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

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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.