GLP-1s and Lean Mass-Preserving Therapies: What to Know

This transcript has been edited for clarity. Hello. This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. I’d like to talk with you about several studies on GLP-1s, together with myostatin and activin pathway inhibitors, for preserving muscle and lean body mass. What’s important to know and what questions still need to be answered?I’ll focus on two recent phase 2 trial papers published in Nature Medicine, and one trial presented at the European EASD Conference, but pending publication. The two phase 2 trials published in Nature Medicine were of the myostatin or activin signaling inhibitors, bimagrumab and apitegromab, and the study pending publication is of trevogrumab. As you know, investigational antibodies to myostatin and/or activin are being studied as a way to preserve muscle during pharmacologic weight loss with GLP-1s or other treatments. Bimagrumab is a broad agent inhibiting myostatin, activin A, and related ligands.In the BELIEVE trial with 507 participants published earlier this year, bimagrumab, semaglutide, and their combination were tested in adults with obesity, but without diabetes. At 48 and 72 weeks, the combination produced large reductions in total and visceral fat while largely preserving lean mass. This suggested that activin receptor blockade may protect lean mass as well as augment fat loss. However, bimagrumab raised low-density lipoprotein cholesterol and had several side effects that dampened enthusiasm. Apitegromab is a more selective agent that blocks myostatin and prevents its activation without broadly blocking other related ligands. It previously showed gains in motor function in patients with spinal muscular atrophy. In a small trial of 102 participants over 24 weeks, the EMBRACE trial, the apitegromab added to tirzepatide resulted in a relative preservation of approximately 55% in lean mass loss compared to tirzepatide plus placebo, with similar total weight loss. The trial, however, did not have power to demonstrate improvements in strength or physical function. Trevogromab directly neutralizes myostatin. In the COURAGE trial with 599 participants, adding trevogromab to semaglutide for 26 weeks reduced lean mass loss by about 50% and modestly increased fat loss.These results are promising, but what’s needed now are well-powered phase 3 randomized trials for 12-24 months comparing GLP-1 therapy alone with combination treatment. It would be best to have more than DEXA for body composition and lean mass. Having MRI-defined skeletal muscle change, strength and physical function measurements, and outcomes including falls, fractures, disability, and patient-reported function will be key.Also importantly, more data in adults over age 65, patients with sarcopenic obesity, frailty, or limited mobility are needed. Trials should also assess cardiovascular safety and what these antibodies add to the benefits of resistance exercise and adequate protein intake. Additionally, in patients using GLP-1s, we need more information on the role of amylin-related treatments and what benefits they can provide in this clinical setting.Thank you so much for your attention. This is JoAnn Manson.