The strongest criticism of these drugs is that a quarter or more of what comes off is lean tissue, a problem this site has covered from several directions including what these drugs do to muscle. The pharmaceutical answer is a second drug, and one has now been tested [1].
Apitegromab is a monoclonal antibody that blocks the activation of myostatin, the signal that limits how much muscle the body builds. Everyone in the trial took tirzepatide; half also received apitegromab. At week 24 the apitegromab group had lost 1.9 kg less lean mass than placebo, which the authors describe as retaining 54.9% of what would otherwise have gone, and total weight loss was similar in both arms.
The second limit is what lean mass means. It is measured by scan and it includes organs and body water alongside skeletal muscle. This trial reports no grip strength, no walking speed and no measure of physical function, so what was preserved is a compartment on a scan rather than a demonstrated ability to do anything. That distinction runs through the whole field, as the grip strength evidence sets out, and it is the reason a kilogram of retained lean mass is a promising signal rather than a clinical benefit.
Safety looked unremarkable at this scale, with adverse events in 76% of the apitegromab group against 71% on placebo and one serious event in each arm — though 51 people per arm over 24 weeks can only detect common problems. The authors call it a proof-of-concept study, which is the right description.
Apitegromab is investigational and cannot be bought, so nothing here changes what anyone should do now. What it changes is the shape of the argument: the lean mass problem has moved from something to be managed with protein and resistance training to something a second prescription might address, with all the cost and complexity that implies. Whether that is worth it depends on outcomes nobody has measured yet, and the existing non-pharmaceutical answer is still the one with evidence behind it, discussed in the measured lunch and the analysis in older adults.