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

使用 GLP-1 加强重度肥胖青少年的减肥维持

• 批准号: 8936755
• 负责人: Aaron S Kelly
• 金额: $ 58.13万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8936755
• 关键词: Address; Adolescent; Adult; Agonist; Behavior Therapy; Beta Cell; Biological Adaptation; Blood Pressure; Body Weight; Body Weight decreased; Body fat; Childhood; Clinical Trials; Comorbidity; Controlled Clinical Trials; Data; Desire for food; Diet; Double-Blind Method; Energy Intake; Energy Metabolism; Female; Functional disorder; GLP-I receptor; Gastric Emptying; Gender; Glucose; HDL-triglyceride; High Prevalence; Hormones; Hypertension; Immune; Individual; Inflammation; Insulin; Insulin Resistance; Maintenance; Medical; Modification; Morbid Obesity; Obesity; Oxidative Stress; Participant; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebo Control; Placebos; Public Health; Randomized; Relapse; Replacement Therapy; Research; Rest; Risk Factors; Satiation; Structure; Time; United States; Visceral; Weight; Work; Youth; arterial stiffness; base; cardiometabolic risk; clinical practice; glucagon-like peptide; glucagon-like peptide 1; glucose tolerance; improved; innovation; novel; obesity in children; pleiotropism; prevent; psychosocial; public health relevance; response; sobriety; subcutaneous

 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.

 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，肥胖个体很少能实现长期减肥维持。体重减轻后，外周和中枢机制会传达能量储备减少的感觉，从而激活强烈的反反应以增加热量摄入。严重肥胖的青少年也不能幸免于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实现并维持有临床意义的体重减轻。因此，迫切需要注重长期减肥维持的新治疗模式。药物疗法有可能通过针对减肥后环境中的特定反调节机制来防止体重反弹。最有前途的候选药物之一是胰高血糖素样肽-1 受体激动剂 (GLP-1RA) 类，它极大地增强了肥胖成人短期低热量饮食后的减肥维持效果。此类药物针对的多种中枢和外周作用机制支持了专注于 GLP-1RA 治疗以防止体重反弹的基本原理；其中许多专门针对已知会诱发复发的生物适应。我们有强有力的初步数据证明 GLP-1RA 治疗可降低严重肥胖青少年的 BMI。此外，我们和其他人已经表明，尽管膳食替代疗法（已知热量含量的结构化膳食）可以在严重肥胖的青少年中引起短期的强烈减肥，但体重反弹是一个普遍的问题。因此，在本次临床试验中，我们的创新方法将利用 GLP-1RA 治疗来靶向治疗 严重肥胖青少年短期代餐治疗后体重反弹。在代餐阶段体重指数降低 5% 的参与者将被随机分配接受 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体重恢复机制，研究 GLP-1RA 的其他多效性益处，并确定体重减轻反应的预测因素。这项研究解决了重大的公共卫生威胁，利用创新的治疗概念和方法，通过引导研究和临床实践范式转向药物治疗的应用，实现有意义和持久的减肥和危险因素改变，对儿科肥胖领域产生强大、持续的影响。