Pediatric Obesity Pharmacotherapy: State of the Science, Research Gaps, and Opportunities.

Pediatric obesity is a major public health problem, affecting nearly 20% of children and adolescents living in the United States. In 2023, the American Academy of Pediatrics released its first clinical practice guideline for the evaluation and management of child and adolescent obesity and recommended integrating health behavior and lifestyle interventions with pharmacological treatment when medically indicated. However, there is a limited evidence base to guide antiobesity medication treatment decisions in clinical practice and limited data on long-term safety during this critical period of growth and development in youth. Thus, in November of 2023, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop to identify knowledge gaps and opportunities for research on the use of pharmacotherapy for obesity in children and adolescents. Leading scientific and clinical experts in obesity pathophysiology and treatment, pharmacotherapy, clinical trial design, and health equity and disparities, among others, identified gaps in clinical trial design, guidance for clinical use of medications in children and adolescents, additional treatment outcomes beyond body fat or weight, and improvement in care delivery. Adolescent patients and caregivers with lived experience of obesity and weight management were also invited to participate in a panel discussion, providing personal perspectives on living with obesity, clinical care considerations, and research needs. This article summarizes the workshop proceedings on the state of the science and identifies gaps and opportunities for future research to inform optimal and equitable medical management of children and adolescents with obesity.

Association between endogenous sex hormones and adiposity in youth across a weight status spectrum.

BACKGROUND: While endogenous sex hormones (e.g., testosterone, estradiol) are important factors regulating adipose tissue distribution, studies evaluating such relationships in youth across a wide weight status spectrum are limited. METHODS: We performed a cross-sectional analysis of 8-21-year-old youth. Multiple linear regression models were used to evaluate associations between sex hormones and adiposity measures (android/gynoid ratio (A/G), total fat mass (FM), visceral adipose tissue (VAT), waist circumference (WC)) and total lean mass (LM), adjusting for pubertal stage and race/ethnicity, and stratified by sex and weight status. RESULTS: Among 342 youth, the mean age was 13.0 ± 2.8 years old (52.6% female; 38.9% normal weight [NW]; 27.8% overweight/obesity [OW/OB]; 33.3% severe obesity [SO]). Testosterone was positively associated with LM among males with NW (1462 g, 95% CI: 255-2668 g) and OW/OB (3792 g, 95% CI: 1244-6340 g), with A/G and WC among males with NW (0.01, 95% CI: 0-0.2 and 10 mm, 95% CI: 4-16 mm, respectively), and negatively associated with WC among males with SO (-43 mm, -81 to -5 mm). Estradiol was positively associated with A/G, FM, and WC among males with SO, and VAT in females with NW. CONCLUSION: Our findings showed that sex hormones were associated with adipose tissue deposition in youth across the weight spectrum. IMPACT STATEMENT: Sex hormones (e.g., testosterone, estradiol) are associated with various adiposity measures among male and female children and adolescents across a weight status spectrum. We evaluated associations between sex hormones and various adiposity measures among 8-21-year-olds across a weight status spectrum (normal weight, overweight/class 1 obesity, class 2-3 obesity). We found that estradiol was positively associated with total fat mass, android/gynoid ratio, and waist circumference in males with class 2-3 obesity, and testosterone was positively associated with lean mass in males with normal weight and overweight/class 1 obesity. Sex hormones may influence, or may be influenced by, adiposity in youth.

Anti-Obesity Medication in the Management of Children and Adolescents With Obesity: Recent Developments and Research Gaps.

BACKGROUND: Paediatric obesity is a global public health concern. While in most countries the incidence keeps rising, the need for effective and long-term management for children and adolescents living with this chronic, relapsing disease is pressing. Health behaviour and lifestyle treatment (HBLT) is recommended as first-line treatment. METHODS: Narrative review. RESULTS: A new generation of recently approved anti-obesity medications (AOM) now has the potential to fill the gap between limited effects on body mass index (BMI) by HBLT alone and large effects by metabolic and bariatric surgery in adolescents with obesity aged 12 years and older. While, for semaglutide and phentermine/topiramate, effectiveness is substantial with relevant, but mostly mild to moderate adverse events, there is a gap in evidence regarding long-term effects and safety, effects on outcomes beyond BMI reduction and data for certain groups of patients, such as children < 12 years and minority groups. When integrating AOM treatment into national healthcare systems it should be offered as part of a comprehensive patient-centred approach. CONCLUSION: This article summarizes recent AOM developments, integration into paediatric obesity management, and identifies research gaps.

Do Children's Health Behaviors Buffer the Impact of Cumulative Environmental Stress on Emerging Cardiometabolic Risk?

BACKGROUND: Previous studies have found that exposure to childhood environmental stress is associated with cardiometabolic risk. However, it is not known whether individual health behaviors disrupt this relationship. This study prospectively evaluated the relationship between cumulative environmental stress in a low-income sample and cardiometabolic risk in middle childhood and examined whether child health behaviors attenuated this relationship. METHODS AND RESULTS: In a cohort of children (n=338; 57% Hispanic children; 25% Black children), environmental stressors (family and neighborhood factors representing disadvantage/deprivation) and child health behaviors (accelerometry measured physical activity; parent-reported screen time and diet recalls) were measured over 5 time points beginning when children were aged 2 to 4 years and ending when they were aged 7 to 11 years. Children's cardiometabolic risk factors (body mass index, blood pressure, triglyceride/high-density lipoprotein ratio, glucose, hemoglobin A1c, C-reactive protein) were measured at 7 to 11 years. Emerging cardiometabolic risk was defined as having ≥1 elevations that exceeded clinical thresholds. In adjusted path analyses, greater cumulative environmental stress was associated with higher likelihood of emerging cardiometabolic risk in middle childhood (P<0.001). Higher levels of moderate to vigorous physical activity and fewer sedentary minutes attenuated the positive relationship between stress and cardiometabolic risk (P<0.05). Children with >2 hours of average daily screen time had a higher likelihood of elevated cardiometabolic risk (P<0.01), but screen time did not moderate the stress-cardiometabolic risk relationship. Dietary intake was not related to cardiometabolic risk. CONCLUSIONS: Interventions that promote moderate to vigorous physical activity and limit sedentary behavior may have particular importance for the cardiometabolic health of children exposed to high levels of cumulative environmental stress.

Considerations for the design and conduct of pediatric obesity pharmacotherapy clinical trials: Proceedings of expert roundtable meetings.

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.

Obesity in Adolescents: A Review.

Importance: Obesity affects approximately 21% of US adolescents and is associated with insulin resistance, hypertension, dyslipidemia, sleep disorders, depression, and musculoskeletal problems. Obesity during adolescence has also been associated with an increased risk of mortality from cardiovascular disease and type 2 diabetes in adulthood. Observations: Obesity in adolescents aged 12 to younger than 18 years is commonly defined as a body mass index (BMI) at the 95th or greater age- and sex-adjusted percentile. Comprehensive treatment in adolescents includes lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery. Lifestyle modification therapy, which includes dietary, physical activity, and behavioral counseling, is first-line treatment; as monotherapy, lifestyle modification requires more than 26 contact hours over 1 year to elicit approximately 3% mean BMI reduction. Newer antiobesity medications, such as liraglutide, semaglutide, and phentermine/topiramate, in combination with lifestyle modification therapy, can reduce mean BMI by approximately 5% to 17% at 1 year of treatment. Adverse effects vary, but severe adverse events from these newer antiobesity medications are rare. Surgery (Roux-en-Y gastric bypass and vertical sleeve gastrectomy) for severe adolescent obesity (BMI ≥120% of the 95th percentile) reduces mean BMI by approximately 30% at 1 year. Minor and major perioperative complications, such as reoperation and hospital readmission for dehydration, are experienced by approximately 15% and 8% of patients, respectively. Determining the long-term durability of all obesity treatments warrants future research. Conclusions and Relevance: The prevalence of adolescent obesity is approximately 21% in the US. Treatment options for adolescents with obesity include lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery. Intensive lifestyle modification therapy reduces BMI by approximately 3% while pharmacotherapy added to lifestyle modification therapy can attain BMI reductions ranging from 5% to 17%. Surgery is the most effective intervention for adolescents with severe obesity and has been shown to achieve BMI reduction of approximately 30%.

Assessing the state of obesity care: Quality, access, guidelines, and standards.

Background: An international panel of obesity medicine experts from multiple professional organizations examined patterns of obesity care and current obesity treatment guidelines to identify areas requiring updating in response to emerging science and clinical evidence. Aims: The panel focused on multiple medical health and societal issues influencing effective treatment of obesity and identified several unmet needs in the definition, assessment, and care of obesity. Methods: The panel was held in Leesburg, Virginia in September 2019. Results: The panelists recommended addressing these unmet needs in obesity medicine through research, education, evaluation of delivery and payment of care, and updating clinical practice guidelines (CPG) to better reflect obesity's pathophysiological basis and heterogeneity, as well as the disease's health, sociocultural, and economic complications; effects on quality of life; need for standards for quantitative comparison of treatment benefits, risks, and costs; and the need to more effectively integrate obesity treatment guidelines into routine clinical practice and to facilitate more direct clinician participation to improve public understanding of obesity as a disease with a pathophysiological basis. The panel also recommended that professional organizations working to improve the care of people with obesity collaborate via a working group to develop an updated, patient-focused, comprehensive CPG establishing standards of care, addressing identified needs, and providing for routine, periodic review and updating. Conclusions: Unmet needs in the definition, assessment and treatment of obesity were identified and a blueprint to address these needs developed via a clinical practice guideline that can be utilized worldwide to respond to the increasing prevalence of obesity.

High BMI z-Scores from Different Growth References Are Not Comparable: An Example from a Weight Management Trial with an Anti-Obesity Medication in Pubertal Adolescents with Obesity.

Background: The BMI z-score is a standardized measure of weight status and weight change in children and adolescents. BMI z-scores from various growth references are often considered comparable, and differences among them are underappreciated. Methods: This study reanalyzed data from a weight management clinical study of liraglutide in pubertal adolescents with obesity using growth references from CDC 2000, CDC Extended, World Health Organization (WHO), and International Obesity Task Force. Results: BMI z-score treatment differences varied 2-fold from -0.13 (CDC 2000) to -0.26 (WHO) overall and varied almost 4-fold from -0.05 (CDC 2000) to -0.19 (WHO) among adolescents with high baseline BMI z-score. Conclusions: Depending upon the growth reference used, BMI z-score endpoints can produce highly variable treatment estimates and alter interpretations of clinical meaningfulness. BMI z-scores cited without the associated growth reference cannot be accurately interpreted.

Effectiveness and predictors of weight loss response to phentermine plus lifestyle modifications among youth in a paediatric weight management clinical setting.

BACKGROUND: Anti-obesity medications (AOMs) are promising lifestyle modification (LSM) adjuncts for obesity treatment, and phentermine is commonly prescribed in paediatric weight management clinics. Determining 'real-world' AOM effectiveness and characteristics predicting response is important. OBJECTIVES: We sought to describe phentermine plus LSM effectiveness and identify baseline characteristics predicting response. METHODS: This was a retrospective cohort study among youth seen in a US academic-based weight management clinic from 2012 to 2020. Baseline characteristics (e.g., body mass index (BMI), liver transaminases, eating-related behaviours) and outcomes (%BMI of 95th percentile (%BMIp95), BMI, %BMI change, weight) were determined through electronic health records and intake surveys. RESULTS: Among 91 youth prescribed phentermine plus LSM over 8 years (mean %BMIp95 150%), %BMIp95 was statistically significantly reduced at 1.5, 3, 6 and 12 months (peak reduction 10.9 percentage points at 6 months; p < 0.001). Considering multiple comparisons, the presence of baseline elevated alanine aminotransferase was associated with statistically significant smaller 1.5-month %BMIp95 reductions (p = 0.001) and higher food responsiveness with smaller 3- (p = 0.001) and 6-month (p < 0.001) reductions. CONCLUSIONS: Phentermine plus LSM reduced %BMIp95 among youth in a weight management clinic, and baseline characteristics may help determine those more or less likely to respond. Prospective studies are needed to further characterize effectiveness and confirm response predictors.

Financial Incentives and Treatment Outcomes in Adolescents With Severe Obesity: A Randomized Clinical Trial.

Importance: Adolescent severe obesity is usually not effectively treated with traditional lifestyle modification therapy. Meal replacement therapy (MRT) shows short-term efficacy for body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) reduction in adolescents, and financial incentives (FIs) may be an appropriate adjunct intervention to enhance long-term efficacy. Objective: To evaluate the effect of MRT plus FIs vs MRT alone on BMI, body fat, and cardiometabolic risk factors in adolescents with severe obesity. Design, Setting, and Participants: This was a randomized clinical trial of MRT plus FIs vs MRT alone at a large academic health center in the Midwest conducted from 2018 to 2022. Participants were adolescents (ages 13-17 y) with severe obesity (≥120% of the 95th BMI percentile based on sex and age or ≥35 BMI, whichever was lower) who were unaware of the FI component of the trial until they were randomized to MRT plus FIs or until the end of the trial. Study staff members collecting clinical measures were blinded to treatment condition. Data were analyzed from March 2022 to February 2024. Interventions: MRT included provision of preportioned, calorie-controlled meals (~1200 kcals/d). In the MRT plus FI group, incentives were provided based on reduction in body weight from baseline. Main Outcomes and Measures: The primary end point was mean BMI percentage change from randomization to 52 weeks. Secondary end points included total body fat and cardiometabolic risk factors: blood pressure, triglyceride to high-density lipoprotein ratio, heart rate variability, and arterial stiffness. Cost-effectiveness was additionally evaluated. Safety was assessed through monthly adverse event monitoring and frequent assessment of unhealthy weight-control behaviors. Results: Among 126 adolescents with severe obesity (73 female [57.9%]; mean [SD] age, 15.3 [1.2] years), 63 participants received MRT plus FIs and 63 participants received only MRT. At 52 weeks, the mean BMI reduction was greater by -5.9 percentage points (95% CI, -9.9 to -1.9 percentage points; P = .004) in the MRT plus FI compared with the MRT group. The MRT plus FI group had a greater reduction in mean total body fat mass by -4.8 kg (95% CI, -9.1 to -0.6 kg; P = .03) and was cost-effective (incremental cost-effectiveness ratio, $39 178 per quality-adjusted life year) compared with MRT alone. There were no significant differences in cardiometabolic risk factors or unhealthy weight-control behaviors between groups. Conclusions and Relevance: In this study, adding FIs to MRT resulted in greater reductions in BMI and total body fat in adolescents with severe obesity without increased unhealthy weight-control behaviors. FIs were cost-effective and possibly promoted adherence to health behaviors. Trial Registration: ClinicalTrials.gov Identifier: NCT03137433.

Clinical effectiveness and predictors of response to topiramate plus lifestyle modification in youth with obesity seen in a weight management clinical setting.

Introduction: Obesity affects approximately 20% of U.S. youth. Anti-obesity medications (AOMs) are promising lifestyle modification adjuncts for obesity treatment, and topiramate is commonly prescribed in pediatric weight management clinics. It is important to determine "real-world" effectiveness of AOMs and, given shifts towards personalized approaches, characteristics potentially predicting better or worse response. We therefore sought to describe clinical effectiveness from topiramate plus lifestyle modification, and to determine if baseline phenotypic characteristics are associated with better or worse response. Methods: We performed a retrospective cohort study (2012-2020) among youth (<18 years old) followed in a U.S. academic-based weight management clinic. Baseline characteristics (i.e., body mass index (BMI), liver function tests, eating-related behaviors) and outcomes (%BMI of 95th percentile (%BMIp95), BMI, percent %BMI change, weight) were determined through review of electronic health records and clinic intake survey data. Results: Among 282 youth prescribed topiramate plus lifestyle modifications (mean baseline age 12.7 years, %BMIp95 144%), %BMIp95 and percent BMI change were statistically significantly reduced at each time point (1.5-, 3-, 6-, and 12-month %BMIp95 reductions: -2.2, -3.9, -6.6, and -9.3 percentage points, respectively; percent BMI reduction: -1.2%, -1.9%, -3.2%, and -3.4%, respectively; all p<0.01). Considering multiple comparisons, no baseline characteristics statistically significantly predicted response at any time point. Conclusions: We found that topiramate plus lifestyle modification reduced %BMIp95 and BMI among youth in a weight management clinical setting, and that no baseline characteristics evaluated were associated with response. These results should be considered preliminary given the observational nature of this study, and prospective studies are needed to further characterize clinical effectiveness and identify and confirm potential predictors of response.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Pharmacological interventions for the management of children and adolescents living with obesity-An update of a Cochrane systematic review with meta-analyses.

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/m2. 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/m2 (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], I2 = 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.

Cumulative environmental stress and emerging cardiometabolic risk during childhood.

OBJECTIVE: To prospectively evaluate the relationship between cumulative environmental stress and cardiometabolic risk in middle childhood, and to examine whether hair cortisol, a measure of hypothalamic pituitary adrenal-axis activity, mediates this relationship. METHODS: In a cohort of children from low-income households (n = 320; 59% Hispanic, 23% Black, body mass index (BMI) percentile >50th at enrollment), environmental stressors including family and neighbourhood factors representing disadvantage/deprivation, and cortisol concentrations from hair samples, were measured over five timepoints beginning when children were 2-4 years old. Cardiometabolic risk factors (i.e., BMI, blood pressure, lipids, blood sugar, C-reactive protein) were measured at the final timepoint when children were 7-11 years of age. RESULTS: In adjusted logistic regression models, greater cumulative environmental stress was associated with a higher likelihood of elevated cardiometabolic risk in middle childhood (p = 0.01). Children from minoritized racial/ethnic groups had a higher prevalence of both stressors and cardiometabolic risk factors. Cumulative environmental stress was associated with higher hair cortisol concentrations (p < 0.01). However, hair cortisol was not directly associated with cardiometabolic risk factors and did not explain the association between environmental stress and cardiometabolic risk in causal mediation analysis. CONCLUSIONS: The influence of cumulative stress on cardiometabolic health can be observed in middle childhood and may contribute to cardiometabolic health disparities, highlighting the importance of public health interventions to mitigate disadvantage.

Current and future state of pharmacological management of pediatric obesity.

Pediatric obesity is a highly prevalent chronic disease, which has traditionally been treated with lifestyle therapy alone. Yet for many youth, lifestyle intervention as a monotherapy is often insufficient for achieving clinically significant and durable BMI reduction. While metabolic/bariatric surgery achieves robust and long-lasting outcomes, it is neither widely accessible nor wanted by most pediatric patients and families. In the past 3 years, this treatment gap between lifestyle therapy and metabolic/bariatric surgery has been filled with a number of landmark clinical trials examining the safety and efficacy of anti-obesity medication (AOM) for use in children and adolescents. These trials include studies of liraglutide, phentermine/topiramate ER, semaglutide, and setmelanotide, all of which have led to FDA and/or EMA approval. Concurrent with this developing evidence base, in 2023, the American Academy of Pediatrics published their first Clinical Practice Guideline on the assessment and management of childhood obesity. The Guideline includes the recommendation that pediatric health care providers should offer AOM to youth ages ≥12 years with obesity. Recognizing that AOM use in the pediatric population will likely become the standard of care and to provide perspective on the recently generated data regarding new AOM, this narrative review summarizes the published randomized controlled trials (RCTs) from the past 10 years that examine AOM for the pediatric population. This report additionally includes RCTs examining AOM for special populations of pediatric obesity including monogenic obesity, Bardet Biedl syndrome, Prader Willi syndrome, and hypothalamic obesity. Finally, the clinical application of AOM for children and adolescents, as well as future directions and challenges are discussed.

Evaluating appetite/satiety hormones and eating behaviours as predictors of weight loss maintenance with GLP-1RA therapy in adolescents with severe obesity.

INTRODUCTION: Whilst glucagon-like peptide-1 receptor agonists (GLP1-RAs) are effective for treating adolescent obesity, weight loss maintenance (WLM; preventing weight regain) remains a challenge. Our goal was to investigate appetite/satiety hormones and eating behaviours that may predict WLM with exenatide (a GLP1-RA) versus placebo in adolescents with severe obesity. METHODS: Adolescents who had ≥5% body mass index (BMI) reduction with meal replacement therapy were randomized to 52 weeks of once-weekly exenatide extended release or placebo. In this secondary analysis, eating behaviours and appetite/satiety regulation hormones post-meal replacement therapy (pre-randomization to exenatide or placebo) were evaluated as possible predictors of WLM. Percent change in BMI from randomization to 52 weeks served as the primary measure of WLM. RESULTS: The analysis included 66 adolescents (mean age 16.0 years; 47% female). Lower leptin response to meal testing was associated with greater WLM in terms of BMI percent change in those receiving exenatide compared to placebo (p = 0.007) after adjusting for sex, age and BMI. There were no other significant predictors of WLM. CONCLUSIONS: Prior to exenatide, lower leptin response to meals was associated with improved WLM with exenatide compared to placebo. The mostly null findings of this study suggest that GLP1-RA treatment may produce similar WLM for adolescents with obesity regardless of age, BMI, sex and eating behaviours.

SMART use of medications for the treatment of adolescent severe obesity: A sequential multiple assignment randomized trial protocol.

BACKGROUND: Severe obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their "one-size-fits-all" approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions. METHODS: This paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), "SMART Use of Medications for the Treatment of Adolescent Severe Obesity." The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy. CONCLUSION: Data from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard "one-size-fits-all" treatments.

Cost-Effectiveness of Pharmacotherapy for the Treatment of Obesity in Adolescents.

Importance: Antiobesity pharmacotherapy is recommended for adolescents ages 12 years and older with obesity. Several medications have been approved by the US Food and Drug Administration for adolescent use, but the most cost-effective medication remains unclear. Objective: To estimate the cost-effectiveness of lifestyle counseling alone and as adjunct to liraglutide, mid-dose phentermine and topiramate (7.5 mg phentermine and 46 mg topiramate), top-dose phentermine and topiramate (15 mg phentermine and 92 mg topiramate), or semaglutide among adolescent patients with obesity. Design, Setting, and Participants: This economic evaluation used a microsimulation model to project health and cost outcomes of lifestyle counseling alone and adjunct to liraglutide, mid-dose phentermine and topiramate, top-dose phentermine and topiramate, or semaglutide over 13 months, 2 years, and 5 years among a hypothetical cohort of 100 000 adolescents with obesity, defined as an initial body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 37. Model inputs were derived from clinical trials, published literature, and national sources. Data were analyzed from April 2022 to July 2023. Exposures: Lifestyle counseling alone and as adjunct to liraglutide, mid-dose phentermine and topiramate, top-dose phentermine and topiramate, or semaglutide. Main Outcomes and Measures: The main outcome was quality-adjusted life years (QALYs), costs (2022 US dollars), and incremental cost-effectiveness ratios (ICERs), with future costs and QALYs discounted 3.0% annually. A strategy was considered cost-effective if the ICER was less than $100 000 per QALY gained. The preferred strategy was determined as the strategy with the greatest increase in QALYs while being cost-effective. One-way and probabilistic sensitivity analyses were used to assess parameter uncertainty. Results: The model simulated 100 000 adolescents at age 15 with an initial BMI of 37, of whom 58 000 (58%) were female. At 13 months and 2 years, lifestyle counseling was estimated to be the preferred strategy. At 5 years, top-dose phentermine and topiramate was projected to be the preferred strategy with an ICER of $56 876 per QALY gained vs lifestyle counseling. Semaglutide was projected to yield the most QALYs, but with an unfavorable ICER of $1.1 million per QALY gained compared with top-dose phentermine and topiramate. Model results were most sensitive to utility of weight reduction and weight loss of lifestyle counseling and top-dose phentermine and topiramate. Conclusions and Relevance: In this economic evaluation of pharmacotherapy for adolescents with obesity, top-dose phentermine and topiramate as adjunct to lifestyle counseling was estimated to be cost-effective after 5 years. Long-term clinical trials in adolescents are needed to fully evaluate the outcomes of pharmacotherapy, especially into adulthood.

Evaluating potential predictors of weight loss response to liraglutide in adolescents with obesity: A post hoc analysis of the randomized, placebo-controlled SCALE Teens trial.

BACKGROUND: As childhood obesity prevalence increases, determining which patients respond to anti-obesity medications would strengthen personalized approaches to obesity treatment. In the SCALE Teens trial among pubertal adolescents with obesity (NCT02918279), liraglutide 3.0 mg (or maximum tolerated dose) significantly reduced body mass index (BMI) standard deviation score on average versus placebo. That said, liraglutide effects on BMI reduction varied greatly among adolescents, similar to adults. OBJECTIVES: To identify post hoc characteristics predictive of achieving ≥5% and ≥10% BMI reductions at 56 weeks with liraglutide versus placebo in adolescents from the SCALE Teens trial. METHODS: Logistic regression analysis was performed in 251 adolescents treated with liraglutide (n = 125) or placebo (n = 126) for 56 weeks. Baseline characteristics (selected a priori) included sex, race, ethnicity, age, Tanner (pubertal) stage, glycemic status (hyperglycemia [type 2 diabetes/prediabetes] vs. normoglycemia), obesity category (Class II/III vs. I), severity of depression symptoms (Patient Health Questionnaire-9), and weight variability (weight fluctuations over time). The effects of early responder status (≥4% BMI reduction at week 16) on week 56 response were assessed using descriptive statistics. RESULTS: Baseline characteristics did not affect achievement of ≥5% and ≥10% BMI reductions at week 56 in adolescents treated with liraglutide. Further, there was no association between weight variability and BMI reduction. Early liraglutide responders appeared to have greater BMI and body weight reductions at week 56 compared with early non-responders. CONCLUSIONS: This secondary analysis suggests that adolescents with obesity may experience significant BMI reductions after 56 weeks of liraglutide treatment, regardless of their sex, race, ethnicity, age, pubertal stage, glycemic status, obesity category, severity of depression symptoms, or weight variability. Early response may predict greater week 56 response.

Current and future pharmacotherapies for obesity in children and adolescents.

Obesity is a common chronic disease in children and adolescents and its prevalence is increasing worldwide. The causes are multifactorial but involve biological predisposition towards a specific body-weight set point and defended adipose tissue mass converging with an obesogenic environment. Comprehensive treatment of paediatric obesity includes lifestyle modification therapy, anti-obesity medications (AOMs) and/or metabolic surgery. Lifestyle modification therapy used alone produces fairly modest weight loss for most youth with obesity. The emergence of new AOMs has changed the landscape of paediatric weight management, improving the outlook for youth with obesity. This Review briefly highlights obesity development pathways in youth and the role that pharmacotherapy can play in counteracting these pathophysiological forces. Here, results from adolescent AOM clinical trials published since 2020 are reviewed, including the safety, efficacy and tolerability of the newest treatments (glucagon-like peptide 1 receptor agonists and phentermine-topiramate). The importance of a comprehensive and chronic care model, including both lifestyle modification and ongoing pharmacotherapy, will be discussed in the context of maximizing long-term health outcomes. Finally, insight will be provided into the emerging pipeline of AOMs (for example, incretin receptor co-agonists and tri-agonists) and how future therapies might fundamentally change the prognosis for youth with obesity.