Tirzepatide vs Retatrutide: Two Receptors or Three
Last updated: October 2026
Tirzepatide and retatrutide are close relatives: both are 39-amino-acid peptides from the same laboratory, both carry a long fatty acid, and both share most of their sequence. The big difference is one receptor. Tirzepatide acts at the GIP and GLP-1 receptors; retatrutide adds the glucagon receptor. Here is how the two compare, residue by residue, receptor by receptor and milestone by milestone.
Same Family, One Big Difference
Retatrutide wasn't designed from scratch. It extends an idea that tirzepatide proved could work.
Both peptides belong to the family of gut and pancreas hormones that includes glucagon, GIP and GLP-1. These hormones share a family resemblance in their sequences, and each acts through its own receptor. That resemblance is what lets chemists build one peptide that reaches more than one receptor.
Tirzepatide, described by Eli Lilly in 2018, is built on GIP's sequence and tuned to reach GLP-1R as well. It engages GIPR about as strongly as GIP does, and GLP-1R more weakly. Retatrutide, described by the same company in 2022, keeps the GIP-leaning design and adds activity at the glucagon receptor, making it a triple agonist.
Both peptides use the same tricks to last: non-standard amino acids that resist breakdown, a C20 fatty diacid that rides on albumin in the blood, and a C-terminal tail borrowed from exendin-4. Where they differ is in nine positions of the chain, and in what those positions let the peptide do.
- TirzepatideDual agonist: GIPR and GLP-1R
- RetatrutideTriple agonist: GIPR, GLP-1R and GCGR
- Same length39 amino acids each
- 30 of 39 positions sharedIncluding the whole exendin-4 tail
- About 82 g/mol apartAbout 4813 vs about 4731 g/mol
Side by Side
The essentials of each peptide in one table.
| Tirzepatide | Retatrutide | |
|---|---|---|
| Development code | LY3298176 | LY3437943 |
| First described | 2018, Molecular Metabolism | 2022, Cell Metabolism |
| Receptors | GIPR and GLP-1R | GIPR, GLP-1R and GCGR |
| Receptor profile | GIPR about equal to native GIP; GLP-1R weaker than native GLP-1, with a bias toward cAMP | GIPR stronger than native GIP; GLP-1R and GCGR weaker than their native hormones |
| Length | 39 amino acids | 39 amino acids |
| Non-standard residues | Aib at 2 and 13 | Aib at 2 and 20, α-methyl-leucine at 13 |
| Fatty acid on | Lysine 20 | Lysine 17 |
| Molecular formula | C225H348N48O68 | C221H342N46O68 |
| Molecular weight | About 4813 g/mol | About 4731 g/mol |
| CAS number | 2023788-19-2 | 2381089-83-2 |
| Reported half-life | About 5 days | About 6 days |
| Receptor structures | Cryo-EM, 2022 | Cryo-EM, 2024 |
| Status | Approved medicine (Mounjaro in Canada and the US; Zepbound in the US) | Investigational, phase 3 results published in 2026 |
Two Chains, Nine Differences
Here are both peptides lined up position by position. Highlighted positions are where they differ. Hover over or tap any position to compare.
The two chains match at their first two positions and across the whole exendin-4 tail. Their nine differences sit in the middle of the helix, including the swapped positions of the fatty acid (lysine 20 in tirzepatide, lysine 17 in retatrutide).
Receptor by Receptor
What the published assays report for each receptor. Each line comes from a cited paper.
GIPR
Tirzepatide: binds about as strongly as native GIP and mimics GIP's signalling.
Retatrutide: more potent than native GIP. Both peptides lean toward this receptor.
Coskun 2018 · Willard 2020 · Coskun 2022 · Li 2024
GLP-1R
Tirzepatide: about five times weaker binding than native GLP-1, favouring cAMP over β-arrestin.
Retatrutide: weaker than native GLP-1, with activity balanced against its glucagon-receptor activity.
Coskun 2018 · Willard 2020 · Coskun 2022
GCGR
Tirzepatide: not one of its targets.
Retatrutide: active, weaker than native glucagon. In mice, its effect on energy expenditure was traced to this receptor.
Coskun 2022 · Li 2024
Two Research Timelines, Side by Side
Tirzepatide had a four-year head start. Here is how the two stories interleave, one chapter at a time. Keep scrolling.
- 2013
The dual-incretin idea
Finan et al., Science Translational Medicine · rodents, monkeys and a first human study
Before either peptide existed, a research network spanning Indiana University and Munich showed that a single peptide could be engineered to act at both the GIP and GLP-1 receptors. Two years later the same group described a triple agonist that also reached the glucagon receptor. Tirzepatide and retatrutide follow those two ideas.
- 2018
Tirzepatide is unveiled
Coskun et al., Molecular Metabolism · cell assays, mice and phase 1 studies
Eli Lilly described LY3298176, later named tirzepatide: a GIP-based peptide that also engages GLP-1R, with a half-life of about five days. The same year, its first phase 2 trial in type 2 diabetes was published.
- 2020
Tirzepatide's signalling explained
Willard et al., JCI Insight · cell signalling and islet studies
A detailed signalling study showed tirzepatide engaging GIPR more than GLP-1R, and at GLP-1R favouring cAMP over β-arrestin with less receptor internalisation. "Imbalanced and biased" became the shorthand for how it works.
- 2022
Retatrutide is unveiled
Coskun et al., Cell Metabolism · cell assays, mice and a phase 1 study
Four years after tirzepatide, the same company described LY3437943, later named retatrutide: active at GIPR, GLP-1R and GCGR, with more GIPR activity and balanced GLP-1R and GCGR activity. Its first study in people with type 2 diabetes followed the same year and reported a half-life of about six days.
- 2022
Tirzepatide in its receptors, and approved
Sun et al., PNAS · U.S. FDA, May 2022 · Health Canada, November 2022
Cryo-EM structures showed tirzepatide sitting in GIPR much as GIP does, but differently from GLP-1 in GLP-1R. The same year, tirzepatide was approved as Mounjaro for type 2 diabetes, by the FDA in May and by Health Canada in November.
- 2023
Retatrutide's phase 2, tirzepatide's second approval
Jastreboff et al., NEJM · Rosenstock et al., The Lancet · U.S. FDA, November 2023
Two phase 2 trials of retatrutide as an investigational medicine were published, moving the program into phase 3. In November, the FDA approved tirzepatide a second time, as Zepbound, for chronic weight management in adults.
- 2024
Retatrutide in its receptors
Li et al., Cell Discovery · cryo-electron microscopy
Structures of retatrutide in all three receptors showed one continuous helix, with its two ends doing most of the work of deciding how it engages each receptor. With both peptides now solved, their receptor contacts can be compared directly.
- 2026
Retatrutide reaches phase 3 results
Bajaj et al., The Lancet · Jastreboff et al., NEJM · Bellido et al., The Lancet
Retatrutide's phase 3 programs began publishing in 2026, with TRANSCEND-T2D-1 in June, TRIUMPH-1 in September and TRIUMPH-2 in October. Retatrutide remains investigational; tirzepatide remains the approved reference point it is most often compared with.
So where does that leave us? Tirzepatide showed that one peptide could be tuned to two incretin receptors, unequally and with a signalling bias. Retatrutide carries the same design forward and adds the glucagon receptor. The two are now the clearest pair in the field for asking what a third receptor contributes. Each paper speaks for its own model, population and conditions, so the references below link every original.
Questions the Comparison Raises
Having two closely related peptides makes some of the biggest questions in incretin research easier to ask.
What does the third receptor add?
With most of the sequence shared, the glucagon receptor is the clearest difference. In mice, retatrutide's energy-expenditure effect was traced to that receptor, which tirzepatide doesn't engage.
Coskun et al., 2022
Why do both lean toward GIP?
Neither peptide treats its receptors equally, and both favour GIPR. Why that tilt was kept across two generations of design is one of the field's open questions.
Willard et al., 2020 · Coskun et al., 2022
Does the fatty-acid position matter?
Tirzepatide carries its fatty acid on lysine 20, retatrutide on lysine 17. Structural work on tirzepatide suggests the fatty acid shapes receptor engagement, not just circulation time.
Sun et al., 2022 · Li et al., 2024
Is retatrutide biased too?
Tirzepatide's GLP-1R bias toward cAMP is well described. Whether retatrutide shows a similar bias has not been reported in the papers cited here.
Willard et al., 2020
Telling Them Apart on a COA
Because the two peptides look so alike, the identity test is what tells them apart.
Tirzepatide
Mass spectrometry should report a mass close to 4813 Da. HPLC purity, a content figure and, where tested, an endotoxin result complete the report.
Retatrutide
Mass spectrometry should report a mass close to 4731 Da, about 82 Da lighter. HPLC purity, a content figure and endotoxin results complete the report.
When reading either COA, match the batch number on the vial to the report and check that the sample is named correctly, since the two names are easy to confuse. Our batches of both peptides are tested by SideChain Analytics, our primary laboratory in Canada, with supplementary Janoshik reports. Every report is on our COA page, and each one can be verified directly with the issuing lab.
Common Comparison Questions
What is the main difference between tirzepatide and retatrutide?
Tirzepatide is a dual agonist at the GIP and GLP-1 receptors. Retatrutide is a triple agonist that also acts at the glucagon receptor. They share 30 of their 39 positions.
Are tirzepatide and retatrutide from the same company?
Yes. Both were developed by Eli Lilly: tirzepatide as LY3298176 (described 2018) and retatrutide as LY3437943 (described 2022).
Is retatrutide a newer version of tirzepatide?
It is a related but different molecule. Retatrutide keeps tirzepatide's GIP-leaning design and adds glucagon-receptor activity, with nine sequence changes and its fatty acid on a different lysine.
How can a COA tell them apart?
By mass. Tirzepatide is about 4813 Da and retatrutide about 4731 Da, so mass spectrometry distinguishes them clearly. Always check that the sample name and batch number match the vial.
Which one is approved?
Tirzepatide is an approved medicine, sold as Mounjaro in Canada and as Mounjaro and Zepbound in the United States. Retatrutide is investigational and not approved; Health Canada's Drug Product Database lists no retatrutide product. Research-grade material of either peptide is supplied for laboratory research only.
What is a triple agonist?
A single molecule that switches on three different receptors. In retatrutide's case those are the receptors for GIP, GLP-1 and glucagon.
Glossary of Terms
GIPR, GLP-1R and GCGR
The receptors for GIP, GLP-1 and glucagon, all class B G protein-coupled receptors.
Dual and triple agonist
A single molecule that switches on two or three different receptors.
Biased agonism
When a molecule favours one of a receptor's signals, such as cAMP, over another, such as β-arrestin recruitment.
Aib
α-Aminoisobutyric acid, a non-standard amino acid that protects peptides from enzymatic cleavage.
Fatty diacid
A long-chain fatty acid with an acid group at each end. Attached to a peptide, it binds albumin and slows clearance.
Exendin-4 tail
The C-terminal GGPSSGAPPPS sequence from a Gila monster venom peptide, shared by both molecules.
Mass spectrometry
A method that measures molecular mass very precisely, used to confirm which peptide is in a sample.
Cryo-electron microscopy
A method that images frozen molecules to reveal their 3D structure.
References
- Finan B et al. (2013). Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Science Translational Medicine 5(209):209ra151. PubMed 24174327
- Finan B et al. (2015). A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nature Medicine 21(1):27–36. PubMed 25485909
- Coskun T et al. (2018). LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Molecular Metabolism 18:3–14. PubMed 30473097
- Willard FS et al. (2020). Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 5(17):e140532. PubMed 32730231
- Sun B et al. (2022). Structural determinants of dual incretin receptor agonism by tirzepatide. PNAS 119(13):e2116506119. PubMed 35333651
- Coskun T et al. (2022). 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 Metabolism 34(9):1234–1247. PubMed 35985340
- Urva S et al. (2022). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The Lancet 400(10366):1869–1881. PubMed 36354040
- Jastreboff AM et al. (2023). Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. New England Journal of Medicine 389(6):514–526. PubMed 37366315
- Rosenstock J et al. (2023). 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. The Lancet 402(10401):529–544. PubMed 37385280
- Li W et al. (2024). Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. Cell Discovery 10(1):77. PubMed 39019866
- Bailey CJ, Flatt PR, Conlon JM (2025). Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities. Peptides 187:171380. PubMed 40081498
- Bajaj HS et al. (2026). 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. The Lancet 407(10546):2402–2413. PubMed 42250575
- Jastreboff AM et al. (2026). Retatrutide, a triple hormone receptor agonist, for treatment of obesity (TRIUMPH-1). New England Journal of Medicine, published online September 2026. PubMed 42814954
- Bellido V et al. (2026). Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. The Lancet 408:1455–1472. PubMed 42810372
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