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

项目总结/摘要 在肥胖的成年人中，5-10%的体重减轻可改善心脏代谢风险，包括胰岛素 敏感性，但并非所有减肥成分都同样有益。个人更愿意 减少脂肪量，特别是内脏脂肪，这是一个主要的心脏代谢风险因素。然而，20-40%的体重减轻 通过饮食，药物治疗或手术治疗成年肥胖症的方法是瘦体重， 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-并有助于通过减少静息能量消耗体重反弹。骨质流失是另一个原因 体重减轻的意外后果，增加了骨质疏松症和骨折的风险。因此，我们认为， 最佳的减肥策略应该保持肌肉和骨骼质量。如果生活方式干预（饮食和 运动）不能达到减肥目标，选择包括药物治疗，如胰高血糖素样 肽1受体激动剂（GLP-1 RA），Semaglutide。尽管Semaglutide具有降低 瘦体重与体重减轻，它抑制骨吸收和增加骨形成的成年肥胖 稳定的体重。这表明骨丢失可能不是Semaglutide的副作用，与其他药物相比， 治疗肥胖症，但这还没有被调查。 Bimagrumab，一种抑制激活素II型受体的研究性肥胖新药 （ActRII），可能是肌肉和骨骼的合成代谢。肌肉生长抑制素/激活素-ActRII通路的阻断增加 肌肉质量，减少脂肪量，提高胰岛素敏感性，同时增加骨形成，减少骨 再吸收和增加啮齿类动物的骨量。肥胖和2型糖尿病成人患者的早期临床数据 表明比麦单抗减少内脏脂肪量并增加瘦体重。尽管仅仅一剂 bimagrumab增加全身胰岛素敏感性，目前尚不清楚bimagrumab是否改善骨骼肌 胰岛素敏感性另一种ActRII抑制剂的一个剂量增加骨形成并减少骨吸收， 但对骨骼的长期影响尚不清楚。 我们假设，在一项对65名肥胖成年人进行的双盲、安慰剂对照试验中， 以2：2：1的比例随机分配至bimagrumab组（30 mg/kg IV，第0、4、16、28和40周）、semaglutide 2.4 mg组 SQ qweek或安慰剂，bimagrumab将导致肌肉（目的1）、内脏脂肪 (Aim 2）和骨（Aim 3）与semaglutide或安慰剂相比，作为生活方式的辅助治疗，持续52周 干预减肥。为了研究bimagrumab是否改善组织特异性胰岛素敏感性， 20例受试者将在基线和第52周接受高胰岛素-正常血糖钳夹和[18 F]FDG-PET/MRI。 了解bimagrumab与Semaglutide或安慰剂的作用（作为生活方式的辅助治疗） 干预减肥）对肌肉，内脏脂肪和骨骼的影响将决定是否抑制 肌肉生长抑制素/激活素-ActRII途径比其他肥胖治疗方法更能降低代谢风险。

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.