The short version: each step adds a receptor. Semaglutide acts on GLP-1; tirzepatide adds GIP; retatrutide adds glucagon. The headline weight-loss figures rise with each step, but they come from different trials in different people, and only semaglutide and tirzepatide have been compared head to head.
Semaglutide
GLP-1 receptor only. 31 residues, Novo Nordisk. Licensed as Ozempic, Rybelsus and Wegovy.8
Tirzepatide
GIP and GLP-1 receptors. 39 residues, Eli Lilly. Licensed as Mounjaro and Zepbound.9
Retatrutide
GIP, GLP-1 and glucagon receptors. 39 residues, Eli Lilly, code LY3437943. Not licensed anywhere.6
Side by side
| Point | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Developer | Novo Nordisk | Eli Lilly | Eli Lilly |
| Receptors | GLP-1 | GIP, GLP-1 | GIP, GLP-1, glucagon |
| Length | 31 residues | 39 residues | 39 residues |
| Avg mass | 4113.6 g/mol | 4813.5 g/mol | ≈ 4731 g/mol |
| Formula | C187H291N45O59 | C225H348N48O68 | C221H342N46O68 |
| Fatty side chain | C18 diacid on lysine 26 (GLP-1 numbering) | C20 diacid on lysine 20 | C20 diacid on lysine 17 |
| CAS | 910463-68-2 | 2023788-19-2 | 2381089-83-2 |
| Main obesity trial | STEP 1: −14.9% at 68 weeks1 | SURMOUNT-1: −20.9% at 72 weeks, top dose2 | TRIUMPH-1: up to −28.3% at 80 weeks, by announcement5 |
| Placebo in that trial | −2.4% | −3.1% | Not stated in the same report |
| Peer-reviewed phase 3 | Yes | Yes | Not yet at this revision |
| Licensed | UK, EU, US | UK, EU, US | Nowhere |
| WADA | Not named | Not named | S0 · non-approved |
One, two, three receptors
All three copy gut hormones that the body releases after eating. GLP-1 acts on insulin release and appetite. GIP is a second hormone with effects on insulin and fat tissue. Glucagon raises energy use and acts on the liver.6 Each molecule also carries a fatty chain that binds albumin in the blood, which is why all three last about a week.
| Receptor | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| GLP-1 | ■ | ■ | ■ |
| GIP | · | ■ | ■ |
| Glucagon | · | · | ■ |
■ acts on the receptor · not a target
What the trials measured
The figure most people search for is weight change in the main obesity trial of each drug. Read the bars as three separate studies, not a race: the people, durations and doses differ, and the retatrutide figure comes from Lilly's phase 3 announcement rather than a published paper.
Highest dose in each trial. Sources: STEP 1,1 SURMOUNT-1,2 retatrutide phase 2,4 TRIUMPH-1 announcement.5
The one head-to-head trial
SURMOUNT-5 randomised 751 adults with obesity to tirzepatide or semaglutide for 72 weeks. Weight fell by 20.2% on tirzepatide and 13.7% on semaglutide.3 No trial has compared retatrutide directly with either.
| Trial | Drug | People | Duration | Result |
|---|---|---|---|---|
| STEP 1 | Semaglutide vs placebo | 1,961 adults, no diabetes | 68 weeks | −14.9% vs −2.4%1 |
| SELECT | Semaglutide vs placebo | 17,604 adults with heart disease | Mean 34 months | Major cardiovascular events 6.5% vs 8.0%7 |
| SURMOUNT-1 | Tirzepatide vs placebo | Adults with obesity, no diabetes | 72 weeks | −15.0% to −20.9% by dose vs −3.1%2 |
| SURMOUNT-5 | Tirzepatide vs semaglutide | 751 adults with obesity | 72 weeks | −20.2% vs −13.7%3 |
| Phase 2 | Retatrutide vs placebo | 338 adults, no diabetes | 48 weeks | −8.7% to −24.2% by dose vs −2.1%4 |
| TRIUMPH-2, -3 | Retatrutide vs placebo | Adults with type 2 diabetes, or with heart disease | 80 weeks | Up to −20.8% and −22.6%; no significant change in cardiovascular events in TRIUMPH-310 |
What this means for a readerFor semaglutide and tirzepatide, cite the peer-reviewed trials. For retatrutide, the only peer-reviewed efficacy data at this revision are the 2023 phase 2 papers; phase 3 figures should be cited as company or conference reports, with the date, until the papers appear.
Licensing and sport
Semaglutide and tirzepatide are licensed prescription medicines in the UK, the EU and the US.8,9 Retatrutide is not approved anywhere; Lilly has said it plans to file in the US in the first quarter of 2027.10 In the UK, the MHRA has raided operations selling unlicensed tirzepatide and retatrutide.12,13
On the WADA list, neither licensed drug is named. Retatrutide is not named either, but as a substance with no approval for human use it falls under class S0, prohibited at all times.11
Common questions
Which causes the most weight loss: semaglutide, tirzepatide or retatrutide?
In separate trials the headline figures were 14.9% for semaglutide, 20.9% for tirzepatide and up to about 28% for retatrutide. Only semaglutide and tirzepatide have been compared directly: 13.7% against 20.2% in SURMOUNT-5.
What is the difference between the three?
The number of receptors. Semaglutide acts on GLP-1. Tirzepatide acts on GLP-1 and GIP. Retatrutide acts on GLP-1, GIP and glucagon.
Is retatrutide approved?
No. It is investigational. Lilly has said it plans to file for US approval in early 2027.
Are they the same kind of molecule?
Yes, broadly. All three are lipidated peptides of 31 to 39 residues that bind albumin, which gives them a once-weekly profile.
Which is called GLP-3?
"GLP-3" is a trade name some suppliers use for retatrutide, because it acts on three receptors. It is not a hormone name; there is no natural GLP-3.
References
- Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989–1002. PMID 33567185
- Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205–216. PMID 35658024
- Aronne LJ, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;393(1):26–36. doi:10.1056/NEJMoa2416394
- Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389(6):514–526. PMID 37366315
- AJMC. Retatrutide achieves up to 30.3% average weight loss in phase 3 TRIUMPH-1 trial. 21 May 2026. ajmc.com
- Coskun T, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234–1247. PMID 35985340
- Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221–2232. doi:10.1056/NEJMoa2307563
- Wikipedia. Semaglutide, for identifiers and approval dates, checked 2 Nov 2026.
- Wikipedia. Tirzepatide, for identifiers and approval dates, checked 2 Nov 2026.
- Pharmaceutical Executive. Retatrutide delivers up to 22.6% weight loss in two new phase III trials. 23 July 2026. pharmexec.com
- World Anti-Doping Agency. The 2026 Prohibited List, class S0. wada-ama.org
- Reuters. UK seizes record haul of illegal weight-loss drugs in factory raid. 24 October 2025.
- The Pharmacist. Almost 2,000 unauthorised weight loss drugs seized in MHRA raids. 26 February 2026. thepharmacist.co.uk
Peptidarium Library. Semaglutide vs tirzepatide vs retatrutide (comparison 02), 2 November 2026. peptidarium.com/compare/semaglutide-vs-tirzepatide-vs-retatrutide