METABOLIC & WEIGHT RESEARCH / SIDE BY SIDE
Four Compounds, One Measurement Question
Where each one acts, what its strongest published result actually measured, whether fat and lean mass were separated, and how mature the evidence behind each answer is.
The short version
Four peptides, sorted by one test: did the published research separate fat from muscle, or only weigh the whole person?
Tirzepatide and semaglutide have the biggest and best-run weight trials. Those trials measured total body weight, blood-sugar markers, and heart and kidney events. They did not report the fat-versus-muscle split.
Tesamorelin has a smaller evidence base, in a narrow patient group, and it is the only one here whose pooled trial data reports lean body mass — which went up rather than down [12].
MOTS-c has the most muscle-focused mechanism and no completed human trial of any kind.
So the compound with the most convincing muscle result is not the one producing large weight loss, and the compound producing the largest weight loss has, in this reference list, no muscle result at all. That mismatch is the honest state of the field, and no amount of comparison chart makes it resolve.
The comparison table
| Compound | Primary molecular target | Largest effect in this reference list | Fat and lean mass reported separately? | Population studied | Regulatory position |
|---|---|---|---|---|---|
| Tirzepatide | GIP receptor and GLP-1 receptor [6] | -20.2% body weight at 72 weeks [1] | No, in the sources numbered here | Adults with obesity without diabetes; adults with type 2 diabetes [4][5] | Approved; multiple indications [2] |
| Semaglutide | GLP-1 receptor | -14.9% body weight at 68 weeks [10] | No, in the sources numbered here | Adults with overweight or obesity; type 2 diabetes with chronic kidney disease; established cardiovascular disease [10][8][9] | Approved; multiple indications and formulations |
| Tesamorelin | GHRH receptor on pituitary somatotrophs | Lean body mass up 1.42 kg and visceral fat down 27.71 cm2 [12] | Yes; imaging plus compartment masses [12][14] | Adults with HIV-associated lipodystrophy [12][14] | Approved for one narrow indication only [13] |
| MOTS-c | AMPK pathway and casein kinase 2 [17][19] | Improved physical performance in mice [20] | No human data of any kind | Cells and rodents; one human biomarker cohort of 94 [18] | Not approved; research chemical |
The fourth column is the column this desk exists for, and three of the four rows say no.
What each study measured, and with what instrument
Comparing effect sizes across these four compounds is only meaningful once the endpoints are lined up, and they do not line up.
Percent body weight is what the incretin trials report. SURMOUNT-5 reported a least-squares mean weight change of -20.2% against -13.7% over 72 weeks in 751 adults [1]. SURMOUNT-1 reported -15.0%, -19.5% and -20.9% across three dose arms against -3.1% on placebo in 2,539 adults [4]. STEP 1 reported -14.9% against -2.4% at week 68 [10]. These are scale measurements, and a scale cannot say what tissue left.
Glycated haemoglobin and weight in kilograms is what the diabetes trial reports. SURPASS-2 reported reductions of 2.01, 2.24 and 2.30 percentage points across dose arms against 1.86 for the comparator, with weight treatment differences of -1.9, -3.6 and -5.5 kg in 1,879 adults [5].
Clinical events is what the two largest trials report. SELECT reported major adverse cardiovascular events in 17,604 participants with a hazard ratio of 0.80 and a 95% confidence interval of 0.72 to 0.90 [9]. FLOW reported major kidney-disease events in 3,533 participants with a hazard ratio of 0.76 and a 95% confidence interval of 0.66 to 0.88 [8]. Both are outcome trials, and outcome trials are the hardest evidence in this entire list — about outcomes, not about tissue.
Compartment masses and depot areas is what the tesamorelin literature reports: visceral adipose tissue down 27.71 cm2, trunk fat down 1.18 kg, hepatic fat fraction down 4.28%, lean body mass up 1.42 kg, pooled across five randomised trials [12]; and a treatment effect of -42 cm2 in visceral fat with a net -2.9% in hepatic lipid over six months in a 50-participant trial [14]. Square centimetres come from cross-sectional imaging at a defined level; kilograms of lean and fat mass come from densitometry. These are the only tissue-resolved numbers in the reference list.
Mechanistic and preclinical readouts is what the MOTS-c literature reports: kinase binding and activation in cell-free systems [17], nuclear translocation and gene regulation under metabolic stress [21], and physical performance in young, middle-aged and old mice [20]. Its one substantial human dataset measures circulating endogenous peptide as a risk biomarker in 94 haemodialysis patients over a median 26.5 months, not the effect of administering anything [18].
Evidence maturity, ranked honestly
Ranked by how much weight a conclusion can carry, and stated plainly rather than diplomatically:
- Semaglutide has the deepest evidence base on this desk, by a distance, and the hardest endpoints — two outcome trials totalling over twenty-one thousand participants [9][8], plus a large weight trial [10] and a head-to-head comparison [1]. What it lacks is composition data in those papers.
- Tirzepatide has the largest measured weight effects and a substantial randomised programme across obesity and diabetes [4][1][5], plus a nine-trial safety meta-analysis in 9,871 participants [3]. Same gap on composition, and a shorter track record than the compound it outperforms.
- Tesamorelin has a smaller but genuinely randomised and pooled body-composition evidence base [12][14][16], with a regulatory approval behind it [13] — narrow in indication and narrow in population, and the most directly relevant to this desk's question.
- MOTS-c has no human interventional evidence. Its mechanism is well characterised and independently interesting [17][21][19], its animal data are striking [20], and neither of those is a clinical result.
One consequence of that ordering deserves emphasis. Depth of evidence and relevance to body composition run in opposite directions here. The compounds a reader is most likely to encounter are the ones whose published trials say least about muscle, and the compound whose trials say most about muscle is the one a reader is least likely to encounter.
Where the muscle-sparing question actually stands
Three findings survive the comparison, and each is narrower than the marketing language that surrounds this category.
One. No compound reviewed here has been shown, in the sources numbered on this site, to spare skeletal muscle during large-magnitude weight loss. The trials that produced large weight loss did not measure the tissue split; the trial that measured the tissue split did not produce large weight loss.
Two. The single lean-mass increase in this literature belongs to a growth-hormone-axis mechanism, not an appetite mechanism [12]. That is mechanistically coherent — growth hormone and insulin-like growth factor-1 act on lean tissue directly, whereas incretin receptor agonism acts on intake — and it means the muscle result is a property of the mechanism, not a property of losing weight with a peptide.
Three. The gap between what is measured and what is claimed is largest exactly where commercial interest is largest. The compound record for MOTS-c states this explicitly: consumer interest in fat loss, longevity and performance, and the search demand attached to it, greatly exceed the strength of the clinical evidence.
What would settle the question is not mysterious. It is a randomised trial in people undergoing meaningful weight loss, with body composition measured by densitometry or imaging rather than estimated by impedance, with a comparator, with objective physical function measured alongside the tissue change, and with follow-up long enough to see whether any difference persists. Elements of that design exist in scattered substudies. Assembled, in the compounds that produce the largest weight loss, it does not.
Until it does, the defensible statement is the modest one: these compounds remove body weight, some of what they remove is lean tissue, the proportion is contested and instrument-dependent, and no product claim on this desk is entitled to the word sparing.