Glucagon-like peptide-1 agonist effects on energy balance in hypothalamic obesity

胰高血糖素样肽-1 激动剂对下丘脑肥胖能量平衡的影响

基本信息

批准号：
9324973
负责人：
M. Jennifer Abuzzahab
金额：
$ 49.15万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-24 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324973
关键词：
Adipose tissue Adolescent obesity Adult Affect Agonist Anti-Obesity Agents Appetitive Behavior Area Behavioral Biological Factors Blood Glucose Body Composition Body Weight Body Weight decreased Body fat Body mass index Brain Brain Neoplasms Brain region Cardiovascular system Cell Nucleus Cerebral Infarction Cerebrovascular Disorders Cessation of life Child Childhood Brain Neoplasm Clinical Clinical Research Clinical Trials Controlled Clinical Trials Craniopharyngioma Data Desire for food Development Diet Disease Double-Blind Method Energy Intake Energy Metabolism Fasting Functional disorder GLP-I receptor Gastrointestinal tract structure General Population Glucose Goals Homeostasis Hormonal Human Hyperinsulinism Hyperphagia Hypothalamic Neoplasms Hypothalamic dysfunction Hypothalamic structure Injection of therapeutic agent Insulin Resistance Intervention Intervention Studies Lead Leptin Leptin resistance Lesion Light Lipids Magnetic Resonance Imaging Measures Medial Metabolic Metabolic syndrome Morbid Obesity Multicenter Studies Multicenter Trials Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Outcome Outcome Measure Patients Peripheral Pharmaceutical Preparations Physical activity Physiology Pilot Projects Placebo Control Placebos Population Population Study Quality of life Randomized Randomized Clinical Trials Regulation Reporting Resistance Risk Risk Factors Rodent Safety Satiation Secondary to Serum Severities Signal Pathway Signal Transduction Site Survival Rate Sweden Testing Treatment outcome Vagus nerve structure Weight Gain Work actigraphy base brain size cardiometabolic risk cardiovascular disorder risk cohort cost effective design doubly-labeled water effective therapy energy balance exenatide glucagon-like peptide 1 glucose tolerance hindbrain improved inflammatory marker innovation insight insulin secretion mortality neuroimaging novel novel therapeutics obesity management open label predictive of treatment response prospective public health relevance randomized placebo controlled trial randomized trial response success successful intervention total energy expenditure treatment response tumor

项目摘要

DESCRIPTION (provided by applicant): Hypothalamic obesity (HO) occurs in patients with tumors and lesions in the medial hypothalamic region. Hypothalamic dysfunction can lead to hyperinsulinemia and leptin resistance. This study is focused on HO caused by craniopharyngiomas (CP), which are the most common childhood brain tumors of nonglial origin. Despite excellent overall survival rates, CP patients have substantially reduced quality of life because of significant long-term sequelae, notably severe obesity in about 50% of patients, leading to a high rate of cardiovascular mortality. Recent studies reported that both hyperphagia and decreased energy expenditure can contribute to severe obesity in HO patients. Previous drug intervention studies were either too small or showed only moderate effects, and it is not clear which biological factors are responsible for successful intervention. Some anti-obesity drugs that require intact hypothalamic signaling pathways for appetite inhibition show poor efficacy in patients with HO. Based on promising results using a glucagon-like-peptide-1 receptor agonist (GLP1RA) in obese adolescents with and without HO, as well as in rodents with HO, the proposed multicenter study will test the effect of the GLP1RA exenatide once weekly extended-release (ExQW) on clinical outcomes and metabolic function in a 36 week double-blind, placebo-controlled randomized trial followed by a 18 week open label extension. Forty-eight subjects will be randomized to GLP1RA (24) or placebo (24). The overall hypothesis is that in severely obese HO subjects with extended hypothalamic damage, drugs causing weight loss via hindbrain signaling, such as GLP1RAs, will reduce body weight, providing a desperately needed non-surgical option for treatment of HO. We recognize that there may be variability of treatment response and will therefore also test potential behavioral, metabolic, and neuroradiological predictors of treatment response. The primary endpoint is to test long-term efficacy of GLP1RA treatment on body mass index reduction after 36 weeks. Secondary endpoints include changes in body composition, parameters of metabolic syndrome, free-living total energy expenditure, appetitive behavior, physical activity, hormonal parameters of energy homeostasis and insulin resistance. Specific Aim (SA) 1 will test if GLP1RA treatment will lead to reduced BMI. SA 2 will test if GLP1RA improves adiposity, cardiometabolic risk factors, glucose tolerance and hyperinsulinemia. SA 3 will include exploratory studies in order to test if GLP1RA will lead to changes in energy intake and expenditure. SA 3 will also test innovative predictors of GLP1RA treatment outcomes such as pretreatment hyperphagia, energy expenditure, serum leptin and the severity of the hypothalamic lesion assessed by a novel neuroimaging score obtained prior to study intervention. The study is guided by an integrated transdisciplinary team. The goals are to implement cost-effective treatments to improve HO outcomes, and to get fundamental mechanistic insights into GLP-1 physiology and factors that determine treatment success, which are also relevant for other forms of obesity.

描述（申请人提供）：下丘脑内侧区域肿瘤和病变患者会出现下丘脑肥胖（HO），该病可导致高胰岛素血症和瘦素抵抗，该研究的重点是颅咽管瘤（CP）引起的下丘脑肥胖。最常见的非神经胶质源性儿童脑肿瘤尽管总体生存率很高，但 CP 患者的生存质量大幅下降。由于严重的长期后遗症，特别是约 50% 的患者出现严重肥胖，导致心血管死亡率较高，最近的研究表明，进食过多和能量消耗减少可能导致 HO 患者出现严重肥胖。研究要么太小，要么只显示中等效果，并且尚不清楚哪些生物因素能够成功干预，一些需要完整的下丘脑信号通路来抑制食欲的抗肥胖药物在 HO 患者中显示出较差的疗效。结果使用胰高血糖素样肽-1受体激动剂（GLP1RA）在患有和不患有HO的肥胖青少年以及患有HO的啮齿动物中进行，拟议的多中心研究将测试每周一次的GLP1RA艾塞那肽缓释剂（ExQW）对临床的影响一项为期 36 周的双盲、安慰剂对照随机试验中的结果和代谢功能，随后进行为期 18 周的开放标签扩展试验，48 名受试者将被随机分配至 GLP1RA 组。 (24) 或安慰剂 (24) 总体假设是，在下丘脑损伤严重的 HO 受试者中，通过后脑信号传导导致体重减轻的药物（例如 GLP1RA）会减轻体重，从而为患者提供迫切需要的非手术选择。我们认识到治疗反应可能存在差异，因此还将测试潜在的行为、代谢和功能。治疗反应的神经放射学预测因素是测试 GLP1RA 治疗 36 周后体重指数降低的长期疗效，次要终点包括身体成分的变化、代谢综合征参数、自由生活总能量消耗、食欲行为。、体力活动、能量稳态和胰岛素抵抗的激素参数特定目标 (SA) 1 将测试 GLP1RA 治疗是否会导致 BMI 降低 SA 2 将测试 GLP1RA 是否会降低。 SA 3 将包括探索性研究，以测试 GLP1RA 是否会导致能量摄入和消耗的变化，SA 3 还将测试 GLP1RA 治疗结果的创新预测因素，例如治疗前的食欲亢进、该研究由一个综合跨学科团队指导，通过在研究干预之前获得的新神经影像评分来评估能量消耗、血清瘦素和下丘脑病变的严重程度。目标是实施具有成本效益的治疗方法以改善 HO 结局，并获得对 GLP-1 生理学和决定治疗成功的因素的基本机制见解，这也与其他形式的肥胖相关。