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The short answer to retatrutide vs tirzepatide (and semaglutide) is receptor pharmacology. Semaglutide activates one receptor, GLP-1. Tirzepatide activates two, GIP and GLP-1. Retatrutide adds a third, the glucagon receptor, making it a triple agonist. Semaglutide and tirzepatide are approved prescription medicines, while retatrutide is still investigational, and no head-to-head trial of retatrutide against either drug had reported results as of September 2026.
This article compares the three molecules as research subjects: how they are built, which receptors they act on, how their pivotal trials were designed, and why the headline numbers from different trials cannot simply be lined up against each other. It does not rank the drugs for any individual.
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Developer | Novo Nordisk | Eli Lilly | Eli Lilly |
| Receptors activated | GLP-1 | GIP and GLP-1 | GIP, GLP-1 and glucagon |
| Structural basis | Human GLP-1 with two substitutions (Aib8, Arg34), acylated at lysine 261 | 39-amino-acid peptide with two Aib residues, a C20 fatty diacid at lysine 20 and an amidated C-terminus2 | Peptide with GIP, GLP-1 and glucagon receptor activity,3 containing Aib (position 2) and α-methyl-L-leucine (position 13), with a fatty diacid at lysine 174 |
| Molecular formula (PubChem) | C187H291N45O59 | C225H348N48O68 | C221H342N46O68 |
| Molar mass (PubChem) | 4114 g/mol | 4813 g/mol | 4731 g/mol |
| US approval status | Approved: Ozempic (type 2 diabetes, 2017) and Wegovy (chronic weight management, 2021)5,6 | Approved: Mounjaro (type 2 diabetes) and Zepbound (chronic weight management, 2023)7 | Not approved; investigational only8 |
| WADA 2026 status | Not prohibited; on the Monitoring Program9 | Not prohibited; on the Monitoring Program9 | Not named on the 2026 Prohibited List |
All three receptors belong to class B1 of the G protein-coupled receptor family, and all three natural ligands are peptide hormones. In textbook physiology, GLP-1 is released from the gut after a meal. It stimulates glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying and acts on appetite pathways in the brain. GIP, the other incretin, also stimulates glucose-dependent insulin secretion. Glucagon works largely in the opposite direction to insulin in the liver, raising glucose output between meals. That makes glucagon-receptor activity a counter-intuitive addition to a metabolic drug. The rationale in Lilly's retatrutide work is that glucagon-receptor signalling also raises energy expenditure, an effect the company demonstrated in obese mice.3 The three molecules differ in which of these receptors they engage and how strongly.
Semaglutide was engineered from human GLP-1. Novo Nordisk's discovery paper says the design goals were high albumin affinity and full stability against metabolic degradation, to prolong exposure. The selected molecule has two amino acid substitutions compared with human GLP-1 (Aib at position 8 and Arg at 34) and a fatty-acid side chain attached through a linker at lysine 26.1 In mini-pigs the plasma half-life after intravenous administration was 46.1 hours. Its action is confined to the GLP-1 receptor.
Lilly's discovery paper describes tirzepatide (LY3298176) as a GIP-based dual incretin receptor agonist. In its receptor studies tirzepatide bound the GIP receptor with an affinity comparable to native GIP. At the GLP-1 receptor it bound about five-fold more weakly than native GLP-1.2 In mice its effects on body weight and food intake were significantly greater than those of a GLP-1 receptor agonist alone.
Retatrutide (LY3437943) extends the same design logic to a third receptor. In cell assays it showed roughly balanced glucagon and GLP-1 receptor activity with greater GIP receptor activity.3 In obese mice the authors reported that glucagon-receptor-mediated increases in energy expenditure added to the intake reduction driven by the GIP and GLP-1 receptors. Cryo-EM structures published in 2024 showed the peptide bound to all three receptors as a single continuous helix.4 Whether the energy-expenditure effect seen in mice carries over to people is still an open question.
For the full retatrutide evidence base, from phase 1 to the TRIUMPH phase 3 program, see our retatrutide research overview.
There is not yet any direct trial evidence on retatrutide vs tirzepatide. Lilly is running TRIUMPH-5 (NCT06662383), a double-blind phase 3 trial randomising adults with obesity to retatrutide or tirzepatide. Its primary endpoint is percentage change in body weight at 80 weeks, with an estimated enrolment of 800. The registry lists primary completion as November 2026 (estimated).10 A second trial, TRANSCEND-T2D-2 (NCT06260722), compares retatrutide with semaglutide in type 2 diabetes. Until these report, any statement that one is "stronger" rests on comparing separate placebo-controlled trials. That approach is weak evidence for the reasons set out below.
When TRIUMPH-5 does report, it will be the first randomised comparison of the two molecules using the same design, population and analysis. Even then it will answer a fairly narrow question: percentage change in body weight over 80 weeks in adults with obesity. It is not designed to compare cardiovascular, kidney or liver outcomes. A single trial in one population also will not settle how the two compare in type 2 diabetes, where other trials in the TRANSCEND program are relevant.
Retatrutide has not been compared directly with semaglutide in a published trial either. The registered head-to-head study is TRANSCEND-T2D-2 (NCT06260722), an open-label phase 3 trial comparing retatrutide with semaglutide in adults with type 2 diabetes whose glucose is inadequately controlled on metformin, with or without an SGLT2 inhibitor. Its primary endpoint is change in HbA1c at 80 weeks, the estimated enrolment is 1,250 and the registry gives an estimated primary completion of August 2026. We found no announced results in the sources we checked in September 2026. Because its primary endpoint is HbA1c rather than body weight, it will answer a glucose-control question before a weight question.
The two best-known published head-to-head trials of tirzepatide and semaglutide were both funded by Eli Lilly:
Both were open-label, meaning participants knew which drug they received, and in both the most common adverse events were gastrointestinal and mostly mild to moderate.
| Head-to-head trial | Comparison | Population | Primary endpoint | Status (Sept 2026) |
|---|---|---|---|---|
| SURPASS-2 | Tirzepatide vs semaglutide | Type 2 diabetes | HbA1c change, 40 weeks | Published 202111 |
| SURMOUNT-5 | Tirzepatide vs semaglutide | Obesity without diabetes | Body-weight change, 72 weeks | Published 202512 |
| TRANSCEND-T2D-2 | Retatrutide vs semaglutide | Type 2 diabetes on metformin ± SGLT2 inhibitor | HbA1c change, 80 weeks | Active, not recruiting; no results announced |
| TRIUMPH-5 | Retatrutide vs tirzepatide | Obesity | Body-weight change, 80 weeks | Active, not recruiting; primary completion est. Nov 202610 |
The table below places the best-known placebo-controlled obesity trials side by side. The full papers are on PubMed, for example STEP 1 and SURMOUNT-1. Read it as a comparison of trial designs, not of drugs.
| Trial | Compound | n | Length | Mean body-weight change vs placebo | Estimand / status |
|---|---|---|---|---|---|
| STEP 1 (NEJM 2021) | Semaglutide | 1,961 | 68 weeks | −14.9% vs −2.4%13 | All randomised, regardless of discontinuation; peer-reviewed |
| SURMOUNT-1 (NEJM 2022) | Tirzepatide (3 arms) | 2,539 | 72 weeks | −15.0% to −20.9% vs −3.1%14 | Treatment-regimen; peer-reviewed |
| Phase 2 (NEJM 2023) | Retatrutide (several arms) | 338 | 48 weeks | Up to −24.2% vs −2.1%15 | Phase 2; peer-reviewed |
| TRIUMPH-1 (2026) | Retatrutide (3 arms) | 2,339 | 80 weeks | −19.0% to −28.3% vs −2.2%8 | Efficacy estimand; company topline, not yet peer-reviewed |
Gastrointestinal adverse events (nausea, diarrhoea, vomiting, constipation) were the most common in all three programs.13,14,15 In STEP 1, 4.5% of semaglutide participants stopped treatment because of gastrointestinal events, compared with 0.8% on placebo.13 In SURMOUNT-1, adverse events led to discontinuation in 4.3% to 7.1% of tirzepatide participants, compared with 2.6% on placebo.14 The retatrutide phase 2 trial reported dose-dependent heart-rate increases that peaked at 24 weeks,15 and Lilly's phase 3 releases report dysesthesia (altered skin sensation) more often than with placebo.8 Semaglutide and tirzepatide are approved medicines with post-marketing experience, whereas retatrutide's dedicated cardiovascular and kidney outcomes trial (NCT06383390) is still running.
None of the three is prohibited by name. WADA placed markers of semaglutide and tirzepatide on its 2026 Monitoring Program, in and out of competition. The Monitoring Program tracks substances that are not on the Prohibited List to detect patterns of misuse.9 Retatrutide does not appear in the 2026 List text. For how unnamed, unapproved compounds are treated, see peptides and the WADA Prohibited List.
Semaglutide and tirzepatide are prescription medicines supplied through pharmacies. Retatrutide is not a medicine at all yet: Lilly says it is legally available only to participants in its clinical trials.8 Titan Peptides supplies research-grade retatrutide in 10 mg and 20 mg lyophilised vials for laboratory research only. Typical uses include receptor-signalling assays, analytical reference work and animal studies, not human use. For the Australian regulatory picture, read are research peptides legal in Australia?
Both are Eli Lilly peptides. Tirzepatide activates the GIP and GLP-1 receptors and is an approved medicine (Mounjaro, Zepbound). Retatrutide also activates the glucagon receptor, making it a triple agonist, and remains investigational. Their structures differ too: retatrutide contains α-methyl-L-leucine and is lipidated at lysine 17, while tirzepatide is lipidated at lysine 20.
That cannot be answered yet from direct evidence. No head-to-head results have been reported. The TRIUMPH-5 trial comparing the two has an estimated primary completion of November 2026. Placebo-controlled trials of each used different estimands, durations and populations, so placing their headline weight-change figures side by side does not show which molecule has the larger effect.
Yes, in two Lilly-funded open-label trials. In SURPASS-2, in type 2 diabetes, tirzepatide was superior to semaglutide 1 mg on HbA1c change at 40 weeks. In SURMOUNT-5, in obesity without diabetes, mean body-weight change at 72 weeks was −20.2% with tirzepatide and −13.7% with semaglutide at maximum tolerated doses.
No. Neither is on the 2026 WADA Prohibited List. Markers of semaglutide and tirzepatide are on WADA's 2026 Monitoring Program, which tracks non-prohibited substances for patterns of misuse. In September 2026 WADA said the status of GLP-1 receptor agonists would remain unchanged for 2027. Retatrutide is not named on the List.
Yes, but not only that. Retatrutide activates the GLP-1 receptor together with the GIP and glucagon receptors, so it is usually described as a GIP, GLP-1 and glucagon triple receptor agonist rather than a GLP-1 agonist. In cell assays Lilly reported balanced glucagon and GLP-1 receptor activity with greater activity at the GIP receptor.
Retatrutide (LY3437943) is Eli Lilly's investigational GIP, GLP-1 and glucagon triple agonist. Here is what the phase 1 to phase 3 research reports, and where it stands in September 2026.
Which peptides does the 2026 WADA Prohibited List name, in which section, and what does "not named" really mean? Includes GLP-1 drugs, retatrutide and Sport Integrity Australia.
What the TGA, the June 2026 Poisons Standard, the Therapeutic Goods Act and customs law actually say about peptides, "research use only" labels, importing and advertising in Australia.
