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

 描述(申请人提供)：肥胖者很少实现长期的减肥维持，因为在减肥后的环境中，涉及食欲、饱腹感和能量消耗的许多生物适应。随着体重的减轻，外周和中枢机制传递出一种能量储备已经减少的感觉，激活了一种强烈的相反反应，以增加卡路里的摄入。患有严重肥胖症的青少年也不能幸免于体重恢复这一令人烦恼的问题。事实上，只有2%的人能够通过改变生活方式的疗法实现并保持具有临床意义的减肥效果。因此，迫切需要着眼于长期减肥维持的新的治疗模式。药物治疗有可能通过在减肥后环境中针对特定的反调节机制来防止体重回升。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-1RA)，它在肥胖成年人短期低卡路里饮食后极大地增强了减肥的维持。专注于GLP-1RA治疗以防止体重回升的理由得到了这类药物所针对的多种中枢和外围作用机制的支持；其中许多机制具体涉及已知的诱导复发的生物适应。我们有强有力的初步数据表明，GLP-1RA治疗可以降低患有严重肥胖的青少年的BMI。此外，我们和其他人已经表明，尽管膳食替代疗法(已知卡路里含量的结构性膳食)可以在严重肥胖的青少年中产生强劲的短期减肥效果，但体重恢复是一个普遍存在的问题。因此，在这项临床试验中，我们的创新方法将利用GLP-1RA治疗来靶向 患有严重肥胖症的青少年接受短期膳食替代治疗后体重恢复。在饮食替代阶段体重指数下降5%的参与者将被随机接受GLP-1RA治疗或安慰剂治疗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-1RA治疗在多大程度上解决了体重恢复的机制，调查了GLP-1RA的其他多效性好处，并确定了体重减轻反应的预测因素。这项研究解决了一个重大的公共健康威胁，利用了一种创新的治疗概念和方法，并通过指导研究和临床实践范式，对儿童肥胖症领域产生了强大而持久的影响，以实现有意义和持久的减肥和风险因素修正。

 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.