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

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 在肥胖的成年人中，体重减轻5%-10%可以改善心脏代谢风险，包括胰岛素 敏感，但并不是所有的减肥成分都同样有益。个人会优先考虑 减少脂肪量，特别是内脏脂肪，这是心脏代谢的主要风险因素。然而，20%-40%的体重减轻了 通过饮食、药物治疗或手术治疗肥胖的成年人是瘦体重，这缓解了 胰岛素敏感性--与骨骼肌负责大部分胰岛素介导的葡萄糖的事实一致 处置--并通过减少静息能量消耗来帮助体重恢复。骨量丢失是另一个原因 体重减轻的意外后果，增加了骨质疏松和骨折的风险。因此， 最佳的减肥策略应该保持肌肉和骨量。如果生活方式干预(节食和 运动)不能达到减肥目标，选择包括药物治疗，如类胰高血糖素 多肽1受体激动剂(GLP-1RA)，赛马路德。尽管赛马路德具有降低 瘦体重与体重减轻，它确实抑制了骨吸收，并增加了肥胖成年人的骨形成 体重稳定。这表明，与其他药物相比，骨丢失可能不是赛格鲁特的副作用 肥胖症的治疗方法，但这还没有被调查。 抑制激活素II型受体的肥胖症研究新药bImagruab (ActRII)，可能对肌肉和骨骼是合成代谢的。对肌肉生长抑素/激活素-ActRII途径的阻断增加 肌肉质量，减少脂肪质量，改善胰岛素敏感性，同时促进骨形成，减少骨骼 吸收，并增加啮齿动物的骨量。成人肥胖和2型糖尿病患者的早期临床资料 提示bImagruab可减少内脏脂肪质量，增加瘦肉量。虽然只有一剂 BImagruab增加全身胰岛素敏感性，目前尚不清楚bImagruab是否能改善骨骼肌 胰岛素敏感性。另一种ActRII抑制剂的剂量增加了骨形成，减少了骨吸收， 但对骨骼的长期影响尚不清楚。 我们假设，在一项对65名成年肥胖症患者进行的双盲安慰剂对照试验中 按2：2：1的随机比例给予bImagruab(30 mg/kg静脉注射，分别在0、4、16、28和40周)，赛马路德2.4 mg SQ周，或安慰剂，bImagruab将导致肌肉(目标1)，内脏脂肪的代谢改善 (目标2)，骨(目标3)与赛马路德或安慰剂相比，超过52周作为生活方式的辅助 对减肥的干预。为了研究bImagruab是否能改善组织特异性胰岛素敏感性， 20名受试者将在基线和52周用[18F]FDG-PET/MRI进行高胰岛素-正常血糖钳夹治疗。 了解bImagruab与赛马路德或安慰剂(作为生活方式的补充)的效果 对肌肉、内脏脂肪和骨骼的干预)将决定是否抑制 与其他肥胖治疗方法相比，myostatin/激活素-ActRII途径更能降低代谢风险。