GLP-3 (Retatrutide)

What retatrutide is

Retatrutide is a synthetic, single-chain peptide of 39 amino acids that acts as an agonist at three receptors at once: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). It was developed at Eli Lilly under the code LY3437943, and the discovery paper by Coskun and colleagues describes it as a "triple glucagon, GIP, and GLP-1 receptor agonist" built on a GIP-derived backbone, extending the approach that produced tirzepatide by one further receptor [1].

The design follows a now-familiar pattern. The backbone carries substitutions that give it activity at the GLP-1 and glucagon receptors in addition to the GIP receptor it was derived from. Non-natural residues, 2-aminoisobutyric acid (Aib) at two positions and an α-methyl-leucine at a third, protect the N-terminal region from dipeptidyl peptidase-4 (DPP-4) and stiffen the helix. A lysine at position 17 carries a C20 fatty diacid through a γ-glutamate and AEEA linker; the diacid binds reversibly to serum albumin, which slows renal clearance and gives the molecule a circulating half-life of about six days in humans, long enough for once-weekly administration in the clinical programme [1, 2]. The C-terminus is amidated.

In its research presentation the compound is a white to off-white lyophilised powder. The reference identifiers are in the table below; the values on any given batch certificate should agree with them within the precision of the method used. The molecular weight quoted is the average (isotope-weighted) value, which is the figure that supplier datasheets and most certificates report.

How the literature describes its mechanism

The three receptors retatrutide engages belong to the same class B family of G-protein-coupled receptors, and each is the target of a native gut or pancreatic hormone. GIP and GLP-1 are incretins: they potentiate glucose-dependent insulin secretion, and GLP-1 also slows gastric emptying and reduces food intake through central pathways. Glucagon is the counter-regulatory hormone to insulin, raising hepatic glucose output in the fasting state, but it also increases energy expenditure and hepatic fat oxidation. The rationale for adding glucagon receptor agonism to an incretin co-agonist is that the incretin components should restrain the hyperglycaemic effect of glucagon while the glucagon component adds a thermogenic and hepatic contribution that neither incretin provides on its own [1].

Coskun and colleagues report that in vitro the molecule shows roughly balanced activity at the glucagon and GLP-1 receptors and greater activity at the GIP receptor, so, like tirzepatide, it is deliberately imbalanced in favour of GIPR. In diet-induced obese mice, the compound reduced body weight and improved glycaemic control, and the authors attribute the additional weight loss over a GIP/GLP-1 co-agonist to the glucagon-receptor-mediated increase in energy expenditure rather than to a further reduction in food intake [1]. The paper also includes a first-in-human single ascending dose study in which the pharmacokinetic profile supported once-weekly dosing and body-weight reduction was still measurable 43 days after a single dose [1].

Urva and colleagues then characterised the molecule in a 12-week multiple ascending dose study in 72 adults with type 2 diabetes, confirming a half-life of around six days and dose-dependent, placebo-adjusted weight reduction that reached roughly 10% in the highest-dose cohort over the study period [2]. The same paper describes a dose-related rise in heart rate, a finding that has recurred across the later trials and is generally attributed in the literature to the GLP-1 and glucagon components.

For an in-vitro programme the relevant readouts are cAMP accumulation in cells expressing each of the three receptors separately, receptor internalisation and β-arrestin recruitment, and insulin or glucagon secretion from isolated islets under varying glucose. Potency values depend heavily on receptor expression level, cell background and assay format, and because the published characterisation rests on a single discovery paper, cross-laboratory comparison of EC50 figures is less mature than for semaglutide or tirzepatide. Compounds should be compared side by side in the same system rather than through literature values.

The clinical research record

Retatrutide's clinical record is shorter than tirzepatide's but is growing quickly. The phase 2 trials were published in 2023 and 2024, and the phase 3 programme, named TRIUMPH, began reporting topline results in 2026. The phase 3 data below are taken from the sponsor's press releases and have not yet appeared in peer-reviewed form at the time of writing; they should be read as provisional.

Phase 1b, type 2 diabetes (Urva et al., The Lancet, 2022). Seventy-two adults with type 2 diabetes were randomised to once-weekly LY3437943 at 0.5, 1.5 or 3 mg, or to stepwise regimens reaching 6 or 12 mg, against placebo and dulaglutide 1.5 mg, for 12 weeks. Treatment-emergent adverse events occurred in 63% of LY3437943 recipients against 54% on placebo and were mostly gastrointestinal, principally diarrhoea and nausea [2].

Phase 2, obesity (Jastreboff et al., New England Journal of Medicine, 2023; NCT04881760). This is the trial most often cited for the compound. Three hundred and thirty-eight adults with obesity, or overweight with a weight-related condition, and without diabetes, were randomised to once-weekly retatrutide at 1, 4, 8 or 12 mg (with 2 mg or 4 mg starting doses in the 4 mg and 8 mg groups) or placebo for 48 weeks. Least-squares mean change in body weight at 48 weeks was −8.7% at 1 mg, −17.1% at 4 mg, −22.8% at 8 mg and −24.2% at 12 mg, against −2.1% with placebo. Adverse events were mainly gastrointestinal, dose-related and mostly mild to moderate; 8% of retatrutide participants discontinued because of an adverse event. Heart rate rose in a dose-dependent manner, peaking at 24 weeks and declining thereafter, and skin hyperaesthesia was reported in 7% of retatrutide participants against 1% on placebo [3].

Phase 2, type 2 diabetes (Rosenstock et al., The Lancet, 2023; NCT04867785). Two hundred and eighty-one adults with type 2 diabetes were randomised to retatrutide at 0.5, 4, 8 or 12 mg (with several escalation schemes), dulaglutide 1.5 mg or placebo for 36 weeks. HbA1c reduction at 36 weeks ranged from −0.54% at 0.5 mg to −2.16% at 12 mg, against −0.30% with placebo and −1.36% with dulaglutide. Body-weight reduction at 36 weeks reached 16.9% in the 12 mg group and had not plateaued. Gastrointestinal events occurred in 35% of retatrutide participants, the same proportion as on dulaglutide, and no severe hypoglycaemia was reported [4].

Phase 2a substudy, MASLD (Sanyal et al., Nature Medicine, 2024). Ninety-eight participants from the obesity trial with at least 10% liver fat by MRI proton density fat fraction formed a pre-specified substudy. At 24 weeks the relative change in liver fat was −42.9% at 1 mg, −57.0% at 4 mg, −81.4% at 8 mg and −82.4% at 12 mg, against +0.3% with placebo, and the proportion of participants with liver fat below 5% (the conventional threshold for normal) was 27%, 52%, 79% and 86% respectively, against none on placebo [5]. The authors note that the liver fat reduction correlated with weight loss but was larger at the higher doses than weight loss alone would predict, which they attribute in part to the glucagon receptor component.

Phase 3, TRIUMPH programme (sponsor topline results, 2026). TRIUMPH-1 (NCT05929066) randomised 2,339 adults with obesity or overweight without diabetes to retatrutide 4, 9 or 12 mg or placebo for 80 weeks; mean weight change was −19.0%, −25.9% and −28.3% respectively against −2.2% with placebo, and an extension to 104 weeks in participants with a baseline body mass index of 35 or above reported reductions of up to 30.3% [6]. TRIUMPH-2 (NCT05929079), in 1,152 adults with type 2 diabetes and obesity or overweight, reported weight change of −12.7%, −19.1% and −20.8% at the same three doses against −4.0% with placebo, with HbA1c reductions of 1.4 to 1.6 percentage points. TRIUMPH-3 (NCT05882045), in 1,949 adults with severe obesity and established cardiovascular disease, reported −21.6% at 9 mg and −22.6% at 12 mg against −3.2% with placebo [7]. Across the three trials the sponsor describes the adverse event profile as consistent with other incretin-based therapies, with gastrointestinal events, dysaesthesia and urinary tract infections reported more often than with placebo [6, 7]. The sponsor has stated an intention to submit the compound for regulatory review in the United States in the first quarter of 2027 [7].

For the laboratory reader, retatrutide is now the reference compound for glucagon-receptor-containing incretin multi-agonists, and several of its distinctive findings, notably the effect on liver fat, the heart-rate signal and the cutaneous sensory adverse events, are mechanistic questions that in-vitro and animal work can usefully address.

Regulatory status in the United Kingdom

Retatrutide is an investigational compound. It has no marketing authorisation in the United Kingdom, the European Union or the United States, is not the active ingredient of any licensed medicine, and is available to patients only within clinical trials. The phase 3 topline announcements do not change that status; a marketing authorisation, if one is granted, would follow a regulatory review that has not yet begun.

BuyUK Peptides supplies research-grade retatrutide as a chemical for in-vitro laboratory use under the Terms of Sale. It is not a medicine, is not manufactured or presented as one, carries no therapeutic claim and is not for human or veterinary administration. Purchasers must be 18 or over and are responsible for ensuring their use of the material complies with the laws and institutional rules that apply to them. Because the compound is unlicensed, the regulatory position differs from that of a research-grade copy of a licensed medicine such as tirzepatide or semaglutide; our guide to the UK rules on research compounds sets out the distinction in more detail.

Handling, storage and stability

Retatrutide is supplied lyophilised, sealed under nitrogen in a glass vial with a rubber stopper and an aluminium flip-off crimp. In that state it is stable for extended periods when kept cold and dark. Its handling behaviour is that of a lipidated incretin peptide and the guidance below mirrors what we give for tirzepatide, with one difference noted under solubility.

Sealed vial. Store at 2–8 °C for routine use. For storage beyond a few months, −20 °C or below is preferable. Protect from light. Avoid repeated freeze–thaw cycles; take the vial out once and keep it at the working temperature from then on. Allow a refrigerated vial to reach room temperature before opening, so that moisture does not condense onto the cake.

Reconstitution. For most in-vitro work the compound is reconstituted in sterile bacteriostatic water, sterile water for injection, or a buffer appropriate to the assay. Add the solvent slowly down the side of the vial rather than onto the cake, and swirl gently; do not shake, because peptides carrying a hydrophobic fatty diacid can aggregate or foam under agitation. A lipidated peptide of this size dissolves more slowly than a short unmodified fragment, and a minute or two of gentle swirling is normal. The reconstitution calculator gives the volume to add for a target concentration.

Reconstituted solution. Keep at 2–8 °C and protect from light. Lipidated GLP-1-class peptides are generally stable in aqueous solution at refrigerator temperature for several weeks. Because retatrutide has no licensed product label to borrow from, there is no published in-use stability claim; the conservative practice for a research solution is to use it within 28 days and to discard it if it becomes cloudy or shows particles. Solutions should not be frozen after reconstitution unless the specific buffer has been validated for that.

Solubility. Retatrutide is soluble in water at the concentrations used in research. The C20 diacid side chain makes the molecule amphipathic, so very high concentrations and low pH both encourage self-association. The glucagon-derived substitutions in the backbone make retatrutide somewhat more hydrophobic than tirzepatide, and in our experience it benefits from a slightly longer dissolution time and from buffers at or above neutral pH. Where a solution must be filtered, use a low-binding membrane (PES or PVDF rather than nylon), because the lipid chain adsorbs to some filter materials.

What a sound certificate for retatrutide looks like

Every batch we release carries an independent certificate of analysis, and the figures from it are transcribed on the product page and in the certificate register. For retatrutide, a certificate should contain the following, and a reader should be able to check each item against this monograph.

Purity by RP-HPLC. Reversed-phase HPLC on a C18 column with UV detection, usually at 214 or 220 nm, reports purity as the area of the main peak as a percentage of all integrated peaks. A good batch of retatrutide shows a single dominant peak with purity of 99% or above. Because the sequence contains three non-natural residues and a lipidated lysine, synthesis is demanding, and the impurity profile deserves attention. Small late-eluting peaks may represent oxidised or deamidated species; a large early-eluting shoulder is more often a truncated or deletion sequence, and a peak close to the main peak may be a species missing the fatty diacid, which should prompt questions.

Identity by LC-MS. Electrospray mass spectrometry confirms that the main peak has the expected mass. For retatrutide the average molecular weight is 4731.3 Da. Electrospray produces multiply charged ions, so a certificate may report the deconvoluted mass, the most abundant charge state, or both. The observed mass should agree with the theoretical value to within a few tenths of a dalton for a deconvoluted result. A mass roughly 340 Da short of the expected value indicates loss of the diacid side chain, and a mass 86 Da short at the N-terminus is consistent with a missing Aib residue; neither should appear as the main peak.

Net peptide content. Lyophilised peptides contain bound water and counter-ions, typically trifluoroacetate from purification, so the mass of powder in the vial is more than the mass of peptide. Net peptide content, where reported, expresses the fraction that is actual peptide, and it matters for preparing solutions of accurate concentration.

Endotoxin. Where the batch has been tested, a limulus amoebocyte lysate (LAL) result is reported in endotoxin units per milligram. This is relevant to cell-based assays, where endotoxin contamination can confound results.

Our guide to reading a certificate of analysis goes through a complete report line by line.

Related compounds

Retatrutide sits at one end of a family of incretin-receptor peptides that are frequently compared in the literature. Tirzepatide is the GIP/GLP-1 dual agonist from which the design approach descends; it shares the GIP-derived backbone, the Aib substitutions and the C20 diacid lipidation but lacks glucagon receptor activity. Semaglutide is a selective GLP-1 receptor agonist lipidated with a C18 diacid, and remains the most widely characterised reference compound in the class. Cagrilintide is a long-acting amylin analogue, pharmacologically distinct from the incretins, that is studied in combination with semaglutide. The structural and pharmacological differences between them, and what the glucagon component adds, are the subject of our GLP-1 family comparison. Our head-to-head of tirzepatide and GLP-3 compares the dual and triple agonists directly.

Frequently asked questions

Is retatrutide a licensed medicine? No. It is an investigational compound with no marketing authorisation in the UK or elsewhere. The research material sold here is a chemical for in-vitro use and is not for human or veterinary administration.

How does retatrutide differ from tirzepatide structurally? Both are 39-residue, GIP-derived, C20-diacid-lipidated peptides with Aib substitutions. Retatrutide carries additional backbone substitutions that confer glucagon receptor activity, includes an α-methyl-leucine residue, and places its lipidated lysine at position 17 rather than position 20. The molecular weights differ by about 82 Da.

Why does the certificate quote a different mass from the formula weight? Electrospray results are often reported as a monoisotopic mass or a particular charge state rather than the average molecular weight. Both are valid; the certificate should say which it is reporting.

Why is retatrutide supplied in milligram quantities rather than by activity? It is a defined synthetic chemical, so it is characterised by mass and purity. Biological activity at each of the three receptors is determined by the researcher in their own assay.

How long does a sealed vial last? Lyophilised peptides of this class are stable for years at −20 °C and for many months at 2–8 °C. The batch certificate reports the test date; the storage guidance on this page applies from receipt.

References

1. 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. PMID 35985340.
2. Urva S, Coskun T, Loh MT, et al. 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. 2022;400(10366):1869–1881. doi:10.1016/S0140-6736(22)02033-5.
3. 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. PMID 37366315.
4. 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. The Lancet. 2023;402(10401):529–544. doi:10.1016/S0140-6736(23)01053-X. PMID 37385280.
5. 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. Nature Medicine. 2024;30(7):2037–2048. doi:10.1038/s41591-024-03018-2.
6. Eli Lilly and Company. Lilly's triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial (TRIUMPH-1). Press release, 21 May 2026. investor.lilly.com.
7. Eli Lilly and Company. Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C (TRIUMPH-2 and TRIUMPH-3). Press release, 23 July 2026. investor.lilly.com.

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.