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

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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.