Search

Summary: 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. [ABSTRACT FROM AUTHOR]

Introduction: Childhood-onset obesity poses significant health risks, including early-onset type 2 diabetes, cardiovascular disease, and reduced quality of life. Hospital-based non-pharmacological obesity care can reduce childhood obesity, but 25% of children do not respond. Therefore, this study investigates the effect of the glucagon-like peptide-1 receptor agonist, semaglutide, as an add-on to hospital-based obesity care in youth who still have obesity following hospital-based obesity care as children. Furthermore, biomedical and psychosocial factors linked to treatment response will be investigated, alongside an exercise-based strategy to prevent weight regain and maintain a healthy body composition after semaglutide treatment., Methods and Analysis: This is an investigator-initiated, randomised, placebo-controlled, double-blind trial. We will enrol expectedly 180-270 young adults aged 18-28 years based on their previous response to a paediatric obesity management programme and their current body mass index (BMI). Participants are categorised into four groups: low treatment response (BMI SD score (SDS) reduction <0.10; BMI ≥30 kg/m 2 ); medium treatment response (BMI SDS reduction >0.25; BMI ≥30 kg/m 2 ); high treatment response (BMI SDS reduction >0.50; BMI <30 kg/m 2 ) and a population-based reference group with normal weight development in childhood. Participants with BMI ≥30 kg/m 2 are randomised 2:1 to subcutaneous injections of semaglutide 2.4 mg/week or placebo as an add-on to hospital-based obesity care for 68 weeks. The primary outcome is the change in BMI from randomisation to the end of treatment with semaglutide compared with placebo. Secondary endpoints are changes in weight and body composition., Ethics and Dissemination: The trial has been approved by the Danish Medicines Agency and the Ethical Committee of the Capital Region of Denmark (H-20039422). The trial will be conducted in accordance with the Declaration of Helsinki and follow the guidelines for Good Clinical Practice. Results will be presented at international scientific conferences and published in peer-reviewed scientific journals., Trial Registration Number: EudraCT 2019-002274-31., Competing Interests: Competing interests: The planning and conduct of the study, interpretation of data, and writing of manuscripts are completely independent of the funders. SST: Research grants, honoraria for lectures, and membership on an advisory panel for Novo Nordisk. RMS: A family member holds stocks in Novo Nordisk. TH: Holds stocks in Novo Nordisk. JCH: Honoraria for lectures from Novo Nordisk. SB: Support for attending a meeting from Novo Nordisk. JH, LAH, LBH, BJC, and SBKJ report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients' gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The treatment of obesity remains underprioritized. New pharmacologic options for the treatment of obesity have shown effectiveness and safety but are not widely reimbursed. Despite the unmet need and the existence of effective prevention and treatment strategies, substantial barriers exist to effectively address obesity as a disease. The purpose of this scoping review was to investigate the barriers for decision makers in prioritizing interventions for obesity and to seek out interconnection between barriers to prevention and treatment. A scoping review was conducted using a systematic search of both scientific databases and Health Technology Assessment (HTA) databases. Studies that addressed barriers to reimbursement or prioritization of obesity treatment and prevention were included. A total of 26 articles and 14 HTAs were included. Four main barriers for decision makers to prioritize new interventions for obesity were identified: perceptions, knowledge, economics, and politics. There was a high degree of interconnectedness among barriers, as well as large overlaps between barriers in relation to bariatric surgery, pharmacologic treatments, and prevention regulation. Multiple barriers exist that impact decision makers in prioritizing interventions for treating obesity. A strong interconnectedness of the barriers was found, indicating a systems approach to improve global prioritization to address the disease. This study suggests that decision makers should carefully consider all main barriers when addressing the obesity epidemic., (© 2024. The Author(s).)

Context: Pediatric obesity is characterized by insulin resistance, yet it remains unclear whether insulin resistance contributes to abnormalities in glucagon and incretin secretion., Objective: To examine whether fasting and stimulated glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) concentrations differ between children and adolescents with obesity and insulin resistance (OIR), obesity and normal insulin sensitivity (OIS), and controls with normal weight (NW)., Methods: 80 (34 boys) children and adolescents, aged 7-17 years with OIR (n = 22), OIS (n = 22), and NW (n = 36) underwent an oral glucose tolerance test with measurements of serum insulin, plasma glucose, glucagon, total GLP-1, and total GIP. Homeostatic model assessment of insulin resistance (HOMA-IR), single point insulin sensitivity estimator (SPISE), Matsuda index, insulinogenic index (IGI), and oral disposition index (ODI) were calculated., Results: Fasting concentrations of glucagon and GLP-1 were higher in the OIR group, with no significant differences for GIP. The OIR group had higher glucagon total area under the curve (tAUC0-120) and lower GLP-1 incremental AUC (iAUC0-120), with no significant differences in GIP iAUC0-120. Higher fasting glucagon was associated with higher HOMA-IR, lower Matsuda index, lower SPISE, higher IGI, and higher plasma alanine transaminase, whereas higher fasting GLP-1 was associated with higher HOMA-IR, lower Matsuda index, and lower ODI. Higher glucagon tAUC0-120 was associated lower SPISE and lower Matsuda index, whereas lower GLP-1 iAUC0-120 was associated with a higher HOMA-IR, lower Matsuda index, and lower ODI., Conclusion: Children and adolescents with OIR have elevated fasting concentrations of glucagon and GLP-1, higher glucagon and lower GLP-1 responses during an OGTT compared to those with OIS and NW. In contrast, individuals with OIS have similar hormone responses to those with NW., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Polycystic ovary syndrome (PCOS) has historically been conceptualized as a disorder of the reproductive system in women. However, offspring of women with PCOS begin to show metabolic features of PCOS in childhood, suggestive of childhood manifestations., Objective: To identify childhood manifestations of genetic risk for PCOS., Methods: We calculated a PCOS polygenic risk score (PRS) for 12 350 girls and boys in 4 pediatric cohorts-ALSPAC (UK), COPSAC (Denmark), Project Viva (USA), and The HOLBÆK Study (Denmark). We tested for association of the PRS with PCOS-related phenotypes throughout childhood and with age at pubarche and age at peak height velocity and meta-analyzed effects across cohorts using fixed-effect models., Results: Higher PRS for PCOS was associated with higher body mass index in midchildhood (0.05 kg/m2 increase per 1 SD of PRS, 95% CI 0.03, 0.07, P = 3 × 10-5) and higher risk of obesity in early childhood (OR 1.34, 95% CI 1.13, 1.59, P = .0009); both persisted through late adolescence (P all ≤.03). Higher PCOS PRS was associated with earlier age at pubarche (0.85-month decrease per 1 SD of PRS, 95% CI -1.44, -0.26, P = .005) and younger age at peak height velocity (0.64-month decrease per 1 SD of PRS, 95% CI -0.94, -0.33, P = 4 × 10-5)., Conclusion: Genetic risk factors for PCOS are associated with alterations in metabolic, growth, and developmental traits in childhood. Thus, PCOS may not simply be a condition that affects women of reproductive age but, rather, a possible manifestation of an underlying condition that affects both sexes starting in early life., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)