Effects of bimagrumab on body composition, insulin sensitivity, and bone in adults with obesity

bimagrumab 对肥胖成人的身体成分、胰岛素敏感性和骨骼的影响

• 批准号: 10716254
• 负责人: Melanie Schorr Haines
• 金额: $ 71.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716254
• 关键词: Activins; Adipocytes; Adipose tissue; Adult; Agonist; Area; Body Composition; Body Weight decreased; Bone Density; Bone Resorption; Clinical Data; Cyclophosphamide; Diet; Dose; Double-blind trial; Dual-Energy X-Ray Absorptiometry; Energy Intake; Energy Metabolism; FDA approved; Failure; Fatty acid glycerol esters; Finite Element Analysis; Fracture; GDF8 gene; GLP-I receptor; Glucose Clamp; Goals; Health; Hyperinsulinism; Individual; Insulin; Investigational Drugs; Ligands; Magnetic Resonance Imaging; Mediating; Metabolic; Muscle; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Pharmacotherapy; Placebos; Pre-Clinical Model; Proliferating; Protein Biosynthesis; Randomized; Rest; Risk; Risk Factors; Rodent; Serum; Skeletal Muscle; Thinness; Tissues; Translating; Type II Activin Receptors; Visceral; Visceral fat; Weight; adult obesity; bone; bone loss; bone mass; bone strength; cardiometabolic risk; diet and exercise; double-blind placebo controlled trial; falls; fluorodeoxyglucose positron emission tomography; frailty; glucose disposal; glucose uptake; hip bone; improved; inhibitor; insulin sensitivity; lifestyle intervention; mechanical load; mortality; muscle form; obesity treatment; pre-clinical; preservation; sarcopenia; side effect; weight loss intervention; Activins; Adipocytes; Adipose tissue; Adult; Agonist; Area; Body Composition; Body Weight decreased; Bone Density; Bone Resorption; Clinical Data; Cyclophosphamide; Diet; Dose; Double-blind trial; Dual-Energy X-Ray Absorptiometry; Energy Intake; Energy Metabolism; FDA approved; Failure; Fatty acid glycerol esters; Finite Element Analysis; Fracture; GDF8 gene; GLP-I receptor; Glucose Clamp; Goals; Health; Hyperinsulinism; Individual; Insulin; Investigational Drugs; Ligands; Magnetic Resonance Imaging; Mediating; Metabolic; Muscle; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Pharmacotherapy; Placebos; Pre-Clinical Model; Proliferating; Protein Biosynthesis; Randomized; Rest; Risk; Risk Factors; Rodent; Serum; Skeletal Muscle; Thinness; Tissues; Translating; Type II Activin Receptors; Visceral; Visceral fat; Weight; adult obesity; bone; bone loss; bone mass; bone strength; cardiometabolic risk; diet and exercise; double-blind placebo controlled trial; falls; fluorodeoxyglucose positron emission tomography; frailty; glucose disposal; glucose uptake; hip bone; improved; inhibitor; insulin sensitivity; lifestyle intervention; mechanical load; mortality; muscle form; obesity treatment; pre-clinical; preservation; sarcopenia; side effect; weight loss intervention

PROJECT SUMMARY/ABSTRACT In adults with obesity, 5-10% weight loss improves cardiometabolic risk, including insulin sensitivity, but not all components of weight loss are equally beneficial. Individuals would preferentially lose fat mass, particularly visceral fat, a major cardiometabolic risk factor. However, 20-40% of weight lost through diet, pharmacotherapy, or surgery in adults with obesity is lean mass, which mitigates improvements in insulin sensitivity—consistent with the fact that skeletal muscle is responsible for most insulin-mediated glucose disposal—and contributes to weight regain by reducing resting energy expenditure. Loss of bone mass is another unintentional consequence of weight loss, which increases the risk of osteoporosis and fractures. Therefore, optimum weight loss strategies should preserve muscle and bone mass. If a lifestyle intervention (diet and exercise) does not achieve weight loss goals, options include pharmacotherapy such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), semaglutide. Although semaglutide has the detrimental effect of reducing lean mass with weight loss, it does suppress bone resorption and increase bone formation in adults with obesity and stable weight. This suggests bone loss may not be a side effect of semaglutide, in contrast to other therapies for obesity, but this has not been investigated. Bimagrumab, an investigational new drug for obesity that inhibits the activin type II receptor (ActRII), may be anabolic to muscle and bone. Blockade of the myostatin/activin-ActRII pathway increases muscle mass, reduces fat mass, and improves insulin sensitivity while increasing bone formation, reducing bone resorption, and increasing bone mass in rodents. Early clinical data in adults with obesity and type 2 diabetes suggest that bimagrumab reduces visceral fat mass and increases lean mass. Although just one dose of bimagrumab increases whole body insulin sensitivity, it is unclear whether bimagrumab improves skeletal muscle insulin sensitivity. One dose of another ActRII inhibitor increases bone formation and decreases bone resorption, but longer-term effects on bone are unknown. We hypothesize that in a double-blind, placebo-controlled trial of 65 adults with obesity randomized in 2:2:1 ratio to bimagrumab (30mg/kg IV at 0, 4, 16, 28, and 40 weeks), semaglutide 2.4mg SQ qweek, or placebo, bimagrumab will result in metabolic improvements in muscle (Aim 1), visceral fat (Aim 2), and bone (Aim 3) vs. semaglutide or placebo over 52 weeks as an adjunct to a lifestyle intervention for weight loss. To investigate whether bimagrumab improves tissue-specific insulin sensitivity, 20 subjects will undergo hyperinsulinemic–euglycemic clamps with [18F]FDG-PET/MRI at baseline and Week 52. Understanding the effects of bimagrumab vs. semaglutide or placebo (as an adjunct to a lifestyle intervention for weight loss) on muscle, visceral fat, and bone will determine whether inhibiting the myostatin/activin-ActRII pathway reduces metabolic risk more than other treatments for obesity.

项目摘要/摘要 在患有肥胖症的成年人中，减肥5-10％可改善心脏代谢风险，包括胰岛素 敏感性，但并非所有体重减轻的组成部分同样有益。个人会优先 失去脂肪质量，尤其是内脏脂肪，这是主要的心脏代谢危险因素。但是，减肥的20-40％ 通过饮食，药物治疗或肥胖成年人的手术是瘦质量，这可以减轻改善 胰岛素敏感性 - 与骨骼肌负责大多数胰岛素介导的葡萄糖的事实一致 处置 - 通过减少静息能量消耗来恢复体重。骨骼质量的损失是另一种 体重减轻的无意后果，增加了骨质疏松和骨折的风险。所以， 最佳减肥策略应保留肌肉和骨骼质量。如果生活方式干预（饮食和 练习）无法实现减肥目标，选择包括药物治疗，例如胰高血糖素 肽1受体激动剂（GLP-1 RA），semaglutide。虽然semaglutide具有减少的不利影响 体重减轻的瘦质量，确实会抑制骨骼的骨骼分辨率并增加肥胖成人的骨形成 和稳定的体重。这表明与其他 肥胖症的疗法，但尚未进行调查。 Bimagrumab，一种抑制激活素II型受体的肥胖症研究性新药 （Actrii），可能是肌肉和骨骼的代谢。肌生蛋白/激活素-Actrii途径的封锁增加 肌肉质量，减少脂肪质量并改善胰岛素敏感性，同时增加骨形成，从而减少骨骼 啮齿动物的分解和增加骨质。肥胖和2型糖尿病的成年人的早期临床数据 表明双子幼虫可以减少内脏脂肪质量并增加瘦质量。虽然只有一剂 Bimagrumab提高了全身胰岛素的敏感性，目前尚不清楚双子abab是否会改善骨骼肌肉 胰岛素灵敏度。一种剂量的另一种ACTRII抑制剂会增加骨形成并减少骨骼分辨率， 但是长期对骨骼的影响尚不清楚。 我们假设在65名肥胖成年人的双盲，安慰剂对照试验中 在2：2：1与Bimagrumab的比例（30mg/kg IV时为0、4、16、28和40周），Semaglutide 2.4mg SQ Qweek或安慰剂，双子木单抗将导致肌肉的代谢改善（AIM 1），内脏脂肪 （AIM 2）和骨头（AIM 3）与Semaglutide或安慰剂在52周内作为生活方式的辅助 减肥干预。为了调查双子幼犬是否改善组织特异性胰岛素敏感性， 20名受试者将在基线和第52周时接受高胰岛素血糖夹夹。 了解Bimagrumab与Semaglutide或安慰剂的影响（作为生活方式的辅助 干预体重减轻）在肌肉，内脏脂肪和骨骼上都将决定是否抑制 与其他治疗方法相比，Myostatin/Activin-Actrii途径可降低代谢风险。