Anti-obesity pharmacotherapy to decrease BMI and improve insulin sensitivity in adolescents with obesity and type 2 diabetes

抗肥胖药物治疗可降低肥胖和 2 型糖尿病青少年的 BMI 并提高胰岛素敏感性

• 批准号: 10281728
• 负责人: Megan O Bensignor
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281728
• 关键词: 20 year old; Address; Adolescent; Adolescent obesity; Adult; Age; Agonist; Atherosclerosis; Beta Cell; Body Weight decreased; Body fat; Body mass index; Cell physiology; Cells; Childhood; Clinical; Clinical Practice Guideline; Clinical Trials; Clinical Trials Design; Data; Dependence; Desire for food; Deterioration; Development; Diabetes Mellitus; Disease; Disease Progression; Dose; Endocrinology; Enrollment; Evaluation; FDA approved; Foundations; Functional disorder; Future; GLP-I receptor; Glucagon; Glycosylated hemoglobin A; Goals; Health system; Hypertension; Incentives; Infrastructure; Injectable; Instruction; Insulin; Insulin Resistance; Kidney Diseases; Life Style; Measures; Medicine; Mentors; Metabolic; Metformin; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Population; Production; Refractory Disease; Research; Resources; Risk Factors; Safety; Satiation; Training; Visceral; Weight Gain; adult obesity; aged; aggressive therapy; career; comorbidity; design; functional improvement; glucagon-like peptide 1; improved; insight; insulin secretion; insulin sensitivity; liraglutide; novel; obesity in children; obesity treatment; open label; patient population; pilot trial; randomized placebo controlled trial; recruit; sex; skills; slow potential; standard care; standard of care; treatment guidelines

Project Abstract/Summary Development of type 2 diabetes (T2D) prior to the age of 20 years has been associated with rapid disease progression and early exogenous insulin dependence.1 Furthermore, adolescents with T2D are more likely to develop diabetes-related comorbidities, such as hypertension, atherosclerosis, and kidney disease earlier compared to adults, highlighting the need for a fundamentally different (and perhaps more aggressive) treatment approach in adolescents.1 Obesity (body mass index [BMI] >95th percentile for age and sex) is a primary risk factor for the development and progression of T2D.2,3 However, current treatment guidelines for T2D in adolescents recommend lifestyle management and metformin (+ insulin) as first-line therapy, which rarely result in BMI reduction or slowing of T2D disease progression.1,4-7 Therefore, novel treatments that meaningfully reduce BMI, delay exogenous insulin dependence, and potentially slow the progression of T2D need to be investigated in adolescents with T2D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may represent an ideal first- line therapy for adolescent T2D. GLP-1 RAs increase postprandial insulin secretion and reduce glucagon production, and at higher doses, can result in clinically meaningful BMI reduction by suppressing appetite and enhancing satiety.8 Liraglutide (a daily injectable GLP-1 RA) at its 1.8 mg/day dose was approved for adolescents with T2D in 2019, but liraglutide has not been studied with a primary focus on BMI reduction and insulin sensitivity or ß-cell function in adolescents with T2D.9,10 Therefore, the overall objectives of this study will be to 1) evaluate the effects of liraglutide at its obesity medicine dose (3.0 mg/day) versus standard-of-care on BMI reduction, and 2) evaluate its effect on insulin sensitivity and β-cell function in adolescents with T2D and obesity. The overall hypothesis is that liraglutide 3.0 mg/day will result in a greater mean BMI percent change as well as improvements in insulin sensitivity and β-cell function as compared to placebo plus standard-of-care. The focus on using liraglutide at its obesity medicine dose in adolescents with T2D is novel and important; prior studies evaluating liraglutide have not been generalizable to adolescents with this aggressive disease nor have prior studies had the majority of patients on the maximum liraglutide dose, making dose-dependent weight-loss evaluations difficult. The proposed study will generate preliminary data to inform the design of a larger and sufficiently-powered R01 trial. Importantly, this mentored project will provide essential training in clinical trial design and implementation in a unique and challenging patient population, as well as measures of insulin sensitivity/β-cell function. These skills will facilitate my scholarly independence and serve as the foundation of my future career focusing on the application of obesity medicine principles in the treatment of adolescents with T2D.

项目摘要/总结 20 岁之前罹患 2 型糖尿病 (T2D) 与病情快速发展有关 进展和早期外源性胰岛素依赖。1此外，患有 T2D 的青少年更有可能 更早出现糖尿病相关合并症，如高血压、动脉粥样硬化和肾脏疾病 与成人相比，强调需要一种根本不同的（也许更积极的）治疗 1 肥胖（体重指数 [BMI] > 年龄和性别的第 95 个百分位）是主要风险 T2D 发生和进展的因素。2,3 然而，目前 T2D 的治疗指南 青少年建议生活方式管理和二甲双胍（+胰岛素）作为一线治疗，但很少有结果 BMI 降低或 T2D 疾病进展减慢。1,4-7 因此，新的治疗方法可以显着降低 BMI 或减缓 T2D 疾病进展。 需要研究 BMI、延迟外源性胰岛素依赖以及可能减缓 T2D 的进展 患有 T2D 的青少年。胰高血糖素样肽-1 受体激动剂 (GLP-1RA) 可能是理想的首选药物 青少年 T2D 的一线治疗。 GLP-1 RA 增加餐后胰岛素分泌并减少胰高血糖素 较高剂量的生产可以通过抑制食欲和降低体重指数来降低临床意义。 增强饱腹感。8 利拉鲁肽（每日注射 GLP-1 RA）的 1.8 毫克/天剂量被批准用于青少年 2019 年出现了 T2D，但尚未对利拉鲁肽进行研究，主要关注体重指数降低和胰岛素敏感性 或 T2D 青少年的 β 细胞功能。9,10 因此，本研究的总体目标是 1) 评估 肥胖药物剂量（3.0 毫克/天）的利拉鲁肽与标准治疗相比对 BMI 降低的影响，以及 2) 评估其对患有 T2D 和肥胖的青少年的胰岛素敏感性和 β 细胞功能的影响。整体 假设利拉鲁肽 3.0 mg/天会导致平均 BMI 百分比变化更大，并且 与安慰剂加标准护理相比，胰岛素敏感性和 β 细胞功能得到改善。焦点 关于在患有 T2D 的青少年中使用肥胖药物剂量的利拉鲁肽是新颖且重要的；先前的研究 利拉鲁肽的评估尚未推广到患有这种侵袭性疾病的青少年，之前也没有 研究对大多数患者进行了最大利拉鲁肽剂量的研究，使得体重减轻呈剂量依赖性 评价困难。拟议的研究将产生初步数据，为更大和更大规模的设计提供信息。 动力充足的R01试用。重要的是，这个指导项目将提供临床试验方面的必要培训 在独特且具有挑战性的患者群体中设计和实施，以及胰岛素测量 敏感性/β细胞功能。这些技能将促进我的学术独立，并作为我的基础 我未来的职业重点是肥胖医学原理在青少年肥胖症治疗中的应用 T2D。