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）

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要代谢和减肥手术 (MBS) 治疗儿童严重肥胖症越来越常见。年龄意味着需要几十年的时间才能保持或增强其心脏代谢和其他健康益处。 MBS 后体重减轻显着，美国前瞻性队列中超过 50% 的青少年患有持续严重的体重减轻肥胖 > 3 年后，我们还发现 25% 的青少年体重在 6 个月内显着增加。此外，术后 5 年，青少年和成人对 MBS 的合并症反应似乎有所不同。在年轻人中，MBS 后体重减轻的预测因素很少，并且没有足够的机制数据评估此外，缺乏深入的心脏代谢表型分析。这可能有助于定义 MBS 后的残余风险，而不仅仅是体重减轻，我们发现了这一点：1) 生理学。肠道肽、身体成分和静息代谢率 (RMR) 的表型将部分解释变异性在青少年 MBS 减肥（目标 1）中，胰岛素敏感性 (IS) 的改善将与有利的心血管变化独立于 BMI 变化（目标 2），以及 2) 术后辅助胰高血糖素样治疗肽-1 (GLP-1) 药物治疗将增强手术反应欠佳的青少年的 MBS 益处 I。提出一个两阶段设计：一项为期 1 年的前瞻性研究，测量肠道肽、身体成分、 RMR 和心脏代谢测量（IS、24 小时血压、结构/功能超声心动图、动脉 MBS 治疗前至 1 年（n=30），2) 随机、双盲、6- 在 BMI 下降 <20% 的 12-24 岁患者中，索马鲁肽与安慰剂相比，术后 1-2 年进行了为期一个月的干预（n=18）。作为儿科营养科的助理教授，拥有扎实的出版物和资助资金记录和新兴的临床试验经验，我正在个性化领域建立自己的地位我设想未来的青少年体重管理诊断工具和干预措施。根据个人的潜在（病理）生理学、价值观和社会环境影响量身定制。 K23将支持以下研究目标：1）定义MBS机制背后的生理表型和心脏代谢反应，使用以前在青年中未报告过的强有力的措施，2) 完成第一个在 MBS 后的青少年中进行 GLP-1 受体激动剂的随机对照试验，以及 3) 提供来自不同研究的数据我的职业发展计划非常谨慎。旨在 1) 学习如何纵向执行和解释肠道肽、身体的核心动态测量这些措施的经验将包括成分、能量平衡、胰岛素敏感性和心血管健康。产生一个多功能工具箱，可高度转化为未来儿童肥胖的临床干预试验2)。获得较长研究方案（18 个月）的招募/保留经验，以及 3) 了解传统方法如何研究设计可以为后续 R01 的更灵活的适应性临床试验干预提供信息。