Almost every ranking of peptides for weight loss mixes two very different things: drugs tested in thousands of people, and compounds tested in almost nobody. The gap between those categories is enormous.
The incretin drugs win by a wide margin. Retatrutide leads on raw magnitude, with 24.2% weight loss in Phase 2, while semaglutide leads on evidence quality as the only approved agent with a cardiovascular outcome win. Tirzepatide has both: approval plus 20.9% loss in 2,539 people. Everything outside this class is roughly ten times weaker.
The class, by pivotal-trial result
| Compound | Receptors | Peak weight reduction | Status |
|---|---|---|---|
| Retatrutide | GIP + GLP-1 + glucagon | 24.2% / 48 wk (Phase 2) | Phase 3 (TRIUMPH) |
| Tirzepatide | GIP + GLP-1 | 20.9% / 72 wk (SURMOUNT-1, ITT) | Approved — Zepbound, Mounjaro |
| CagriSema | Amylin + GLP-1 | ~20.4% / 68 wk (REDEFINE 1) | Phase 3 complete |
| Survodutide | GLP-1 + glucagon | ~19% / 46 wk (Phase 2) | Phase 3 |
| Semaglutide | GLP-1 | ~14.9% / 68 wk (STEP-1) | Approved — Wegovy, Ozempic |
| Mazdutide | GLP-1 + glucagon | ~14% / 48 wk (GLORY-1) | Approved in China |
Cross-trial comparison carries the usual caveats — different durations, populations and dropout handling — but the ordering is consistent across reviews. The full class comparison lays out where each figure comes from.
Biggest number is not best evidence. Retatrutide's 24.2% comes from 338 people over 48 weeks in Phase 2. Semaglutide's 14.9% comes from 1,961 people over 68 weeks in Phase 3, plus the SELECT trial showing actual cardiovascular event reduction — the only such result in this class. Phase 2 figures systematically regress at Phase 3 scale. Ranking by headline percentage means ranking partly by how early-stage the evidence is.
Why more receptors keeps producing more weight loss
The class has moved in generations, and each one added a receptor. GLP-1 alone suppresses appetite and slows gastric emptying. Adding GIP improves insulin response and appears to soften GI side effects at equivalent efficacy. Adding glucagon contributes an “energy out” component — increased expenditure and hepatic fat oxidation — which is what makes retatrutide mechanistically new rather than merely additive.
Broader receptor engagement has tracked with greater magnitude and with greater complexity in the side-effect profile. Retatrutide's dose-dependent heart-rate increase is the clearest example: the mechanism producing the efficacy is plausibly the mechanism producing the signal. The triple-agonist mechanism goes through it.
GLP3-R (retatrutide)
The triple-agonist reference compound from the Phase 2 literature above. Research use only — supplied with a batch-matched certificate of analysis.
Everything outside the incretin class
Worth covering because these get searched, and worth being blunt about the gap:
- AOD-9604. The hGH 176-191 fragment, a lipolytic signal without the growth-promoting portion of the parent hormone. Mechanistically tidy; the human trial results were disappointing.
- 5-Amino-1MQ. An NNMT inhibitor — a small molecule rather than a peptide. Interesting preclinical fat metabolism data, essentially no human evidence.
- Adipotide. Produced striking fat loss in primates by targeting the vasculature supplying adipose tissue, and produced renal toxicity that ended its development. A cautionary example, not an option.
- Cagrilintide. A long-acting amylin analog. Modest alone; the reason to care about it is CagriSema, where it is paired with semaglutide.
The question that outranks the ranking
SURMOUNT-4 tested what happens on discontinuation and found major weight regain. That single result changed how the entire class should be understood: these are chronic therapies, and the pivotal-trial percentage describes a state maintained by continued treatment rather than a destination reached. Any comparison of peak weight-loss figures that ignores the maintenance question is comparing the wrong thing.
Sourcing guides for the ones you can buy: retatrutide, tirzepatide, semaglutide.
Frequently asked questions
What is the best peptide for weight loss?
By trial magnitude, retatrutide — 24.2% mean body-weight reduction in Phase 2. By evidence quality, semaglutide, which is approved and holds the only published cardiovascular outcome win in the class. By the balance of both, tirzepatide: approved, 20.9% in a 2,539-person Phase 3.
How much weight do these peptides actually produce?
In pivotal trials at top dose: semaglutide about 14.9% at 68 weeks, tirzepatide 20.9% at 72 weeks on intent-to-treat, CagriSema about 20.4%, survodutide about 19%, mazdutide about 14%, and retatrutide 24.2% in Phase 2 — a figure that should be expected to regress at Phase 3 scale.
Which weight-loss peptides are FDA approved?
Semaglutide (Wegovy, Ozempic) and tirzepatide (Zepbound, Mounjaro). Everything else in this class is investigational, including retatrutide, survodutide and CagriSema.
Do you regain the weight if you stop?
Tirzepatide's SURMOUNT-4 maintenance trial found that discontinuation produced major weight regain, which reframed the whole class as chronic therapy rather than a course of treatment. There is no reason to expect the newer compounds behave differently.
Are non-GLP-1 peptides useful for fat loss?
The evidence is much weaker. AOD-9604 is a growth-hormone fragment with a lipolytic signal and disappointing human trial results; 5-Amino-1MQ is an NNMT inhibitor with interesting preclinical data and essentially no human evidence; adipotide produced striking primate fat loss and renal toxicity that stopped its development.
GLP3-R (retatrutide)
Research-use-only material, sold by the vial with batch documentation. Check the certificate of analysis against the batch you receive.
What to know now
- Retatrutide leads on size of effect, with 24.2% weight loss reported in Phase 2.
- Tirzepatide has both: regulatory approval and 20.9% weight loss across 2,539 people.
- Semaglutide leads on evidence quality: it is approved and holds the only heart-outcome win in the class.
- Everything outside the incretin class is roughly ten times weaker on the weight-loss numbers.
- Effect size and evidence quality point at different drugs, so any ranking depends on which one you weigh.
References
- Wilding, J. P. H., Batterham, R. L., Calanna, S., et al. (2021). Once-weekly semaglutide in adults with overweight or obesity (STEP-1). New England Journal of Medicine, 384(11), 989–1002. https://doi.org/10.1056/NEJMoa2032183
- Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., et al. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387(3), 205–216. https://doi.org/10.1056/NEJMoa2206038
- Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., Haupt, A., Milicevic, Z., & Hartman, M. L. (2023). Triple–hormone-receptor agonist retatrutide for obesity — A phase 2 trial. New England Journal of Medicine, 389(6), 514–526. https://doi.org/10.1056/NEJMoa2301972
- Garvey, W. T., Blüher, M., Osorto Contreras, C. K., et al. (2025). Coadministered cagrilintide and semaglutide in adults with overweight or obesity. New England Journal of Medicine, 393(7), 635–647. https://doi.org/10.1056/NEJMoa2502081
- Ji, L., Jiang, H., Bi, Y., et al. (2025). Once-weekly mazdutide in Chinese adults with obesity or overweight. New England Journal of Medicine, 392(22), 2215–2225. https://doi.org/10.1056/NEJMoa2411528
- Aronne, L. J., Sattar, N., Horn, D. B., et al. (2024). Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: The SURMOUNT-4 randomized clinical trial. JAMA, 331(1), 38–48. https://doi.org/10.1001/jama.2023.24945
- Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., et al. (2023). Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine, 389(24), 2221–2232. https://doi.org/10.1056/NEJMoa2307563
- Melson, E., Ashraf, U., Papamargaritis, D., & Davies, M. J. (2024). What is the pipeline for future medications for obesity? International Journal of Obesity, 49(3), 433–451. https://doi.org/10.1038/s41366-024-01473-y
Cross-trial comparison carries the usual asymmetries — different durations, populations and dropout handling. Each figure links to the trial it came from so the comparison can be checked.