Retatrutide, Tirzepatide and Semaglutide: one receptor, two, or three
Semaglutide acts at one receptor, Tirzepatide at two, Retatrutide at three. Each addition was a bet about mechanism, and the published trials record what each bet returned — in separate trials that were, with one exception, never run against each other.
Three peptides, three answers to the same question: how many receptors should one molecule act on. Semaglutide acts at one, the GLP-1 receptor. Tirzepatide acts at two, adding the receptor for glucose-dependent insulinotropic polypeptide. Retatrutide acts at three, adding the glucagon receptor on top of both.
Each addition was a bet. Adding a receptor arm is not the same as adding more of the same molecule — the argument for each new arm was that it would contribute something the existing ones could not, and that the combination would still be tolerated. What follows is what each of those bets was, and what the published trials reported.
Those trials were not run against each other. With a single exception, set out plainly further down, every figure on this page comes from a trial that studied one compound against its own placebo arm, in its own population, over its own length. Placing three such trials side by side shows what each of them reported. It does not rank them, and it cannot.
The trials behind the figures on this page
1,961
Adults in STEP 1
Semaglutide · Phase 3 · 68 weeks (1)
2,539
Adults in SURMOUNT-1
Tirzepatide · Phase 3 · 72 weeks (2)
338
Adults in the retatrutide Phase 2
Retatrutide · Phase 2 · 48 weeks (3)
1
Head-to-head trial among those cited here
SURPASS-2 · Tirzepatide against Semaglutide (4)
One arm at a time
GLP-1
The receptor all three act on
The glucagon-like peptide-1 receptor is Semaglutide's only target and the shared floor of the other two. The effects attributed to this arm in the published work are reduced calorie intake and slowed gastric emptying. STEP 1 studied semaglutide at 2.4 mg once weekly for 68 weeks in 1,961 adults and reported a mean body weight change of −14.9%, against −2.4% in its placebo arm (1).
+ GIP
The second arm Tirzepatide adds
The receptor for glucose-dependent insulinotropic polypeptide. The bet was that a second incretin receptor would add glycaemic and weight effect beyond GLP-1 alone. SURMOUNT-1 studied tirzepatide at 15 mg once weekly for 72 weeks in 2,539 adults and reported a mean body weight change of −20.9%, against −3.1% in its placebo arm (2).
+ GCGR
The third arm Retatrutide adds
The glucagon receptor, the one arm with no counterpart in the other two. Describing the molecule's discovery, Coskun and colleagues reported balanced activity at the glucagon and GLP-1 receptors and greater activity at the GIP receptor, and wrote that weight loss in their preclinical models was augmented by glucagon-receptor-mediated increases in energy expenditure added to the reduction in calorie intake driven by the other two arms — a different mechanism rather than more of the same one (6).
What each trial reported
The three weight figures come from three separate trials. STEP 1 and SURMOUNT-1 are Phase 3 trials of what are now approved medicines, in 1,961 and 2,539 adults respectively (1) (2). The largest retatrutide weight figure comes from a Phase 2 trial of 338 adults over 48 weeks, in which the 12 mg group showed a least-squares mean body weight change of −24.2% against −2.1% on placebo (3).
Those trials differ in more than length. They enrolled different populations, ran different dose-escalation schedules and were designed around different endpoints, and their placebo arms moved by different amounts — −2.4%, −3.1% and −2.1%. A gap between two of the columns further down is a gap between two trials before it is anything else.
The glucagon arm has also been examined on an endpoint on which the other two are not compared here. In a Phase 2a sub-study of 98 adults with metabolic dysfunction-associated steatotic liver disease, the retatrutide 12 mg group showed an 82.4% mean relative reduction in liver fat at 24 weeks, against a 0.3% increase on placebo (7). No trial cited in this post compared that endpoint across the three compounds.
Largest mean weight change reported, by compound
Each bar comes from a different trial, and the trials differ in phase, length, population and design — so these are not head-to-head results. The value drawn under each bar is the placebo arm of that bar's own trial, which is the only figure it can honestly be read against.
Semaglutide 2.4 mg, 68 wks
−14.9%
Tirzepatide 15 mg, 72 wks
−20.9%
Retatrutide 12 mg, 48 wks
−24.2%
Sources. (1) Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989–1002. (2) Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205–216. (3) Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514–526. Each figure is the mean percentage change in body weight at that trial's stated end point. Two of these compounds are authorised medicines; retatrutide is investigational and holds no marketing authorisation in any jurisdiction.
The one head-to-head trial
SURPASS-2 is the exception on this page, and it should be read differently from everything else here. It was an open-label Phase 3 trial that randomly assigned 1,879 adults with type 2 diabetes, in four equal groups, to tirzepatide at 5 mg, 10 mg or 15 mg or to semaglutide at 1 mg, and ran for 40 weeks. Two of these three compounds were compared directly — same protocol, same population, same period (4).
It reported a mean change in glycated haemoglobin of −2.30 percentage points on tirzepatide 15 mg against −1.86 on semaglutide 1 mg, an estimated difference of −0.45 points. Weight reductions were greater on tirzepatide, by an estimated 1.9 kg, 3.6 kg and 5.5 kg at 5 mg, 10 mg and 15 mg (4).
Three limits belong with that result. It was run in type 2 diabetes rather than obesity, so it did not ask the question STEP 1 and SURMOUNT-1 asked. It compared one semaglutide dose, 1 mg, and not the 2.4 mg dose used in STEP 1. And it did not include retatrutide: no published trial has compared retatrutide with either of the other two. A Phase 3 trial that does compare retatrutide with semaglutide in type 2 diabetes is registered and under way, and has not reported (10).
The three compounds, as their own trials describe them
Each column reports figures from a different published trial, and the trials differ in phase, length, population and design — so the columns are not a head-to-head comparison. The one exception is the HbA1c row, where the Semaglutide and Tirzepatide figures come from the same trial, in which the two were compared directly.
| Parameter | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Receptor targets | GLP-1 | GLP-1 and GIP | GLP-1, GIP and glucagon |
| Weight trial cited here | STEP 1, Phase 3, 1,961 adults, 68 weeks (1) | SURMOUNT-1, Phase 3, 2,539 adults, 72 weeks (2) | Phase 2, 338 adults, 48 weeks (3) |
| Largest mean weight change reported | −14.9% (2.4 mg) | −20.9% (15 mg) | −24.2% (12 mg) |
| Placebo arm in the same trial | −2.4% | −3.1% | −2.1% |
| HbA1c change in type 2 diabetes | −1.86 points at 40 weeks, 1 mg (4) | −2.30 points at 40 weeks, 15 mg (4) | −2.02 points at 24 weeks, 12 mg (Phase 2, 281 adults) (5) |
| Administration in the cited trials | Once weekly, subcutaneous | Once weekly, subcutaneous | Once weekly, subcutaneous |
| Regulatory status | Authorised in the European Union — Ozempic since 2018, Wegovy since 2022 (9) | Authorised in the European Union — Mounjaro since 2022 (9) | Investigational; no marketing authorisation in any jurisdiction (10) |
Sources. (1) Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989–1002. (2) Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205–216. (3) Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514–526. (4) Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503–515. (5) Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529–544. Cited elsewhere in this post: (6) Coskun T, Urva S, Roell WC, 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.e9. (7) Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037–2048. (8) Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. 2026;407(10546):2402–2413. (9) European Medicines Agency, European public assessment reports: Ozempic (semaglutide), authorised 8 February 2018; Wegovy (semaglutide), authorised 6 January 2022; Mounjaro (tirzepatide), authorised 15 September 2022. (10) Eli Lilly and Company, What to know about retatrutide, updated July 2026; ClinicalTrials.gov registry records for retatrutide, including NCT06260722, a Phase 3 trial comparing retatrutide with semaglutide in type 2 diabetes, which has not reported.
Two approved medicines and one investigational compound
The receptor arithmetic is the interesting part of this comparison, but it is not the largest difference between the three, and the largest difference does not narrow as the receptor count rises. It is regulatory.
Semaglutide and tirzepatide are authorised medicines in the European Union. The European Medicines Agency records a marketing authorisation for Ozempic, semaglutide for type 2 diabetes, issued on 8 February 2018, and for Wegovy, semaglutide for weight management, issued on 6 January 2022; Mounjaro, tirzepatide, was authorised on 15 September 2022 (9). Each was assessed by a regulator, carries an approved indication, and is prescribed and dispensed under it.
Retatrutide has none of that. It holds no marketing authorisation in any jurisdiction, and its developer's own published statement, updated in July 2026, describes it as investigational and not approved by the FDA (10). Phase 3 trials are registered and under way, and one has reported: TRANSCEND-T2D-1, a 40-week trial of 537 adults with type 2 diabetes, published in the Lancet in 2026, in which the 12 mg group showed a mean HbA1c change of −1.94 percentage points against −0.81 on placebo — against its own placebo arm, not against either of the other two compounds (8).
Publication is not authorisation. A trial result describes what happened to the people enrolled in that trial; an authorisation is a separate decision, taken afterwards by a regulator, about whether a medicine may be sold and for what. Two of the columns above describe medicines that have cleared that second step. The third describes a compound still being studied, and every figure in it is a Phase 2 or Phase 3 read-out rather than the basis of any approved use.
How to read the figures above
- Every weight figure is a mean for a trial group, not an outcome anyone was promised. Results within each of these trials varied widely between participants.
- The three weight trials were separate — different populations, different lengths, different phases — so a gap between two columns is a gap between two trials before it is a gap between two compounds.
- The placebo arms differed too, by −2.4%, −3.1% and −2.1%, which means the three columns do not sit on a common baseline.
- SURPASS-2 is the only direct comparison among these compounds, it covered only tirzepatide and semaglutide, and it was run in type 2 diabetes rather than obesity (4).
- Doses appear here as trial design, because the results cannot be read without them. They are not a schedule, and nothing on this page is a protocol for use in people.
- Retatrutide's largest published weight figure comes from a Phase 2 trial; the two figures it is set beside come from Phase 3 trials several times larger.
Research use only
Peptio is not a pharmacy and supplies these compounds for research use only — not for human or veterinary consumption. Retatrutide is investigational and holds no marketing authorisation in any jurisdiction; semaglutide and tirzepatide are authorised medicines elsewhere, and nothing Peptio supplies is an approved medicine. Every figure in this post comes from a published trial and describes that trial's participants. None of it is guidance for use in people, and none of it is a claim about what any product does.