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.

Enhanced Patient Portal Engagement Associated with Improved Weight Loss Outcomes in Post-Bariatric Surgery Patients.

Background: Bariatric surgery is an effective intervention for obesity, but it requires comprehensive postoperative self-management to achieve optimal outcomes. While patient portals are generally seen as beneficial in engaging patients in health management, the link between their use and post-bariatric surgery weight loss remains unclear. Objective: This study investigated the association between patient portal engagement and postoperative body mass index (BMI) reduction among bariatric surgery patients. Methods: This retrospective longitudinal study included patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at Vanderbilt University Medical Center (VUMC) between January 2018 and March 2021. Using generalized estimating equations, we estimated the association between active days of postoperative patient portal use and the reduction of BMI percentage (%BMI) at 3, 6, and 12 months post-surgery. Covariates included duration since surgery, the patient's age at the time of surgery, gender, race and ethnicity, type of bariatric surgery, severity of comorbid conditions, and socioeconomic disadvantage. Results: The study included 1,415 patients, mostly female (80.9%), with diverse racial and ethnic backgrounds. 805 (56.9%) patients underwent RYGB and 610 (43.1%) underwent SG. By one-year post-surgery, the mean (SD) %BMI reduction was 31.1% (8.3%), and the mean (SD) number of patient portal active days was 61.0 (41.2). A significantly positive association was observed between patient portal engagement and %BMI reduction, with variations revealed over time. Each 10-day increment of active portal use was associated with a 0.57% ([95% CI: 0.42- 0.72], P < .001) and 0.35% ([95% CI: 0.22- 0.49], P < .001) %BMI reduction at 3 and 6 months postoperatively. The association was not statistically significant at 12 months postoperatively (ß=-0.07, [95% CI: -0.24- 0.09], P = .54). Various portal functions, including messaging, visits, my record, medical tools, billing, resources, and others, were positively associated with %BMI reduction at 3- and 6-months follow-ups. Conclusions: Greater patient portal engagement, which may represent stronger adherence to postoperative instructions, better self-management of health, and enhanced communication with care teams, was associated with improved postoperative weight loss. Future investigations are needed to identify important portal features that contribute to the long-term success of weight loss management.

High Prevalence of Positive Genetic Obesity Variants in Postoperative Bariatric Surgery Patients with Weight Regain Presenting for Medical Obesity Intervention.

INTRODUCTION: Genetic obesity susceptibility in postoperative bariatric surgery weight regain (PBSWR) remains largely unexplored. METHODS: A retrospective case series of adult (N = 27) PBSWR patients who had undergone genetic obesity testing was conducted between Sept. 2020 and March 2022. PRIMARY OUTCOME: frequency of genetic variants in patients experiencing weight regain following bariatric surgery. SECONDARY OUTCOMES: prevalence of obesity-related comorbidities, nadir BMI achieved post-bariatric surgery, and percent total body weight loss (%TBWL) achieved with obesity pharmacotherapies. RESULTS: Heterozygous mutations were identified in 22 (81%) patients, with the most prevalent mutations occurring in CEP290, RPGR1P1L, and LEPR genes (3 patients each). Median age was 56 years (interquartile range (IQR) 46.8-65.5), 88% female. Types of surgery were 67% RYGB, 19% SG, 4% gastric band, and 13% revisions. Median nadir BMI postoperatively was 34.0 kg/m2 (IQR 29.0-38.5). A high prevalence of metabolic derangements was noted; patients presented median 80 months (IQR 39-168.5) postoperative for medical weight management with 40% weight regain. BMI at initiation of anti-obesity medication (AOMs) was 41.7 kg/m2 (36.8-44.4). All received AOM and required at least 3 AOMs for weight regain. Semaglutide (N = 21), topiramate (N = 14), and metformin (N = 12) were most prescribed. Median %TBWL for the cohort at the first, second, and third visit was 1.7, 5.0, and 6.5 respectively. Fourteen (52%) achieved 5%TBWL, 10 (37%) achieved 10%TBWL, and 4 (15%) achieved 15%TBWL with combination AOMs and supervised medical intervention. CONCLUSION: An unusually high prevalence of genetic obesity variants in PBSWR was found, warranting further research.

Combined GLP-1 Receptor Agonist and Amylin Analogue Pharmacotherapy to Treat Obesity Comorbid With Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) with obesity is increasingly common, prompting effective clinical interventions to induce weight loss in this population. We present 3 patients with T1DM and obesity prescribed a glucagon-like peptide 1 receptor agonist (GLP-1RA) and pramlintide. Case 1: A 32-year-old male with obstructive sleep apnea (OSA) who lost -20.9 kg (-16.1% of total body weight [TBW]) over 10 months on semaglutide and pramlintide. Case 2: A 68-year-old female with diabetic retinopathy, coronary artery disease, hypertension, hypothyroidism, and depression/anxiety initially treated with topiramate, losing -8.4 kg, but experiencing weight plateau. After adding dulaglutide and pramlintide, she lost an additional -12.8 kg (-14.0% TBW) over 7 months, with total weight loss of -21.2 kg (-23.1% TBW). Case 3: A 49-year-old female with hypertension, hypothyroidism, and depression who lost -14.6 kg (-17.9% TBW) over 6 months on semaglutide and pramlintide. No significant side effects were experienced. All patients reported decreased insulin requirements on pramlintide, and hemoglobin A1c levels remained constant or decreased throughout the treatment period. Pramlintide and GLP-1RA resulted in excellent weight loss in our patients with obesity and T1DM. This combination may have a synergistic effect on the gut-brain axis. More research is required to substantiate these findings.

Diagnostic challenge: A pediatric patient with severe obesity and complications of imminent death.

Background: A 15-year-old patient suffering from severe obesity (400 pounds, BMI 71.6 kg/m2) with a clinical phenotype suggestive of syndromic obesity was hospitalized for severe heart failure and cardiogenic shock. The hospital admission prompted a palliative care and heart transplant consultation given end-stage-disease and poor prognosis. It further necessitated a pediatric inpatient obesity consult, which was complicated by several significant hurdles including lack of insurance coverage, FDA approvals, availability of medications, and inadequate knowledge among the medical community. Methods: Innovative treatment, proactive, persistent advocacy, anti-obesity medication combination strategies modeled after diabetes and hypertension treatment algorithms, and latest evidence in obesity management were utilized to effectively and expeditiously overcome major challenges to care and the medical emergency. Results: The patient was stabilized and ultimately discharged home, after -25.2% weight loss over 4 months (weight down to 299 pounds, BMI 49.9 kg/m2) through collaborative medical obesity intervention. Conclusion: The typical delay in care sought by patients suffering from obesity, often due to stigma and lack of disease awareness, results in missed opportunities to prevent serious obesity-related complications. Skilled specialist expertise, fund of obesity-specific knowledge, and constant advocacy can be crucial in surmounting regulatory barriers to obesity care and in generating successful weight loss outcomes.

Metaflammation in obesity and its therapeutic targeting.

Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation.

Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial.

The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg/m2 and at least one obesity-related complication (excluding diabetes), who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579). The treatment regimen estimand assessed effects regardless of treatment adherence in the intention-to-treat population. The coprimary endpoint of additional mean per cent weight change from randomization to week 72 was met with changes of -18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo (estimated treatment difference -20.8 percentage points (95% confidence interval (CI) -23.2%, -18.5%; P < 0.001). The coprimary endpoint of the percentage of participants achieving additional weight reduction ≥5% was met with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving this threshold (odds ratio 34.6%; 95% CI 19.2%, 62.6%; P < 0.001). The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity. Tirzepatide provided substantial additional reduction in body weight in participants who had achieved ≥5.0% weight reduction with intensive lifestyle intervention. ClinicalTrials.gov registration: NCT04657016 .

Prevalence of genetic causes of obesity in clinical practice.

Background: While obesity is common in the United States, monogenic obesity is rare, accounting for approximately 5% of individuals with obesity. New targeted therapies for genetic forms of obesity are available but there is limited guidance on who requires testing. The aims of this study were to evaluate the prevalence of potentially clinically significant variants among individuals in Pediatric Endocrinology or Medical Weight Center clinics at a single center and to identify clinical characteristics that may make genetic obesity more likely. Methods: Children and adults who had a genetic test for obesity, Uncovering Rare Obesity Gene panel, ordered during routine clinic visits from December 2019 to March 2021 were identified. Results: Of the 139 patients with testing ordered, 117 had available results and clinical data. Over 40% (52/117, 44%) had at least one positive result (variant) with a variant that is considered pathogenic, likely pathogenic, or a variant of uncertain significance. No association was detected between age, sex, race, and body mass index (BMI) or BMI z-score with a variant. Twenty-six individuals (22%) had one or more variants in genes associated with Bardet Biedl Syndrome, and 8 (6.8%) of them had pathogenic variants, higher than expected. Conclusion: Overall, clinical suspicion for genetic obesity is important in determining who requires genetic testing but no clinical factors were found to predict results. While obesity is multifactorial, novel medications for genetic forms of obesity indicate the need for evidence-based guidelines for who requires genetic testing for obesity.

Combination anti-obesity medications to effectively treat bariatric surgery weight regain at an academic obesity center.

Background: Combination anti-obesity medications (AOMs) to treat postoperative bariatric surgery weight regain have limited data on their use in the clinical setting. Understanding the optimal treatment protocol in this cohort will maximize weight loss outcomes. Methods: A retrospective review of bariatric surgery patients (N = 44) presenting with weight regain at a single academic multidisciplinary obesity center who were prescribed AOM(s) plus intensive lifestyle modification for 12 months. Results: Age: 28-76 years old, 93% female, mean weight 110.2 ± 20.3 kg, BMI 39.7 ± 7.4 kg/m2, presenting 5.2 ± 1.6 years post-bariatric surgery [27 (61.4%), 14 (31.8%), and 3 (6.8%) laparoscopic Roux-en-Y gastric bypass (RYGB), laparoscopic vertical sleeve gastrectomy (VSG), and open RYGB, respectively], with 15.1 ± 11.1 kg mean weight gain from nadir. Mean weight loss after medical intervention at 3-, 6-, and 12-month time points was 4.4 ± 4.6 kg, 7.3 ± 7.0 kg, and 10.7 ± 9.2 kg, respectively. At 12 months, individuals prescribed 3 or more AOMs lost more weight than those prescribed one (-14.5 ± 9.0 kg vs. -4.9 ± 5.7 kg, p < 0.05) irrespective of age, gender, number of comorbidities, initial weight or BMI, type of surgery, or GLP1 use. RYGB patients lost less weight overall (7.4% vs. 14.8% VSG respectively; p < 0.05). Conclusions: Combination AOMs may be needed to achieve optimal weight loss results to treat post-operative weight regain.

Obesity Management in Children and Adolescents.

Obesity in the pediatric population is increasing in the United States and globally. Childhood obesity is associated with cardiometabolic and psychosocial comorbidities and decreased overall life span. The cause of pediatric obesity is multifactorial and includes genetic predisposition, lifestyle, behavioral patterns, and consequences of social determinants of health. Routine screening of BMI and comorbid conditions is essential to identifying patients who require treatment. The AAP recommends immediate Intensive Health Behavior and Lifestyle Treatment for children with obesity, encompassing lifestyle changes, behavioral changes, and mental health treatments. Pharmacologic interventions and metabolic and bariatric surgery are also available when indicated.

Literature review on antiobesity medication use for metabolic and bariatric surgery patients from the American Society for Metabolic and Bariatric Surgery Clinical Issues Committee.

The following literature search is in response to inquiries made to the American Society for Metabolic and Bariatric Surgery (ASMBS) regarding antiobesity medication (AOM) use in patients who are having or have already had metabolic and bariatric surgery (MBS). These recommendations are based on current clinical knowledge, expert opinion, and published peer-reviewed scientific evidence available at this time. This paper is not intended to establish a local, regional, or national standard of care. The paper will be revised in the future as additional evidence becomes available.

Overcoming congressional inertia on obesity requires better literacy in obesity science.

Obesity-focused health policies, including the landmark Treat and Reduce Obesity Act, have stalled at the federal level over the past decade. Congressional inaction on obesity reflects both misconceptions of obesity as a lifestyle choice and limited awareness for the burden obesity imposes on our health care system. Given these challenges, we argue that health professionals must bolster their efforts to partner with public figures with obesity and to directly educate the public. These strategies may help destigmatize obesity and build awareness of obesity as a disease. Furthermore, we suggest that these strategies may empower patients to flex their unrealized political muscle and demand more from their elected leaders. A bold, multilevel approach that elicits a public demand for change can propel obesity policy into the 21st century.

Understanding the pathophysiologic pathways that underlie obesity and options for treatment.

INTRODUCTION: Obesity is a chronic, multifactorial condition with devastating health consequences. It was thought that obesity could be controlled with discipline and lifestyle changes, but we now know that the underlying pathophysiology is a dysregulation of the body's energy balance system, controlled by a complex interplay of neural, hormonal, and metabolic pathways. Recognizing obesity as a chronic disease places a greater responsibility on all health care professionals to screen and identify patients at risk and develop long-term tailored treatment plans. AREAS COVERED: This narrative review describes the central and peripheral pathways regulating obesity, the factors contributing to its development and how to effectively manage this disease. EXPERT OPINION: Obesity is a disease with pathophysiologic mechanisms and should be treated accordingly to reduce the significant risk of morbidity and mortality. Lifestyle interventions remain the cornerstones of treatment; however, these measures alone are rarely enough for long-term maintenance of weight loss. Additional interventions, such as pharmacotherapy or bariatric surgery, are indicated for many patients and should be recommended. Treatment considerations should include assessment of comorbidities or risk factors, as many anti-obesity agents and bariatric surgeries also have beneficial effects on other weight-associated comorbidities.Plain language summary: This plain language summary highlights information from a recent scientific article about obesity. Obesity is a disease that leads to excess accumulation of body fat that may negatively affect health. People can check if they have obesity by measuring their body mass index (BMI for short). The BMI is a screening tool to see if you are at risk of obesity. Obesity is defined as a BMI of 30 kg/m2 or higher with lower cut-offs in Asian populations. Obesity is a chronic health condition that leads to a shorter life span. People with obesity have a higher chance of having other health conditions, such as type 2 diabetes, fatty liver disease, heart disease, kidney problems, osteoarthritis, and some types of cancer. It can be hard for people with obesity to lose weight for various reasons. The aim of this article is to help doctors who treat people with obesity understand more about the causes for obesity, as well as the available treatment options, which include lifestyle changes, medicines, and for some people, weight loss surgery.[Figure: see text][Figure: see text][Figure: see text][Figure: see text].

Evaluation and Management of Early Onset Genetic Obesity in Childhood.

One in five children and adolescents in the United States are diagnosed with obesity and nearly 6% of them are being classified under the severe obesity category. With over 7% of severe obesity being attributed to genetic disorders, in this review we aim to focus on monogenic and syndromic obesity: its etiology, wide spectrum of clinical presentation, criticalness of early identification, and limited management options. Advanced genetic testing methods including microarray and whole genome sequencing are imperative to identify the spectrum of mutations and develop targeted treatment strategies including personalized multidisciplinary care, use of investigational drugs, and explore surgical options in this unique subset of severe pediatric obesity.

Caring for US Children: Barriers to Effective Treatment in Children with the Disease of Obesity.

In 2020, impediments to pediatric obesity (PO) treatment remain pervasive, even though these barriers are clearly documented in medical literature. Providers must invest considerable resources to overcome these barriers to care. Notable barriers include gaps in medical education, misperceptions of the disease, weight bias and stigma, exclusion of coverage in health plans, and thus an unsustainable financial framework. Hence, this review offers an updated social-ecological framework of accessibility to care, wherein each barrier to care or variable is interdependent on the other and each is critical to creating forward momentum. The sum of all these variables is instrumental to overall smooth function, configured as a wheel. To treat PO effectively, all variables must be adequately addressed by stakeholders throughout the health care system in order to holistically comprehend and appreciate undertakings to advance the burgeoning field of PO medicine.