Aaron S. Kelly, Ph.D. - US grants

Abstract Validation of chronic disease biomarkers in children is of paramount importance especially in the burgeoning arena of pediatric obesity research. Because cardiovascular disease (CVD) is a cumulative process occurring over time, identifying the earliest signs in order to intervene sooner may have a large impact on slowing its progression. The challenge is identifying which obese youth have early vascular problems. Looking to the vascular endothelium for signs of damage is a reasonable approach because of its prominent role in the origins of atherosclerosis. However, accurately quantifying endothelial health in children has proven to be a major challenge. Brachial artery flow-mediated dilation (FMD) is the most commonly-used method to quantify endothelial health in children. However, this technique is not widely applicable because it requires specialized equipment, a highly-trained technician, and results can be highly variable. More direct measures of endothelial cell biology, such as circulating endothelial cells (CEC) and endothelial microparticles (EMP), may offer greater precision in characterizing the state of the endothelium and may identify high-risk individuals. Despite being validated in adults, CEC and EMP have not been formally evaluated in youth. Our primary focus in this study will be the evaluation of CEC and EMP as biomarkers of CVD risk, throughout a spectrum of adiposity in children and adolescents, with a goal of validating CEC and EMP for use in pediatric research studies. We propose a robust study design with a three-tiered approach toward validating these biomarkers: 1) evaluation of the association of CEC and EMP concurrently with CVD risk factors and measures of endothelial function (FMD) and sub-clinical atherosclerosis (carotid intima-media thickness), 2) evaluation of the change in CEC and EMP in response to substantial weight loss in extremely obese adolescents undergoing elective, clinically- indicated bariatric surgery, and 3) longitudinal assessment of the reproducibility of CEC and EMP to inform the design of future pediatric studies using these endpoints.

? DESCRIPTION (provided by applicant): Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to numerous biological adaptations involving appetite, satiety, and energy expenditure in the post- weight loss setting. Following a loss in body weight, peripheral and central mechanisms convey a sense that energy reserves have dwindled, activating a strong counter response to increase caloric intake. Adolescents with severe obesity are not immune to the vexing issue of weight regain. Indeed, only 2% are able to achieve and maintain clinically- meaningful weight loss with lifestyle modification therapy. Therefore, novel treatment paradigms focused on long-term weight loss maintenance are urgently needed. Pharmacotherapy has the potential to prevent weight regain by targeting specific counter-regulatory mechanisms in the post- weight loss setting. One of the most promising candidates is the glucagon like peptide-1 receptor agonist (GLP-1RA) class, which greatly enhanced weight loss maintenance following a short-term low calorie diet among adults with obesity. The rationale for focusing on GLP-1RA treatment to prevent weight regain is supported by the multiple central and peripheral mechanisms of action targeted by this class of drug; many of which specifically address the biological adaptations known to induce relapse. We have strong preliminary data demonstrating that GLP-1RA treatment reduces BMI in adolescents with severe obesity. Moreover, we and others have shown that although meal replacement therapy (structured meals of known caloric content) can elicit robust short-term weight loss among adolescents with severe obesity, weight regain is a pervasive problem. Therefore, in this clinical trial, our innovative approach will utilize GLP-1RA treatment to target weight regain following short-term meal replacement therapy in youth with severe obesity. Participants who achieve =5% BMI reduction during the meal replacement phase will be randomized to GLP-1RA treatment or placebo for an additional 12 months while simultaneously engaging in lifestyle modification therapy. Importantly, this study will also allow us to examine the extent to which GLP-1RA treatment addresses mechanisms of weight regain, investigate other pleiotropic benefits of GLP-1RA, and identify predictors of weight loss response. This research tackles a significant public health threat, utilizes an innovative treatment concept and approach, and exerts a powerful, sustained influence on the field of pediatric obesity by steering research and clinical practice paradigms toward the application of pharmacotherapy for meaningful and durable weight loss and risk factor modification.

? DESCRIPTION (provided by applicant): Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to numerous biological adaptations involving appetite, satiety, and energy expenditure in the post- weight loss setting. Following a loss in body weight, peripheral and central mechanisms convey a sense that energy reserves have dwindled, activating a strong counter response to increase caloric intake. Adolescents with severe obesity are not immune to the vexing issue of weight regain. Indeed, only 2% are able to achieve and maintain clinically- meaningful weight loss with lifestyle modification therapy. Therefore, novel treatment paradigms focused on long-term weight loss maintenance are urgently needed. Pharmacotherapy has the potential to prevent weight regain by targeting specific counter-regulatory mechanisms in the post- weight loss setting. One of the most promising candidates is the glucagon like peptide-1 receptor agonist (GLP-1RA) class, which greatly enhanced weight loss maintenance following a short-term low calorie diet among adults with obesity. The rationale for focusing on GLP-1RA treatment to prevent weight regain is supported by the multiple central and peripheral mechanisms of action targeted by this class of drug; many of which specifically address the biological adaptations known to induce relapse. We have strong preliminary data demonstrating that GLP-1RA treatment reduces BMI in adolescents with severe obesity. Moreover, we and others have shown that although meal replacement therapy (structured meals of known caloric content) can elicit robust short-term weight loss among adolescents with severe obesity, weight regain is a pervasive problem. Therefore, in this clinical trial, our innovative approach will utilize GLP-1RA treatment to target weight regain following short-term meal replacement therapy in youth with severe obesity. Participants who achieve =5% BMI reduction during the meal replacement phase will be randomized to GLP-1RA treatment or placebo for an additional 12 months while simultaneously engaging in lifestyle modification therapy. Importantly, this study will also allow us to examine the extent to which GLP-1RA treatment addresses mechanisms of weight regain, investigate other pleiotropic benefits of GLP-1RA, and identify predictors of weight loss response. This research tackles a significant public health threat, utilizes an innovative treatment concept and approach, and exerts a powerful, sustained influence on the field of pediatric obesity by steering research and clinical practice paradigms toward the application of pharmacotherapy for meaningful and durable weight loss and risk factor modification.

Abstract Severe obesity is the fastest growing category of pediatric obesity, with a reported prevalence near 6% in the United States. Unfortunately, conventional treatment approaches rarely result in sufficient weight loss in adolescents with severe obesity; therefore, innovative and effective strategies are desperately needed. The financial incentive model has been used successfully in adult obesity trials to address suboptimal adherence to lifestyle modification therapy and improves weight loss outcomes. Although yet to be investigated as a weight loss intervention among adolescents, financial incentives have been shown to improve many health-related behaviors in teenagers. Owing to the refractory nature of pediatric severe obesity, financial incentives are more likely to be effective if used in concert with a structured dietary plan such as meal replacement therapy (liquid shakes and frozen entrées). In a recent trial, meal replacement therapy produced promising short-term weight loss in adolescents with severe obesity; however, initial weight lost by participants was regained after 4 months, owing to diminished adherence to the meal replacement regimen over time. Our concept is to capitalize on the synergy of meal replacement therapy and financial incentives to optimize weight loss and improve cardiometabolic risk factors and vascular health in teens with severe obesity. This study will afford a unique opportunity to address another key unanswered question related to the treatment of pediatric severe obesity: how much weight loss is necessary to elicit clinically-meaningful improvements in cardiometabolic risk factors and vascular health? Although evidence-based benchmarks have been established for adults, no such thresholds have been identified for youth with severe obesity. Therefore, we plan to conduct a 12-month randomized, controlled clinical trial to evaluate the effects of meal replacement therapy plus financial incentives on weight loss and cardiometabolic/vascular outcomes among 142 adolescents with severe obesity and to identify thresholds of weight loss required to achieve clinically-meaningful cardiometabolic/vascular improvements in this patient population. This research targets a significant public health problem, will utilize an innovative treatment concept and approach, and will generate new knowledge to guide selection of treatment type and intensification, ultimately exerting a powerful and sustained influence on the field of pediatric obesity.

Abstract The prevalence of adolescent severe obesity is at an all-time high in the U.S. (~8%), and the refractory nature of this disease has led to uncertainty regarding how to provide effective, safe, scalable, and durable treatments without placing undue strain on the healthcare system. In 2017, the U.S. Preventive Services Task Force (USPSTF) released updated screening recommendations concluding that comprehensive, intensive behavioral interventions with a total of ?26 contact hours over a period of 2-12 months resulted in weight loss in youth with obesity, with ?52 contact hours leading to even greater weight loss and improvements in some cardiometabolic risk factors. However, the practicality of delivering these types of intensive behavioral services to the millions of youth with severe obesity in the U.S. is debatable not only because of the treatment-resistant nature of severe obesity, but also the time-commitment, acceptability, and sustainability of this approach for patients and their families and the extensive resources required to offer these interventions. While behavior change is an indispensable component of any effective weight loss approach, adjunctive strategies such as pharmacotherapy may enhance health outcomes. Pharmacotherapy combined with relatively low-intensity behavioral counseling (<26 contact hours) represents a potentially effective, durable, and safe treatment strategy for this population. This approach may be more practical and feasible to implement on a broad scale, preferred by patients and families, utilize fewer healthcare resources, and cost less to deliver compared to comprehensive, intensive behavioral interventions. We propose a two-arm, randomized clinical trial in adolescents with severe obesity evaluating two years of comprehensive, intensive behavioral counseling, aligned with the USPSTF report (52 contact hours during year one; 26 contact hours during year two), vs. two years of medical management with liraglutide plus relatively low-intensity behavioral counseling (12 contact hours during year one; six contact hours during year two). Outcomes will include weight loss effectiveness and durability, cardiometabolic risk factor improvements, quality of life, safety, and implementation feasibility.

Abstract Long-term weight loss maintenance is seldom achieved by individuals with obesity owing to numerous biological adaptations occurring in the post-weight loss setting, including neuroendocrine-mediated changes in appetite/satiety and reduction of energy expenditure. Following weight loss, peripheral and central mechanisms respond in a way similar to starvation by conveying a sense that energy reserves have dwindled, activating a strong counter-response to increase caloric intake. Moreover, metabolic rate drops, further compounding the propensity for weight rebound. Adolescents with severe obesity are not immune to the vexing issue of weight regain; therefore, effective and scalable treatments are urgently needed. Pharmacotherapy has the potential to prevent weight regain by targeting counter-regulatory mechanisms in the post-weight loss setting. Unfortunately, only one obesity medication is FDA-approved for long-term use in adolescents and is seldom prescribed owing to modest efficacy and notable side effects. Among the most promising candidates in the pediatric pipeline is the combination of phentermine and topiramate, which is the most effective adult weight loss medication currently available. The mechanisms of action are thought to reduce appetite, enhance satiety, and potentially increase energy expenditure, making this medication particularly well-suited for the purpose of weight loss maintenance since it targets many of the biological adaptations known to induce relapse and subsequent weight regain. Our group has generated preliminary data demonstrating that both phentermine and topiramate reduce BMI in adolescents with severe obesity and have acceptable safety profiles. In this clinical trial, we will utilize phentermine/topiramate to target counter- regulatory pathways responsible for weight regain after meal replacement therapy (structured meals of known caloric content) in adolescents with severe obesity with a goal of enhancing weight loss maintenance and improving co-morbidity outcomes. Importantly, we will maximize the clinical utility and overall impact of our study by comprehensively characterizing the safety of phentermine/topiramate utilizing sensitive measures of cardiac autonomic function, arterial stiffness, cognition, and bone health, as well as examine the extent to which this medication counteracts mechanisms of weight regain.