Physiologic response to bariatric surgery and the impact of adjunct semaglutide - in adolescents (the PRESSURE trial)

青少年对减肥手术的生理反应和辅助索马鲁肽的影响（PRESSURE 试验）

• 批准号: 10590377
• 负责人: Jaime M. Moore
• 金额: $ 18.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590377
• 关键词: Adherence; Adolescence; Adolescent; Adult; Affect; Age; Agonist; Basal metabolic rate; Behavioral; Biological; Blood Pressure; Blood Pressure Monitors; Body Composition; Body Weight; Body Weight decreased; Body mass index; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Childhood; Clinical; Clinical Trials; Data; Desire for food; Development Plans; Disease remission; Double-Blind Method; Dual-Energy X-Ray Absorptiometry; Eating Behavior; Echocardiography; Environment; Fasting; Fatty acid glycerol esters; Funding; Future; GLP-I receptor; Gastrectomy; Gastric Inhibitory Polypeptide; Goals; Grant; Health; Health Benefit; Hispanic; Hour; Hypertension; Indirect Calorimetry; Individual; Injectable; Intervention; Intervention Trial; Learning; Life Style; Link; Measures; Mechanics; Medicine; Mental Health; Metabolic; Methods; Morbid Obesity; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Peptide YY; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiologic pulse; Physiological; Physiology; Placebos; Postoperative Period; Predictive Factor; Prospective Studies; Protocols documentation; Publications; Randomized; Randomized, Controlled Trials; Reporting; Research; Research Design; Residual state; Risk; Risk Factors; Risk Marker; Risk Reduction; Satiation; Social Environment; Solid; Stroke; Structure; Testing; Training; Weight; Weight maintenance regimen; Youth; arterial stiffness; bariatric surgery; cardiometabolic risk; cardiometabolism; cardiovascular health; career development; cohort; comorbidity; diagnostic tool; double-blind placebo controlled trial; energy balance; experience; gastrointestinal; ghrelin; glucagon-like peptide 1; heart rate variability; improved; insulin secretion; insulin sensitivity; nutrition; obesity in children; pediatric department; phase 2 designs; physical conditioning; predicting response; premature; preservation; professor; prospective; psychologic; recruit; response; risk stratification; social stigma; standard of care; success; therapy design

PROJECT SUMMARY/ABSTRACT Metabolic and bariatric surgery (MBS) to treat pediatric severe obesity is increasingly common. MBS at younger ages means decades longer to preserve or enhance its cardiometabolic and other health benefits. While mean weight loss after MBS is substantial, >50% of adolescents in prospective US cohorts have persistent severe obesity >3 years later. We have also found that 25% of youth show significant weight regain 6 months through 5 years postoperatively. Additionally, comorbidity response to MBS appears to differ between youth and adults. In youth, few predictors of weight loss after MBS are known and there is insufficient mechanistic data evaluating physiologic factors as potential predictors. Further, there is an absence of in-depth cardiometabolic phenotyping, which could help to define residual risk post MBS beyond weight loss alone. We hypothesize that 1) physiologic phenotypes in gut peptides, body composition, and resting metabolic rate (RMR) will partially explain variability in MBS weight loss in adolescents (Aim 1), that improved insulin sensitivity (IS) will be associated with favorable cardiovascular changes independent of BMI change (Aim 2), and 2) Adjunctive postoperative glucagon-like peptide-1 (GLP-1) pharmacotherapy will augment MBS benefits in youth with suboptimal surgical response. I propose a 2-phase design: a 1-year prospective study measuring changes in gut peptides, body composition, RMR, and cardiometabolic measures (IS, 24 hour blood pressure, echocardiogram for structure/function, arterial stiffness, cardiac autonomic function) from pre- to 1 year post-MBS (n=30), 2) A randomized, double-blinded, 6- month intervention of semaglutide vs placebo 1-2 years postop in 12-24 year olds with <20% BMI loss (n=18). As an Assistant Professor in the Department of Pediatrics Section of Nutrition with a solid publication and grant funding record, and emerging clinical trial experience, I am establishing myself within the field of personalized pediatric obesity medicine. I envision future diagnostic tools and interventions for weight management in youth that are tailored to an individual’s underlying (patho)physiology, values, and socioenvironmental influences. A K23 would support the following research goals: 1) define physiologic phenotypes underlying MBS mechanism and cardiometabolic response using robust measures not previously reported in youth, 2) complete the first randomized controlled trial of a GLP-1 receptor agonist in youth post-MBS, and 3) contribute data from a diverse cohort that particularly fills gaps in under-represented Hispanic youth. My career development plan is carefully constructed to 1) learn how to longitudinally perform and interpret core dynamic measures of gut peptides, body composition, energy balance, insulin sensitivity, and cardiovascular health. Experience with these measures will yield a versatile toolbox that will be highly translatable to future clinical intervention trials in pediatric obesity. 2) gain experience with recruitment/retention for a longer study protocol (18 months), and 3) learn how traditional study designs can inform more nimble adaptive clinical trial interventions for a subsequent R01.

项目总结/文摘