Effects of semaglutide on bone and muscle endpoints in adults with obesity: a pilot study.

索马鲁肽对肥胖成人骨骼和肌肉终点的影响：一项试点研究。

基本信息

批准号：
10350212
负责人：
Melanie Schorr Haines
金额：
$ 11.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350212
关键词：
18 year old Acute Adipose tissue Adult Affect Agonist Area Body Composition Body Weight decreased Bone Density Bone Resorption Bone structure C-terminal type I collagen telopeptide Cardiometabolic Disease Clinical Data Control Groups Cyclophosphamide Data Diet Endocrine Enrollment Epidemic Exercise Extensor FDA approved Fracture GDF8 gene GLP-I receptor Glucocorticoids Habits Hip Fractures Human Impairment In Vitro Individual Knee Knock-out Life Ligands Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Marrow Measures Meta-Analysis Muscle Muscular Atrophy Obesity Osteoblasts Osteocalcin Osteogenesis Osteoporosis Overweight Pharmacology Pilot Projects Placebos Prevalence Prospective Studies Protocols documentation Protons Public Health Publishing Randomized Controlled Trials Research Rodent Rodent Model Serum Thigh structure United States Weight adipocyte differentiation adult obesity bone bone loss bone marrow mesenchymal stem cell bone mass bone metabolism bone preservation bone strength dietary exercise program fall risk fracture risk glucagon-like peptide 1 high risk knock-down lifestyle intervention lipid biosynthesis liraglutide middle age mortality mouse model muscle form muscle strength obesity treatment osteoblast differentiation pre-clinical prevent primary endpoint prospective recruit reduced muscle mass sarcopenia skeletal subcutaneous treatment effect weight loss intervention

项目摘要

PROJECT SUMMARY/ABSTRACT Obesity is a growing epidemic, with more than two-thirds of adults in the United States overweight or obese. Although diet-induced weight loss reduces obesity-related complications, it is increasingly recognized that serious complications of weight loss occur, including fractures and sarcopenia. This is an important public health issue given the large number of adults seeking weight loss, and the increasing prevalence rates of osteoporosis and sarcopenia. However, little is known about the effects of different pharmacologic therapies for weight loss on bone and muscle. The proposed research will investigate whether the glucagon-like peptide 1 receptor agonist (GLP-1 RA), liraglutide, which is FDA-approved for the treatment of obesity, mitigates bone resorption and muscle mass loss associated with weight loss. If this is true, then liraglutide may be a preferred pharmacologic therapy for weight loss, especially in adults with obesity and osteoporosis or sarcopenia. Preclinical data suggest that GLP-1 RAs may be anabolic to bone and muscle. GLP-1 promotes bone formation while suppressing bone resorption in vitro. In rodent models, GLP-1 RAs increase bone density and strength and increase muscle mass. However, clinical data regarding the effects of GLP-1 RAs, as prescribed for weight loss, on bone metabolism markers, as well as muscle mass and strength, are lacking. Osteoblasts and adipocytes are differentiated from common mesenchymal bone marrow stem cells. Weight loss increases marrow adipose tissue (MAT), which can be measured by MR spectroscopy in humans, and is associated with decreased bone mineral density. In vitro data suggest that GLP-1 RAs inhibit marrow adipogenesis while promoting osteoblast differentiation, but whether decreasing MAT is a mechanism by which GLP-1 RAs affect bone mass in humans is not known. Our hypothesis is that 3 months of daily subcutaneous liraglutide will result in lower bone resorption markers, higher bone formation markers, less muscle mass loss, and a reduction in MAT compared to a lifestyle intervention resulting in a comparable amount of weight loss, Healthy Habits for Life (HHL), in 40 otherwise healthy adults with obesity. The current proposal is a pilot study with two aims: Aim 1 investigates the effects of liraglutide on bone metabolism markers and MAT compared to an intensive lifestyle intervention for weight loss, while Aim 2 investigates the effects of liraglutide on muscle mass and strength compared to an intensive lifestyle intervention for weight loss. The proposed protocol builds on Dr. Melanie Schorr Haines’s K23 project and growing area of expertise in the endocrine determinants of body composition, with a focus on muscle, and their contribution to cardiometabolic disease and skeletal integrity. This pilot study will provide critical preliminary data for an R01 proposal to conduct a prospective, randomized, controlled trial to determine whether GLP-1 RAs result in preservation of bone density and muscle mass despite weight loss in individuals with obesity.

项目概要/摘要肥胖是一种日益严重的流行病，超过三分之二的美国成年人体重超重或体重过重尽管饮食引起的减肥可以减少与肥胖相关的并发症，但人们越来越认识到这一点。减肥会出现严重的并发症，包括骨折和肌肉减少症，这是一个重要的公众问题。鉴于大量成年人寻求减肥，以及肥胖患病率不断上升，健康问题然而，对于不同药物疗法对骨质疏松症和肌肉减少症的影响知之甚少。拟议的研究将调查胰高血糖素样肽 1 是否对骨骼和肌肉有减肥作用。受体激动剂（GLP-1 RA）利拉鲁肽已获得 FDA 批准用于治疗肥胖症，可减轻骨质疏松如果这是真的，那么利拉鲁肽可能是首选。减肥的药物治疗，特别是对于患有肥胖症和骨质疏松症或肌肉减少症的成年人。临床前数据表明，GLP-1 RA 可能对骨骼和肌肉有合成代谢作用，可促进骨骼生长。在体外啮齿动物模型中，GLP-1 RA 可以增加骨密度并抑制骨吸收。然而，有关 GLP-1 RA 效果的临床数据，请按照规定进行。对于减肥来说，骨代谢标志物以及肌肉质量和力量都缺乏。成骨细胞和脂肪细胞由常见的间充质骨髓干细胞分化而来。体重减轻会增加骨髓脂肪组织（MAT），这可以通过人类的磁共振波谱进行测量，且与骨矿物质密度降低相关体外数据表明 GLP-1 RA 会抑制骨髓。脂肪生成同时促进成骨细胞分化，但减少 MAT 是否是其中的一个机制 GLP-1 RA 对人类骨量的影响尚不清楚。我们的假设是，每日皮下注射利拉鲁肽 3 个月会导致下骨吸收标志物、更高的骨形成标志物、更少的肌肉质量损失以及 MAT 的减少与导致同等体重减轻的生活方式干预相比，健康习惯 Life (HHL)，在 40 名其他方面健康的肥胖成年人中进行。当前的提议是一项试点研究，有两个目标：目标 1 研究与强化治疗相比，利拉鲁肽对骨代谢标志物和 MAT 的影响生活方式干预以减轻体重，而目标 2 研究利拉鲁肽对肌肉质量和体重的影响与强化生活方式干预减肥相比。拟议的协议建立在 Melanie Schorr Haines 博士的 K23 项目和不断增长的专业领域的基础上在身体成分的内分泌决定因素中，重点关注肌肉及其对该试点研究将为 R01 提供关键的初步数据。提议进行一项前瞻性、随机、对照试验以确定 GLP-1 RA 是否会导致尽管肥胖症患者体重减轻，但仍能保持骨密度和肌肉质量。