Here is the conversation that happens in every serious peptide community, usually about three weeks into someone’s first cycle of a strong GLP-1: how much of what I am losing is actually muscle?
The honest answer has always been uncomfortable. When semaglutide or tirzepatide strips 15 to 25 percent of body weight, roughly a quarter to a third of that loss can be lean mass - muscle, glycogen, water, structural tissue. For people whose goals are athletic, or who are older and worried about sarcopenia, or who simply care about how they look when the scale hits the target, that number is the whole story. Losing 25 kilograms and keeping strength is a different outcome to losing 25 kilograms and feeling like a deflated version of yourself.
EASD 2026 in Milan, which wrapped on 2 October, put three datasets on the table that speak directly to this question, and together they sketch the shape of what the next few years of obesity pharmacology will look like.
Dataset one: the anti-myostatin combination
The one getting the most attention is Regeneron’s COURAGE trial, now in press at The Lancet. The concept is straightforward and a bit blunt: if the drug causes muscle loss, add a second drug that blocks the muscle loss signal.
Trevogrumab is an antibody against GDF8 - myostatin - the protein that puts a brake on muscle growth. Block myostatin and the body builds or preserves more muscle. In COURAGE, adding trevogrumab to semaglutide cut lean-mass loss by roughly half over the trial period, and in the MRI substudy, participants preserved over 70 percent of thigh muscle volume. We covered the phase 2 results in detail last week, so we will not repeat the whole breakdown here - the short version is that the combination looks like the first credible pharmacological answer to the lean-mass problem, and that a semaglutide-plus-antibody combination trial is probably the template for a lot of what follows.
The interesting research question is not whether it works but who it works for. An older participant losing muscle that protects their mobility has a different risk-benefit calculation from a 30-year-old lifter who wants to keep their deadlift while cutting. The same drug serves both, but the trial endpoints mostly reflect the first group.
Dataset two: a new dual agonist with a tolerability angle
Hansoh Pharma’s olatorepatide (HS-20094) turned up at EASD as a late-breaking oral presentation, and it is a genuinely notable molecule even though it says nothing directly about muscle. It is a dual-biased GLP-1/GIP receptor agonist - same two hormone targets as tirzepatide, but engineered with different receptor-signalling bias, which is the pharmacology version of two cars with the same engine but different suspension.
The LIGHTEN phase 3 study randomised 604 adults in China to 5, 10, or 15 mg weekly or placebo for 48 weeks. At the top dose, mean weight loss was 19.3 percent at week 48, with the curve still heading down and no plateau. Waist circumference dropped 16.0 cm versus 3.6 cm on placebo.
The reason it belongs in a muscle conversation: nausea was 7.8 percent and vomiting 4.9 percent, and nobody discontinued for drug-related adverse events. Compare that with the 30 to 40 percent nausea rates in some published semaglutide and tirzepatide trials. If the bias engineering genuinely produces a gentler tolerability profile at comparable efficacy, it changes the maths on who can stay on treatment long enough to finish the job - and finishing the job slowly is how you avoid the crash-diet pattern where everything including muscle gets dropped fast.
Dataset three: the switch to oral
Novo’s OCTANE real-world analysis rounded out the Milan picture: patients who switched from injectable semaglutide or tirzepatide to once-daily oral semaglutide lost an average of 4.1 percent of body weight in the following three months, rather than regaining. That is a needle-mover for the maintenance question we covered a few days ago, because a substantial share of stopping is driven by injection fatigue, and a pill that keeps the drug in the picture - even at somewhat lower systemic exposure - is a different choice architecture than stopping altogether.
The caveats are real: OCTANE is retrospective and self-reported, so treat the number as a signal, not a measurement. But the signal is interesting. The research community has spent a decade assuming oral GLP-1 delivery was too hard to be practical. That assumption is now visibly dead.
What the Research Says
- Regeneron COURAGE phase 2 trial, in press at The Lancet as of October 2026: adding trevogrumab, an anti-GDF8/myostatin antibody, to semaglutide reduced lean-mass loss by approximately 50 percent and preserved over 70 percent of muscle volume in the MRI substudy. Source: BiotechResearch UK briefing on EASD Milan 2026, 2 October 2026, https://biotechresearch.co.uk/intelligence/easd-milan-2026-three-datasets-that-reframe-the-next-wave-of-peptide-based-obesity-treatments, citing the late-breaking EASD session.
- Hansoh Pharma olatorepatide (HS-20090/HS-20094) LIGHTEN phase 3: 19.3 percent mean weight loss at week 48 in the 15 mg arm versus placebo in 604 adults, waist circumference minus 16.0 cm versus minus 3.6 cm, nausea 7.8 percent and vomiting 4.9 percent, no drug-related discontinuations. Source: PR Newswire, “19.3% Weight Loss at Week 48 Phase 3 Data of Olatorepatide,” presented at EASD Milan on 2 October 2026, and Hansoh Pharmaceutical Group announcement.
- Novo Nordisk OCTANE real-world analysis: 4.1 percent average weight loss within three months after switching from injectable semaglutide or tirzepatide to once-daily oral semaglutide. Source: same EASD Milan 2026 briefing. Retrospective, self-reported design limits causal inference.
- Prior context on lean-mass loss with incretin therapy: body composition substudies of semaglutide and tirzepatide trials have consistently reported roughly one quarter to one third of total weight lost as lean mass. Source: our own review of the published TRIUMPH and SURMOUNT body composition data.
Why the combination approach is the story
Step back from the individual datasets and there is a pattern. The first generation of this pharmacology asked one question: how much weight can we take off? The answer got so extreme - 25 percent, then 30 percent in later trials - that a second question became unavoidable: what else is coming off with it?
The answer to that question is now the research frontier, and the front line is combination therapy. Trevogrumab plus semaglutide is the furthest along, but the same logic applies to every myostatin pathway drug in development, to selective androgen pathway modulators, and to the compounds testing whether the glucagon arm of a triple agonist can be tuned to bias energy expenditure toward fat rather than lean tissue. Retatrutide’s own body composition data, from the trial we covered in September, will be scrutinised for exactly this.
For anyone in this community doing their own research, the practical takeaway is modest but real: the era of judging these compounds by the scale alone is ending. Body composition endpoints - DEXA lean mass, MRI muscle volume, grip strength - are moving from substudy curiosities to the numbers that actually differentiate drugs. When the next wave of readouts lands, the compound that loses slightly less weight but preserves substantially more muscle may well be the one that wins the market, particularly in the ageing population segment that every pharmaceutical company is now chasing.
Our retatrutide, semaglutide and tirzepatide pages have the compound-level background, and if you want to follow the trevogrumab and olatorepatide developments as they publish - COURAGE is due in print at The Lancet shortly - the Grey Highway Telegram group is where we flag it first.
The muscle question is no longer a niche concern for gym-goers. It is the centre of the next decade of this pharmacology, and Milan showed the field has noticed.
Disclaimer: This article is for educational and informational purposes only. It does not constitute medical advice, therapeutic recommendations, or endorsements of any compound. Grey Highway is a research-education community. We do not sell, supply, or promote the use of research compounds. Always consult a qualified healthcare professional regarding health decisions. For Australian regulatory information, visit the TGA website.