Currently, GLP-1 therapies dominate the weight-loss drug market, achieving 20%–25% weight reduction within a year while continually pushing the upper limits of weight loss. However, research indicates that approximately 30-40% of weight loss from GLP-1 drugs like semaglutide stems from muscle loss. This may lead to reduced metabolic rates and increased risk of weight regain.
Amidst intensifying competition in weight-loss drug development, the quality and sustainability of fat loss have emerged as new focal points beyond efficacy alone. For obesity patients, whether using monotherapy or in combination with GLP-1 drugs, an ideal approach should achieve significant fat reduction while maintaining or even increasing lean body mass (muscle mass).
Against this backdrop, ActRII inhibition—currently the only mechanism clinically proven to achieve comprehensive body composition optimization (fat loss + muscle gain)—has garnered widespread attention. This mechanism holds promise to pioneer breakthroughs in next-generation high-quality weight loss therapies, positioning it as a true game-changing “potential seed contender.”
Understanding the ActRII Target
The Activin Type II Receptor (ActRII) belongs to the transforming growth factor beta (TGF-β) receptor family. It functions as a type II receptor for TGF-β family members including Activin A, Activin B, BMP7, BMP9, BMP10, GDF1, GDF8 (myostatin), GDF11, and Nodal.
ActRII is present in both fat and muscle cells. In adipocytes, activins signal through ActRII to promote lipid storage—a key driver of obesity. Blocking this pathway enhances fat metabolism. In muscle cells, the ActRⅡ-mediated signaling pathway inhibits muscle growth and induces atrophy. Blocking activin signaling in skeletal muscle suppresses this atrophy and promotes muscle mass gain, aiding obese patients in improving body composition and metabolism while losing weight.
Activation of the ActRII receptor pathway leads to muscle atrophy and fat accumulation in adipose tissue. Therefore, targeting this pathway holds promise for a dual effect: driving fat loss while increasing muscle composition in patients, addressing the limitations of GLP-1 therapies.
Bimagrumab Clinical Data
On June 23, 2025, Eli Lilly presented Phase 2b clinical data for Bimagrumab weight loss treatment at the ADA conference:
– After 72 weeks, the Bimagrumab group achieved 10.8% weight loss, with 100% derived from fat and a 2.5% increase in muscle mass. The semaglutide group lost 15.7% body weight, but only 71.5% was fat loss, with a 7.4% muscle loss. The combination therapy group achieved a 22.1% weight loss, with 92.9% coming from fat loss and only a 2.9% muscle loss. The Bimagrumab data is nothing short of spectacular!
As GLP-1 drugs enter a phase of rapid advancement, weight loss is no longer merely a “numbers game.” True healthy weight loss requires achieving optimal body composition remodeling—reducing fat while preserving or even increasing muscle mass. New drugs like Bimagrumab are propelling the industry toward a new era of multi-target synergistic action, structural remodeling, and precise metabolic regulation. In the future, “fat loss + muscle gain” will be the protagonists of the next revolution.