- Tirzepatide activates two receptors (GIP and GLP-1); retatrutide activates three (GIP, GLP-1 and glucagon). Both are 39-amino-acid lipidated peptides from Eli Lilly.
- Tirzepatide's pivotal SURMOUNT-1 trial (NEJM, 2022) reported up to 20.9 % mean weight loss at 72 weeks versus 3.1 % on placebo.
- Retatrutide's phase 3 TRIUMPH-1 trial reported up to 28.3 % mean weight loss at 80 weeks versus 2.2 % on placebo (Lilly press release, May 2026; full peer-reviewed paper pending).
- Tirzepatide is an approved medicine (Mounjaro, Zepbound). Retatrutide is investigational; Lilly plans a US filing in Q1 2027.
- No head-to-head result exists yet: the TRIUMPH-5 trial comparing the two directly is due to reach primary completion around November 2026.
The short answer
Tirzepatide and retatrutide are the two most discussed incretin peptides of the decade, and they come from the same lab. Tirzepatide proved that hitting a second receptor, GIP, on top of GLP-1 pushes weight loss well past the single-receptor GLP-1 drugs. Retatrutide adds a third target, the glucagon receptor, and in phase 3 it has reported the largest average weight reductions yet seen for an anti-obesity drug candidate. The trade-off is maturity: tirzepatide has years of approved use and several published phase 3 papers behind it, while most retatrutide phase 3 data so far comes from company announcements.
Mechanism: dual agonist vs triple agonist
Both molecules mimic gut hormones that the body releases after a meal. GLP-1 receptor activation is linked to fullness, slower stomach emptying and glucose-dependent insulin release. GIP receptor activation adds its own insulin signal and acts on fat tissue, and in combination with GLP-1 it appears to improve tolerability and amplify the weight effect. That pairing is what tirzepatide (development code LY3298176) was built to test.
Retatrutide (LY3437943) keeps the GIP and GLP-1 activity and adds the glucagon receptor. Glucagon signalling in the liver is associated with fat oxidation and higher energy expenditure, so the design hypothesis is that retatrutide not only reduces intake but also raises the energy the body burns. The most visible fingerprint of this third pathway is liver fat: in a phase 2a substudy (Nature Medicine, 2024) liver fat fell by up to 82.4 % in 24 weeks.
Structurally the two are close cousins. Both are 39 amino acids long, both start from a GIP-like backbone, both use non-natural residues to resist the DPP-4 enzyme, and both carry a C20 fatty diacid that binds plasma albumin, which is why their activity lasts days rather than the minutes of the native hormones.
Headline trial results
Tirzepatide: SURMOUNT and SURPASS
- SURMOUNT-1 (NEJM, 2022; 2,539 adults with obesity, no diabetes): mean weight change of -15.0 %, -19.5 % and -20.9 % across three doses at 72 weeks versus -3.1 % on placebo; 57 % of the top-dose group lost 20 % or more.
- SURMOUNT-5 (NEJM, 2025; 751 adults): the first head-to-head obesity trial against semaglutide, with 20.2 % vs 13.7 % weight loss at 72 weeks.
- SURPASS-2 (NEJM, 2021; type 2 diabetes): HbA1c reductions of 2.01 to 2.30 points, superior to semaglutide on both glucose and weight.
- SYNERGY-NASH (NEJM, 2024; phase 2): resolution of MASH without worsening fibrosis in 44 % to 62 % of participants versus 10 % on placebo at 52 weeks.
Retatrutide: phase 2 and the TRIUMPH programme
- Phase 2 obesity trial (NEJM, 2023; 338 adults): up to -24.2 % mean weight change at 48 weeks versus -2.1 % on placebo; 100 % of the top-dose group lost at least 5 % and 83 % lost at least 15 %.
- TRIUMPH-4 (press release, December 2025; obesity with knee osteoarthritis): up to 28.7 % mean weight loss at 68 weeks with a marked drop in WOMAC knee-pain scores.
- TRIUMPH-1 (press release, May 2026; 2,339 adults): 19.0 %, 25.9 % and 28.3 % mean weight loss across three doses at 80 weeks versus 2.2 % on placebo; 45.3 % of the top-dose group lost 30 % or more. Participants with a starting BMI of 35 or higher on the top dose reached 30.3 % at 104 weeks.
- TRIUMPH-2 and TRIUMPH-3 (press release, July 2026): up to 20.8 % weight loss at 80 weeks in people with type 2 diabetes, and up to 22.6 % versus 3.2 % on placebo in people with severe obesity and established cardiovascular disease.
- TRANSCEND-T2D-1 (Lancet, 2026; phase 3, type 2 diabetes): HbA1c reduced by up to 1.94 points and body weight by up to 15.3 % at 40 weeks.
Read the numbers with care. The trials enrolled different populations over different durations (72 vs 80 weeks), and company releases usually quote the efficacy estimand, which counts participants who stayed on treatment. Cross-trial comparison suggests retatrutide goes further, roughly 28 % vs 21 % at the top dose, but only a randomised head-to-head study can confirm the size of that gap.
| Tirzepatide | Retatrutide | |
|---|---|---|
| Receptors | GIP + GLP-1 (dual) | GIP + GLP-1 + glucagon (triple) |
| Developer / code | Eli Lilly / LY3298176 | Eli Lilly / LY3437943 |
| Structure | 39 aa, C20 fatty diacid | 39 aa, C20 fatty diacid |
| Pivotal obesity trial | SURMOUNT-1 (72 wk) | TRIUMPH-1 (80 wk) |
| Top mean weight loss | 20.9 % (placebo 3.1 %) | 28.3 % (placebo 2.2 %)* |
| Liver fat signal | MASH resolution up to 62 % (phase 2) | Liver fat down up to 82.4 % (phase 2a) |
| Most common AEs | Nausea, diarrhoea, vomiting | GI events, dysesthesia, heart rate rise |
| US status | Approved 2022 (T2D), 2023 (obesity) | Investigational; BLA planned Q1 2027 |
| EU status | Authorised (Mounjaro) | Not authorised |
| Head-to-head | TRIUMPH-5, primary completion ~Nov 2026 | TRIUMPH-5, primary completion ~Nov 2026 |
Side effects reported in trials
For both peptides the most common adverse events were gastrointestinal: nausea, diarrhoea, vomiting and constipation, mostly mild to moderate and concentrated in the dose-escalation phase. In SURMOUNT-1, adverse events led to discontinuation in 4.3 % to 7.1 % of tirzepatide participants versus 2.6 % on placebo.
Retatrutide shows two additional signals. The phase 2 trial reported dose-dependent increases in heart rate that peaked at 24 weeks and then declined. In TRIUMPH-1 Lilly reported dysesthesia, an altered or tingling skin sensation, more often than on placebo; the company described most events as mild to moderate and said most participants continued treatment. Discontinuation due to adverse events was company-reported at up to 11.3 % on the top dose versus 4.9 % on placebo. The full peer-reviewed publications will allow a clearer safety comparison.
Approval status in 2026
Tirzepatide is an established medicine. The US FDA approved it as Mounjaro for type 2 diabetes in May 2022 and as Zepbound for chronic weight management in November 2023, adding obstructive sleep apnea in 2024. In the EU it is authorised by the European Medicines Agency under the Mounjaro name.
Retatrutide is not approved anywhere as of September 2026. With TRIUMPH-1, -2, -3 and -4 and TRANSCEND-T2D-1 reported, Lilly has said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027. The dedicated TRIUMPH-5 head-to-head study against tirzepatide (about 800 adults, roughly 89 weeks) lists primary completion around November 2026, and a cardiovascular and kidney outcomes trial, TRIUMPH-Outcomes, is still running.
Why researchers study both
In laboratory work the pair form a natural experiment. Because they share a backbone, lipidation strategy and developer, comparing them isolates the contribution of glucagon-receptor activity: liver lipid handling, energy expenditure, heart-rate effects and receptor bias in cell models. Tirzepatide serves as the reference dual agonist; retatrutide is the test of what a third receptor adds.
Research information only, not medical advice. Cryopept products are for laboratory research use only, not for human or veterinary use.
