One receptor, two receptors, three receptors: semaglutide changed obesity research, tirzepatide beat it head-to-head, and retatrutide’s first phase 3 readout in May 2026 posted the largest average weight reductions ever reported for a drug in this class. This briefing lines up what each molecule is, what the landmark trials actually measured, why the headline numbers are not directly comparable, and where each stands in Canada.
The scoreboard
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Receptors | GLP-1 | GIP + GLP-1 | GIP + GLP-1 + glucagon |
| Landmark obesity trial | STEP 1 (2021) | SURMOUNT-1 (2022) | TRIUMPH-1 (topline, May 2026) |
| Trial length | 68 weeks | 72 weeks | 80 weeks |
| Average weight change, top dose | about −15% | about −21% | about −25% to −28%* |
| Placebo | about −2% | about −3% | about −2% to −4%* |
| Peer-reviewed? | Yes (NEJM) | Yes (NEJM) | Phase 2 yes; phase 3 topline only |
| Approved in Canada? | Yes | Yes | No (investigational) |
*Retatrutide TRIUMPH-1 figures were reported by the manufacturer using two statistical approaches; the range reflects both. See below.
1, 2 or 3 receptors: how they differ
All three molecules are long-acting peptides engineered from gut-hormone signals. The difference is how many receptors each one switches on:
- GLP-1 (all three): boosts glucose-dependent insulin release, slows stomach emptying and acts on appetite centres in the brain.
- GIP (tirzepatide and retatrutide): another incretin that also boosts insulin release and appears to influence fat tissue and energy balance.
- Glucagon (retatrutide only): best known for raising blood sugar, but glucagon receptor activation also increases energy expenditure and liver fat breakdown. The design bet is that GLP-1 and GIP keep blood sugar in check while glucagon adds a metabolic push.
Each step up added a receptor, and in trials each step up produced larger average weight reductions. Whether that trend continues, and at what cost in tolerability, is the central question of the field.
Semaglutide: the benchmark
Semaglutide is a GLP-1-only agonist, sold as Ozempic (diabetes) and Wegovy (weight management). In STEP 1 (Wilding et al., NEJM 2021), adults with obesity or overweight without diabetes lost about 15% of body weight on average over 68 weeks, versus about 2% on placebo. That result reset expectations for what a medication could achieve and set the bar every later molecule is measured against.
Tirzepatide: the first dual agonist
Tirzepatide adds GIP to GLP-1. In SURMOUNT-1 (Jastreboff et al., NEJM 2022), average weight reductions ranged from about 15% to 21% across dose groups over 72 weeks, versus about 3% on placebo. Then came the direct comparison: SURMOUNT-5 (NEJM 2025) put tirzepatide against semaglutide in the same trial, and tirzepatide produced an average reduction of about 20% versus about 14%. More detail in our tirzepatide briefing.
Retatrutide: the triple agonist
Retatrutide (Eli Lilly, development code LY3437943) is the first agonist to hit all three receptors in a single molecule.
Phase 2 (peer-reviewed)
Jastreboff and colleagues reported the phase 2 obesity trial in the New England Journal of Medicine in 2023. At 48 weeks, average weight reduction reached about 24% in the highest dose group, versus about 2% on placebo, numbers that immediately made retatrutide the most watched molecule in metabolic research.
Phase 3: TRIUMPH-1 (topline, May 2026)
On May 21, 2026, Lilly announced topline results from TRIUMPH-1, which randomized about 2,300 adults with obesity or overweight (without diabetes) to three retatrutide dose groups or placebo for 80 weeks. As reported by the company and in trade press:
- Average weight reduction rose with dose, from roughly 18–19% in the lowest dose group to roughly 25–28% in the highest, depending on the statistical approach used.
- Placebo groups lost roughly 2–4%.
- In an extension of participants with a BMI of 35 or more, followed to 104 weeks, reductions of up to about 30% were reported.
Important caveats: these are company-announced topline results, not yet a peer-reviewed publication. Full data are expected in journals and at scientific meetings. Retatrutide is investigational and not approved in Canada or anywhere else; regulatory submissions are still ahead.
Why the numbers aren’t apples to apples
It is tempting to line up 15%, 21% and 28% and declare a winner. Three things make that misleading:
- Different trial lengths. 68 vs 72 vs 80 weeks. Weight keeps falling for months on these drugs, so a longer trial captures more of the curve.
- Different statistical estimands. A “treatment-regimen” estimate counts everyone randomized, including people who stopped the drug; an “efficacy” estimate reflects people who stayed on treatment. The second number is always larger. Retatrutide’s two published figures (about 25% and 28%) differ for exactly this reason.
- Different populations and eras. Baseline weight, how many participants dropped out and the background care differ between trials run years apart.
The only clean comparison is a head-to-head trial. That exists for tirzepatide vs semaglutide (SURMOUNT-5, tirzepatide ahead). A head-to-head with retatrutide has not yet been reported.
What the trials reported on tolerability
Across all three programs, the most common side effects reported were gastrointestinal (nausea, diarrhea, vomiting and constipation), usually mild to moderate and most frequent while doses were being increased. Higher-dose and more potent regimens generally reported more of these events and more discontinuations. Researchers are also studying body composition, because part of the weight lost on any of these drugs is lean mass, and whether glucagon agonism changes that balance is an open question. Approved products carry detailed safety warnings in their official labelling. Anyone considering medication for weight or blood sugar should speak with a doctor or pharmacist.
Status in Canada
| Molecule | Canadian status | Research-grade at TrueLabs |
|---|---|---|
| Semaglutide | Approved prescription drug (Ozempic, Wegovy) | Not carried |
| Tirzepatide | Approved prescription drug (Mounjaro) | TZ-2, 5–60 mg |
| Retatrutide | Investigational, not approved | Not currently listed |
| Cagrilintide (amylin analogue) | Investigational | Cagrilintide, 2–10 mg |
Research-grade material is a laboratory reagent, not a substitute for an approved medicine. Labs working with large lipidated peptides like tirzepatide should pay particular attention to identity testing; see how to read a peptide COA and how to reconstitute peptides.
Frequently asked questions
Cliquez sur une question pour afficher la réponse.
Is retatrutide stronger than tirzepatide?
In separate trials, retatrutide produced larger average weight reductions than tirzepatide did, but the trials differed in length and design and no head-to-head result has been reported. Its phase 3 data are still topline only.
How much weight was lost in the retatrutide phase 3 trial?
TRIUMPH-1 topline results reported average reductions of roughly 25% to 28% in the highest dose group at 80 weeks, depending on the statistical method, versus about 2% to 4% on placebo.
Is tirzepatide better than semaglutide?
In the head-to-head SURMOUNT-5 trial, tirzepatide produced an average weight reduction of about 20% versus about 14% for semaglutide over 72 weeks.
Is retatrutide approved in Canada?
No. Retatrutide is investigational and not approved in Canada or elsewhere as of October 2026.
What does a triple agonist mean?
A single molecule that activates three receptors: GLP-1, GIP and glucagon. Retatrutide is the first to reach phase 3.
Related reading
- Peptides for weight loss: every compound ranked by evidence
- Cagrilintide and CagriSema: REDEFINE 1
- Tirzepatide side effects by dose
- Is retatrutide safe? The full safety analysis
- 10 costly retatrutide mistakes to avoid
- Tirzepatide explained: SURMOUNT and SURPASS
- MOTS-C, SS-31 & NAD+: the metabolic toolkit
- Peptides 101
Sources
- Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384:989–1002. PubMed
- Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387:205–216. PubMed
- Aronne LJ, et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). N Engl J Med. 2025. PubMed
- Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med. 2023;389:514–526. PubMed
- The Pharmaceutical Journal. Phase III retatrutide study demonstrates 30% weight loss. May 2026. Article
This article summarizes published and company-announced clinical research for educational purposes. It is not medical advice. TrueLabs products are sold for in vitro and laboratory research use only and are not intended for human or veterinary use. Please speak with a doctor or pharmacist about any health question.