Semaglutide vs tirzepatide vs retatrutide
Three drugs, one grading rubric — and the one with the largest published weight loss is the one we trust least.
Comparison · Rubric v2.3
Three drugs, one grading rubric, and a result that runs backwards: the one with the largest published weight loss is the one this publication trusts least. Here is why, and what would change it.
The marks, side by side
| Compound | Strength | Verdict | Best published loss | Independent groups | Approved? |
|---|---|---|---|---|---|
| SemaglutideGLP-1 | Strong | Supported | −14.9% · 68 weeks1 | 2 + reviews | Yes |
| TirzepatideGIP + GLP-1 | Strong | Supported | −20.9% · 72 weeks3 | 2 + reviews | Yes |
| RetatrutideGIP + GLP-1 + glucagon | Emerging | Supported | −24.2% · 48 weeks5 | 1 | ⚑ No |
Every figure above is from a peer-reviewed publication. The widely-quoted retatrutide numbers — 28.3% at 80 weeks, 30.3% at two years — are not, and are excluded for that reason. More on this below.
The only head-to-head that exists
One trial has put two of these three against each other directly. SURMOUNT-5 randomised 751 adults for 72 weeks, open-label, and reported tirzepatide ahead of semaglutide on every weight endpoint.4
SURMOUNT-5 · tirzepatide vs semaglutide
751 adults · 72 weeks · open-label · funded by tirzepatide's manufacturer
The result is almost certainly real — the gap is wide and consistent with both drugs' own trials. But an unblinded trial run by the winner's manufacturer is the weakest form a head-to-head can take, and both facts belong in the same sentence as the number.
Why retatrutide grades lowest
Retatrutide has the largest published weight loss of the three and the lowest grade on this site. That is not an inconsistency. Our scale measures how thoroughly a claim has been examined, not how impressive the finding is.
The rubric caps a claim at Emerging when fewer than two independent groups have reported on it, and again when every qualifying trial is manufacturer-funded without independent replication. Retatrutide triggers both: every trial ever run on it belongs to one company. Semaglutide and tirzepatide each have at least one trial from a group with no stake in the answer.
The headline number is not evidence yet. The figures most people have seen — 28.3% at 80 weeks, and 30.3% at two years — come from TRIUMPH-1, a 2,339-person phase 3 announced by press release in May 2026 and not yet published.6 A press release has no methods section, no dropout accounting and no adverse-event table. We expect it to publish and we expect it to be impressive. Expectation is not evidence, and it does not move a mark.
The thing only semaglutide has
Weight is a surrogate. It stands in for the outcomes people actually care about — heart attacks, strokes, dying sooner than you would have. Almost no compound on this site has ever been tested against one of those directly.
Semaglutide has. SELECT enrolled 17,604 adults with cardiovascular disease and overweight or obesity but no diabetes, and asked whether the drug prevents cardiovascular events. It did: 6.5% versus 8.0% on placebo, a hazard ratio of 0.80.2
Tirzepatide produces more weight loss. It has not yet been shown to prevent anything. Those trials are running; until they report, the drug with the smaller number is the one with the better-proven consequence.
Safety, in brief
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Boxed warning | Thyroid C-cell tumours (rodent) | Thyroid C-cell tumours (rodent) | No label exists |
| Gastrointestinal | Common, dose-escalation | Common, dose-escalation | Common, dose-escalation |
| Notable | NAION — very rare, irreversible vision loss, added to labels 20257 | No published CV outcomes data | Dose-dependent heart-rate rise; dysesthesia 2.3–4.5% |
| What you can obtain | Licensed product | Licensed product | Unapproved — vendor material of unverified identity |
Everything above describes pharmaceutical-grade drug at a titrated dose under supervision. For retatrutide specifically, that is not what is being sold: it is approved nowhere, and US poison-centre exposures ran at roughly 95 per month in early 2026, up 265% on the preceding four months.8
What would change this page
Tracked, and dated where known
Each of these is a specific publication that would move a mark here
The forward-looking version of this list, with registry IDs and expected read-out dates, is in Tracked Trials. The criteria behind each mark are in the Grade Ledger.
Bottom line
Best evidenced: semaglutide. It is the only one of the three shown to prevent cardiovascular events rather than only to move a scale, and that evidence comes from more than seventeen thousand people.
Most weight lost, on published evidence: tirzepatide. Roughly a fifth of body weight over 72 weeks, and ahead of semaglutide in the only direct comparison — a comparison its own manufacturer ran, unblinded.
Most promising, least verified: retatrutide. The biggest numbers in the field, produced entirely by the company that owns the molecule, with the largest of them still unpublished and the drug approved nowhere.
If you take one thing from this page: the size of an effect and the strength of the evidence for it are different questions, and the ranking changes depending on which one you asked.
Sources
- Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2021;384(11):989–1002. PMID 33567185. pubmed.ncbi.nlm.nih.gov/33567185
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). New England Journal of Medicine. 2023;389(24):2221–2232. PMID 37952131. pubmed.ncbi.nlm.nih.gov/37952131
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine. 2022;387(3):205–216. PMID 35658024. pubmed.ncbi.nlm.nih.gov/35658024
- Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). New England Journal of Medicine. 2025. Open-label; funded by Eli Lilly. PMID 40353578. pubmed.ncbi.nlm.nih.gov/40353578
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. New England Journal of Medicine. 2023;389(6):514–526. PMID 37366315. pubmed.ncbi.nlm.nih.gov/37366315
- Eli Lilly and Company. Retatrutide phase 3 TRIUMPH-1 topline results. Investor news release, May 2026. Topline only; full publication pending. investor.lilly.com
- European Medicines Agency. PRAC concludes NAION is a very rare side effect of semaglutide medicines. 2025. ema.europa.eu
- CBS News. This weight-loss drug hasn't been approved by the FDA. Doctors are prescribing it anyway. 2026. Poison-centre exposure figures. cbsnews.com