up registry (APV; 47% boys) were included. Associations were analysed between sUA/GGT and anthropometrics, transaminases, lipids, fasting insulin (FI), homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides to HDL-cholesterol (TG/HDL)-ratio. Follow-up analyses (3-24 months after baseline) considered a BMI-SDS reduction ≥0.2 (n = 11 096) or ≥0.5 (n = 3728). Partialized correlation analyses for sex and BMI-SDS were performed, taking pubertal development into consideration., Results: At baseline, BMI-SDS showed the strongest correlations to sUA (r = 0.35; n = 26 529), HOMA-IR/FI (r = 0.30; n = 5513 /n = 5880), TG/HDL-ratio (r = 0.23; n = 24 501), and WHtR to sUA (r = 0.32; n = 10 805), GGT (r = 0.34; n = 11 862) and Alanine-aminotransferase (ALAT) (r = 0.33; n = 11 821), with stronger correlations in boys (WHtR and GGT: r = 0.36, n = 5793) and prepubertal children (r = 0.36; n = 2216). GGT and sUA (after partializing effects of age, sex, BMI-SDS) showed a correlation to TG/HDL-ratio (r = 0.27; n = 24 501). Following a BMI-SDS reduction ≥0.2 or ≥0.5, GGT was most strongly related to Aspartate-aminotransferase (ASAT)/ ALAT, most evident in prepuberty and with increasing weight loss, and also to TG/HDL-ratio (r = 0.22; n = 1528). Prepubertal children showed strongest correlations between BMI-SDS/WHtR and GGT. ΔBMI-SDS was strongly correlated to ΔsUA (r = 0.30; n = 4160) and ΔGGT (r = 0.28; n = 3562), and ΔWHtR to ΔGGT (r = 0.28; n = 3562) (all p < 0.0001)., Conclusion: Abdominal obesity may trigger hyperuricemia and hepatic involvement already in prepuberty. This may be stronger in infancy than anticipated to date. Even moderate weight loss has favourable effects on cardiometabolic risk profile and glucose homeostasis., (© 2022 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Relationships between movement-related behaviours and metabolic health remain underexplored in adolescents with obesity., Objectives: To compare profiles of sedentary time (more sedentary, SED+ vs. less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA+ vs. less active, MVPA-) and combinations of behaviours (SED-/MVPA+, SED-/MVPA-, SED+/MVPA+, SED+/MVPA-) in regard to metabolic health., Methods: One hundred and thirty-four subjects (mean age 13.4 ± 2.2 yrs, mean body mass index [BMI] 98.9 ± 0.7 percentile, 48.5% females) underwent 24 h/7 day accelerometry, anthropometric, body composition, blood pressure (BP), lipid profile and insulin resistance (IR) assessments., Results: Metabolic health was better in SED- [lower fat mass (FM) percentage (p < 0.05), blood pressure (BP) (p < 0.05), homeostasis model assessment of insulin resistance (HOMA-IR) (p < 0.001) and metabolic syndrome risk score (MetScore) (p < 0.001), higher high-density lipoprotein-cholesterol (HDL-c) (p = 0.001)] vs. SED+ group and in MVPA+ [lower triglyceridemia (TG), (p < 0.05), HOMA-IR (p < 0.01) and MetScore (p < 0.001), higher HDL-c (p < 0.01)] vs. MVPA- group after adjustment with age, gender, maturation and BMI. SED-/MVPA+ group had the best metabolic health. While sedentary (p < 0.001) but also MVPA times (p < 0.001) were lower in SED-/MVPA- vs. SED+/MVPA+, SED-/MVPA- had lower FM percentage (p < 0.05), HOMA-IR (p < 0.01) and MetScore (p < 0.05) and higher HDL-c (p < 0.05), independently of BMI. Sedentary time was positively correlated with HOMA-IR and Metscore and negatively correlated with HDL-c after adjustment with MVPA (p < 0.05). MVPA was negatively correlated with HOMA-IR, BP and MetScore and positively correlated with HDL-c after adjustment with sedentary time (p < 0.05)., Conclusion: Lower sedentary time is associated with a better metabolic health independently of MVPA and might be a first step in the management of pediatric obesity when increasing MVPA is not possible., (© 2022 World Obesity Federation.)

Background: Relationships between the severity of obesity and bone health remain underexplored., Objectives: To compare whole-body and localized bone mineral content (BMC) and density (BMD), trabecular bone score (TBS) and hip geometry and strength between adolescents with obesity versus extreme obesity., Methods: This cross-sectional study included 154 adolescents (12-15 years, 62% females) who were classified as having obesity (OG, [95th-99th] percentile) or extreme obesity (EOG, >99th percentile). Fat mass (FM), lean mass (LM), BMC, BMD for total-body-less-head (TBLH), lumbar spine (LS), hip, TBS and geometric and strength indices at the narrow-neck (NN), femoral shaft (FS) and intertrochanteric regions (IT) were assessed by Dual-X-ray Absorptiometry (DXA)., Results: There was no significant sex-interaction. For both sexes, TBLH BMC and BMD were not different between groups. TBS was lower in EOG compared with OG in both sexes in univariate analysis and after adjustment with maturation and body weight (p < 0.05). Hip BMD was significantly higher in the EOG compared to OG only after adjustment with maturation and fat mass percentage (p < 0.05 for men, p < 0.01 for women). For both sexes, TBLH, LS and hip BMC and BMD positively correlated with weight, BMI, LM and FM. TBS negatively correlated with BMI-percentile in both sexes, with a negative correlation with FM for males alone. Hip BMC and BMD, BMD, ACT and CSA at the three hip sites positively correlated with BMI-percentile in males., Conclusions: Extreme obesity impacts bone health depending on anatomical sites, altering lumbar trabecular bone in both males and females adolescents., (© 2021 World Obesity Federation.)

Background: There is evidence that nonalcoholic fatty liver disease (NAFLD) increases the risk for dysglycemia in children in cross-sectional studies. However, the extent to which NAFLD may confer the risk for dysglycemia in longitudinal studies remains uncertain., Objectives: We investigated whether elevated levels of alanine aminotransferase (ALT) as a proxy for NAFLD can serve as a predictor for future dysglycemia among children., Methods: We performed survival analysis up to 11 years of follow-up on longitudinal data of 510 children with overweight and obesity from the Leipzig Childhood Cohort., Results: Children with overweight/obesity and elevated ALT values had a more than 2-fold increased risk (hazard ratio 2.59, 95% confidence interval 1.49 to 4.50; P < 0.01) for future dysglycemia independent of age, sex and BMI-SDS., Conclusions: Elevated transaminases are an early predictor for glycemic deterioration. Hence, NAFLD should further be addressed as a risk factor and therapeutic target for the early prevention of type 2 diabetes., (© 2021 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

The traditional approach to childhood obesity prevention and treatment should fit most patients, but misdiagnosis and treatment failure could be observed in some cases that lie away from average as part of individual variation or misclassification. Here, we reflect on the contributions that high-throughput technologies such as next-generation sequencing, mass spectrometry-based metabolomics and microbiome analysis make towards a personalized medicine approach to childhood obesity. We hypothesize that diagnosing a child as someone with obesity captures only part of the phenotype; and that metabolomics, genomics, transcriptomics and analyses of the gut microbiome, could add precision to the term "obese," providing novel corresponding biomarkers. Identifying a cluster -omic signature in a given child can thus facilitate the development of personalized prognostic, diagnostic, and therapeutic approaches. It can also be applied to the monitoring of symptoms/signs evolution, treatment choices and efficacy, predisposition to drug-related side effects and potential relapse. This article is a narrative review of the literature and summary of the main observations, conclusions and perspectives raised during the annual meeting of the European Childhood Obesity Group. Authors discuss some recent advances and future perspectives on utilizing a systems approach to understanding and managing childhood obesity in the context of the existing omics data., (© 2021 World Obesity Federation.)

While most of the time unconsidered, child and adolescent obesity has been also associated with impaired brain health and function that can definitely affect their social interaction and integration, and then well-being and mental health. The European Childhood Obesity Group recently gathered experts in the field who discussed the main available and reliable evidence regarding the role of physical activity on brain health and cognitive functioning in children and adolescents with obesity and who propose here their main conclusions and recommendations., (© 2020 World Obesity Federation.)

Background: Non-alcoholic fatty liver disease (NAFLD), prediabetes and type 2 diabetes mellitus are known to be closely linked with obesity as early as during childhood., Objectives: The study aimed to determine the prevalence of prediabetes and T2DM in children with obesity with or without increased transaminases., Methods: Data from the observational multicentre (n = 51), cross-sectional Adipositas Patienten Verlaufsbeobachtung registry were analyzed. Mild increase (mild group) was defined by alanine transaminase (ALT) >24 to ≤50 U/L and moderate to severe increase (advanced group) by ALT > 50 U/L. Prediabetes and T2DM were defined according to recent IDF/ISPAD guidelines., Results: The prevalence of prediabetes and T2DM was 11.9% (95% CI: 11.0-12.8) and 1.4% (95% CI: 1.1-1.7) among all participants (n = 4932; male = 2481; mean age 12.9 ± 2.7 years; BMI-SDS 2.1 ± 0.5; Tanner stage 3.2 ± 1.5). The prevalence of impaired glucose metabolism (prediabetes and T2DM) was 13.8% (95% CI: 12.1-15.4) in the mild, 21.9% (95% CI: 18.8-25.1) in the advanced group, 10.7% (95% CI: 9.4-11.9) in the control group. Mild and advanced groups had greater odds ratios for prediabetes [1.42; 95% CI: 1.17-1.72, 2.26-fold; (1.78-2.86), respectively], the advanced group also for T2DM [2.39 (1.36-4.21)] compared to controls. While an increase in transaminases predominantly affected boys, girls within the advanced group had a higher T2DM prevalence than males (5.4 vs. male 2.1%)., Conclusions: Children with obesity and increased liver transaminases as surrogates of NAFLD should be screened for T2DM., (© 2019 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Despite therapeutic potential against obesity and diabetes, the associations of brown adipose tissue (BAT) with glucose metabolism in young humans are relatively unexplored., Objectives: To investigate possible associations between magnetic resonance imaging (MRI) estimates of BAT and glucose metabolism, whilst considering sex, age, and adiposity, in adolescents with normal and overweight/obese phenotypes., Methods: In 143 subjects (10-20 years), MRI estimates of BAT were assessed as cervical-supraclavicular adipose tissue (sBAT) fat fraction (FF) and T 2 * from water-fat MRI. FF and T 2 * of neighbouring subcutaneous adipose tissue (SAT) were also assessed. Adiposity was estimated with a standardized body mass index, the waist-to-height ratio, and abdominal visceral and subcutaneous adipose tissue volumes. Glucose metabolism was represented by the 2h plasma glucose concentration, the Matsuda index, the homeostatic model assessment of insulin resistance, and the oral disposition index; obtained from oral glucose tolerance tests., Results: sBAT FF and T 2 * correlated positively with adiposity before and after adjustment for sex and age. sBAT FF, but not T 2 * , correlated with 2h glucose and Matsuda index, also after adjustment for sex, age, and adiposity. The association with 2h glucose persisted after additional adjustment for SAT FF., Conclusions: The association between sBAT FF and 2h glucose, observed independently of sex, age, adiposity, and SAT FF, indicates a role for BAT in glucose metabolism, which potentially could influence the risk of developing diabetes. The lacking association with sBAT T 2 * might be due to FF being a superior biomarker for BAT and/or to methodological limitations in the T 2 * quantification., (© 2019 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)