Enhancing Weight Loss Maintenance with GLP-1 in Adolescents with Severe Obesity

 描述（由申请人提供）：由于减肥后环境中涉及食欲、饱腹感和能量消耗的许多生物适应，肥胖个体很少实现长期减肥维持。在体重减轻后，外周和中枢机制传达了能量储备减少的感觉，激活了强烈的反反应以增加热量摄入。患有严重肥胖症的青少年也无法避免体重反弹这一令人烦恼的问题。事实上，只有2%的人能够通过生活方式改变疗法达到并维持临床意义上的体重减轻。因此，迫切需要关注长期减肥维持的新治疗范例。药物治疗有可能通过靶向减肥后的特定反调节机制来防止体重反弹。最有希望的候选药物之一是胰高血糖素样肽-1受体激动剂（GLP-1 RA）类，它大大增强了肥胖成年人短期低热量饮食后的减肥维持。关注GLP-1 RA治疗以预防体重反弹的依据得到了该类药物靶向的多种中枢和外周作用机制的支持;其中许多机制专门针对已知可诱导复发的生物学适应。我们有强有力的初步数据证明GLP-1 RA治疗可降低重度肥胖青少年的BMI。此外，我们和其他人已经表明，虽然膳食替代疗法（已知热量的结构化膳食）可以在严重肥胖的青少年中引起强烈的短期体重减轻，但体重反弹是一个普遍存在的问题。因此，在本临床试验中，我们的创新方法将利用GLP-1 RA治疗靶向 重度肥胖青年短期代餐治疗后体重恢复在代餐阶段达到BMI降低≥ 5%的受试者将被随机分配至GLP-1 RA治疗或安慰剂组，持续额外12个月，同时接受生活方式改变治疗。重要的是，这项研究还将使我们能够检查GLP-1 RA治疗解决体重恢复机制的程度，研究GLP-1 RA的其他多效性获益，并确定体重减轻反应的预测因子。这项研究解决了一个重大的公共卫生威胁，利用创新的治疗理念和方法，并通过指导研究和临床实践范例，对儿童肥胖症领域施加强大，持续的影响，以应用药物治疗进行有意义和持久的减肥和风险因素修改。

 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.