New approach preserves lean mass during GLP-1 weight loss

Clinical Takeaway: Lean mass loss remains a concern during GLP-1- and GIP-based weight loss therapy, particularly for older adults and others at risk for sarcopenia. These early data suggest that targeted myostatin inhibition may help preserve muscle while maintaining the weight-loss benefits of tirzepatide, although effects on strength, function, and long-term outcomes remain unknown.

Incretin-based therapies have transformed obesity treatment, but approximately one-quarter to one-third of the weight lost with these agents may come from lean mass rather than fat. Whether preserving muscle during pharmacologic weight loss improves long-term health outcomes remains an important unanswered question.

The phase 2 EMBRAZE trial evaluated apitegromab, an investigational monoclonal antibody that inhibits myostatin activation, in adults receiving tirzepatide for obesity treatment. Myostatin is a key regulator of skeletal muscle breakdown, making it an attractive target for lean mass preservation.

After 24 weeks, participants receiving apitegromab lost 1.9 kg less lean mass than those receiving placebo despite achieving similar overall weight loss. Lean mass loss accounted for 14.6% of total weight loss with apitegromab compared with 30.2% with placebo, representing approximately 55% greater lean mass retention.

Importantly, preserving lean mass did not appear to blunt weight reduction. Total body weight loss was similar between groups, while a greater proportion of weight loss came from fat mass in participants receiving apitegromab.

The treatment was generally well tolerated. Rates of adverse events, serious adverse events, and treatment discontinuation were similar between groups, with gastrointestinal symptoms largely attributable to tirzepatide.

The findings are notable because concern about muscle loss has emerged alongside the rapid adoption of GLP-1 and GLP-1/GIP therapies. Although lean mass preservation is biologically appealing, the study did not demonstrate improvements in physical function, strength, or cardiometabolic outcomes over the 24-week treatment period.

The authors emphasized that larger and longer studies will be needed to determine whether preserving lean mass translates into meaningful clinical benefits, particularly in older adults and other populations vulnerable to frailty and sarcopenia.

“Results from EMBRAZE demonstrate clinical proof of concept for a highly selective antimyostatin antibody to preserve lean mass with tirzepatide therapy,” the study authors concluded.

Source: Pratley RE, et al. 2026 June 8. Nat Med. Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial