Tirzepatide vs GLP-3 (retatrutide): the dual and the triple agonist compared

The short version

Tirzepatide activates two receptors, GIP and GLP-1. Retatrutide, which we list as GLP-3, activates those two and the glucagon receptor as well. Both were designed at Eli Lilly on a GIP-derived backbone, both are 39 residues long, both carry a C20 fatty diacid that binds albumin and gives a half-life of several days, and both came out of the same programme of engineering a single peptide to act on more than one incretin-family receptor. Tirzepatide is a licensed medicine in the UK; retatrutide is in phase 3 trials and is not. For a laboratory that question of status, together with the third receptor, is what separates them. Everything else is detail, and the detail is below.

Both compounds are supplied by BuyUK Peptides as research chemicals for in-vitro laboratory use only. Trial doses are quoted here as facts about the trials, not as guidance of any kind.

Receptors

The pharmacology of tirzepatide is unusual and has been studied in some depth. At the GIP receptor it behaves like the native hormone; at the GLP-1 receptor it is roughly five-fold weaker than GLP-1 itself and shows biased signalling, favouring cyclic AMP production over β-arrestin recruitment, which the authors of the key paper argued reduces receptor internalisation and prolongs signalling [1, 2]. Retatrutide's receptor profile was characterised in the paper describing its discovery: an agonist at all three receptors, with the highest potency at GIP, then glucagon, then GLP-1, and the ratio deliberately tuned so that glucagon-receptor activity (which raises hepatic glucose output) is balanced by the incretin activity [3]. The glucagon component is the whole point of the triple design, since glucagon-receptor agonism increases energy expenditure in the models used, and it is also the component that makes dose-finding harder.

Structure and chemistry

Both peptides are 39 residues with a C-terminal amide, both carry the aminoisobutyric acid (Aib) substitutions at positions 2 and 13 that protect against dipeptidyl peptidase-4 cleavage, and both are lipidated at lysine 20 through a linker to a C20 fatty diacid (eicosanedioic acid). The sequences differ at several positions, chosen in retatrutide to add glucagon-receptor activity while keeping the GIP backbone, and the lipidation linkers differ in their spacer chemistry. The result is two molecules that look alike on a chromatogram, elute close together on reversed-phase HPLC, and have molecular weights about 80 Da apart.

The practical consequence of near-identical physical chemistry is that a certificate of analysis cannot tell the two apart on purity alone. The LC-MS identity line is what distinguishes them, and the expected mass on a retatrutide certificate should read close to 4,731 Da, not 4,813 Da. If a supplier's certificate for one compound shows the other's mass, something has been mislabelled.

Clinical record

Tirzepatide has the larger record by a wide margin. The SURPASS programme in type 2 diabetes and the SURMOUNT programme in obesity together enrolled well over ten thousand participants. In SURMOUNT-1, the 72-week phase 3 trial in adults with obesity and without diabetes, the highest dose produced a mean weight reduction of about 21 per cent against 3 per cent on placebo [4]; in SURPASS-2 it outperformed semaglutide 1 mg on HbA1c and body weight in type 2 diabetes [5].

Retatrutide's published record is the phase 2 programme. In the 48-week phase 2 obesity trial published in 2023, the highest dose produced a mean weight reduction of about 24 per cent, the largest figure reported for any single peptide at that time, with the usual gastrointestinal adverse-effect profile of the class and some dose-related increases in heart rate [6]. The phase 3 TRIUMPH programme is under way, and its results are what will decide whether retatrutide becomes a medicine. Until it reports, the honest comparison is between a compound with phase 3 evidence and a licence, and a compound with phase 2 evidence and a great deal of expectation.

Licensing and legal status in the UK

Tirzepatide is authorised by the MHRA under the brand Mounjaro for type 2 diabetes and for weight management, and is a prescription-only medicine. Retatrutide has no marketing authorisation anywhere. For a UK purchaser of research material this difference matters less than it might seem: both are supplied strictly as research chemicals, neither is sold as a medicine, and the conditions of sale are the same. It matters in two other ways. First, a licensed compound has a public reference standard and published analytical methods, which makes a tirzepatide certificate easier to judge against an external benchmark. Second, both are prohibited in sport under the WADA List's S4 section on hormone and metabolic modulators, which names GLP-1 receptor agonists as a class; neither is a consideration for in-vitro work, but it is a fact about the compounds.

Handling at the bench

The two are handled the same way. Both are supplied as lyophilised powders that should be kept at 2 to 8 °C sealed, or at −20 °C for long-term storage, and brought to room temperature before opening. Both reconstitute in water or bacteriostatic water at near-neutral pH to a clear solution, and both are lipidated, which means they adsorb to plastic at low concentration and are best handled in low-binding tubes or at concentrations where loss to surfaces is negligible. Neither has a cysteine, so disulphide scrambling is not a concern, but both have a methionine-free sequence, so oxidation is less of a worry than with some other compounds in the catalogue. The storage and stability guide covers solvents, concentrations and freeze–thaw behaviour for lipidated peptides in general.

Which to choose

For a receptor-pharmacology experiment the choice is made by the question: a dual GIP/GLP-1 agonist that is silent at the glucagon receptor, or a triple agonist that engages it. Tirzepatide is the cleaner tool for separating GIP and GLP-1 effects from glucagon effects; retatrutide is the tool for studying the three together. For analytical or formulation work, where the compound is a model lipidated peptide rather than a pharmacological agent, tirzepatide has the advantage of a licensed reference and a mature literature on its analytical characterisation.

Both monographs carry the full accounts with references: tirzepatide and GLP-3. The wider family, including semaglutide and cagrilintide, is set out in semaglutide, tirzepatide, retatrutide and cagrilintide compared.

References

1. Coskun T, Sloop KW, Loghin C, et al. 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. 2018;18:3–14. doi:10.1016/j.molmet.2018.09.009.
2. Willard FS, Douros JD, Gabe MBN, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532. doi:10.1172/jci.insight.140532.
3. 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 Metabolism. 2022;34(9):1234–1247.e9. doi:10.1016/j.cmet.2022.07.013.
4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387(3):205–216. doi:10.1056/NEJMoa2206038.
5. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. New England Journal of Medicine. 2021;385(6):503–515. doi:10.1056/NEJMoa2107519.
6. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. New England Journal of Medicine. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.