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

项目总结/摘要 代谢和减肥手术（MBS）治疗小儿严重肥胖症越来越普遍。在年轻的MBS 年龄意味着数十年的时间来保持或增强其心脏代谢和其他健康益处。而平均 MBS后体重减轻显著，在前瞻性美国队列中，>50%的青少年患有持续的重度 肥胖>3年后。我们还发现，25%的年轻人在6个月内体重明显反弹， 术后5年。此外，对MBS的共病反应似乎在青年和成年人之间存在差异。 在年轻人中，MBS后体重减轻的预测因素很少，并且没有足够的机械数据评估 生理因素作为潜在的预测因素。此外，缺乏深入的心脏代谢表型， 这可能有助于定义MBS后的剩余风险，而不仅仅是体重减轻。我们假设1）生理 肠道肽、身体组成和静息代谢率（RMR）的表型将部分解释变异性 在青少年MBS体重减轻中（目标1），改善的胰岛素敏感性（IS）将与有利的 不依赖于BMI变化的心血管变化（目的2），和2）辅助术后胰高血糖素样 肽-1（GLP-1）药物治疗将增加MBS的好处，在青年与次优的手术反应。我 提出一个2阶段设计：一项为期1年的前瞻性研究，测量肠道肽，身体组成， RMR和心脏代谢指标（IS、24小时血压、结构/功能超声心动图、动脉 僵硬度、心脏自主神经功能）（n=30），2）随机、双盲、6- 在BMI下降<20%的1-2 -24岁受试者中，semaglutide与安慰剂术后1-2年的干预时间（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，我正在建立自己的领域内的个性化 儿科肥胖症药物我设想未来的诊断工具和干预措施，为体重管理的青年 根据个人潜在的（病态）生理学、价值观和社会环境影响量身定制。一 K23将支持以下研究目标：1）确定MBS机制的生理表型 和心脏代谢反应，2）完成第一个 GLP-1受体激动剂在MBS后青年中的随机对照试验，以及3）提供来自不同研究的数据。 这一群体特别填补了代表性不足的西班牙裔青年的空白。我的职业发展计划是仔细的 构建为1）学习如何纵向执行和解释肠道肽，身体 营养成分、能量平衡、胰岛素敏感性和心血管健康。这些措施的经验将 产生一个多功能的工具箱，这将是高度可转化为未来的临床干预试验在儿童肥胖。（二） 获得更长研究方案（18个月）的招募/保留经验，以及3）了解传统 研究设计可以为后续R 01提供更灵活的适应性临床试验干预。

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.