Retatrutide (revision 35)
Old revision·08:42, 3 Jan 2026·AnalyticalAnnie
| RetatrutideInvestigational | |
|---|---|
A GIP-based backbone engineered for balanced activity at three class B receptors. | |
| INN | retatrutide |
| Development code | LY3437943 |
| Class | Triple agonist (GIP/GLP-1/glucagon) |
| Status | Phase 3; not approved |
| Identifiers | |
| CAS Number | 2381089-83-2 |
| Residues | 39 |
| Molar mass | ≈4,731 g·mol⁻¹ |
| Pharmacokinetics | |
| Half-life | ≈6 days |
| Route | Subcutaneous, weekly |
| Compound infobox · conventions | |
Retatrutide (development code LY3437943) is an investigational 39-residue peptide that agonises three class B receptors: the receptor for Glucose-dependent insulinotropic polypeptide, the GLP-1 receptor, and the glucagon receptor. It is not approved for use in any indication and is under phase 3 evaluation.[1]
The rationale for adding glucagon-receptor agonism to a dual incretin agonist is that glucagon increases resting energy expenditure and hepatic fatty-acid oxidation. The obvious objection — that glucagon raises blood glucose — is addressed by dosing the GLP-1 component sufficiently to dominate the net glycaemic effect, making the intramolecular potency ratio the central design problem.[2]
In a 48-week phase 2 trial in adults with obesity and without diabetes, the highest dose studied produced a mean weight change of −24.2% against −2.1% for placebo.[2] That figure comes from a phase 2 trial and should be read with the caution that phase 2 effect sizes in this field have not always been reproduced at phase 3 scale. Material sold as retatrutide by research-chemical suppliers is an unapproved investigational compound; see Research use only.
Design
[edit]Retatrutide shares its GIP-derived architecture with tirzepatide and adds substitutions that restore appreciable activity at the glucagon receptor. Because the three receptors are evolutionarily related and their ligands derive from a common precursor family — see Proglucagon — the sequence space in which all three activities coexist is real but narrow.[1]
Reported in vitro potencies place the molecule closest to native ligand at the GIP receptor, with somewhat lower relative activity at the GLP-1 and glucagon receptors. These ratios are assay-dependent and should be compared only within a single publication's system; cross-publication comparison of receptor ratios is a common error in secondary sources.
Half-life extension uses the established combination of a protease-resistant residue near the N-terminus and a fatty diacid for albumin binding, giving a reported half-life of about six days and supporting weekly dosing.[1]
Reported clinical findings
[edit]The phase 2 obesity trial randomised adults with a body-mass index of 30 or above, or 27 or above with a weight-related condition, to placebo or one of several retatrutide doses with escalation over 24 weeks and treatment to 48 weeks.
| Group | Mean weight change at 48 weeks |
|---|---|
| Placebo | −2.1% |
| 1 mg | −8.7% |
| 4 mg | −17.1% |
| 8 mg | −22.8% |
| 12 mg | −24.2% |
The weight-change curve had not clearly plateaued by 48 weeks at the higher doses, which is unusual in this field and is one reason the phase 3 programme extends further.[2] A separate phase 2 trial in type 2 diabetes reported glycated-haemoglobin reductions of up to about 2.0 percentage points.
These are phase 2 results in selected populations and are not a basis for comparison with approved agents. A phase 2 programme is powered for dose selection rather than for outcome estimation, and the confidence intervals around the larger figures are correspondingly wide.[1]
Safety signals reported to date
[edit]Gastrointestinal events dominated and were dose-related, as expected for the class. Reported nausea rates at the higher doses exceeded those seen with dual agonists, consistent with the larger overall exposure.[2]
Two findings are specific to the glucagon component. A dose-dependent increase in heart rate was reported, larger than the two-to-four beats per minute typical of GLP-1 monotherapy and peaking during escalation before partially receding. Transient rises in fasting glucose were observed at the lowest dose in participants with diabetes, consistent with glucagon agonism outrunning GLP-1 agonism when the total dose is low — the predicted failure mode of the design.
Long-term safety cannot be assessed from a 48-week phase 2 trial. This article will require revision as phase 3 data are published; the {{update}}
Material sold as retatrutide
[edit]Retatrutide has been widely offered by research-chemical suppliers since the phase 2 publication, in advance of any approval anywhere. Because there is no marketed reference product, there is also no reference standard generally available against which an independent laboratory could confirm identity by comparison — a difference from semaglutide and tirzepatide that is rarely acknowledged.[3]
In practice this means identity confirmation rests on mass determination against the calculated mass, which will not distinguish the intended molecule from an isobaric variant, and on retention behaviour that cannot be compared with an authenticated standard. Purity figures on certificates for this compound are therefore weaker evidence than the same figures would be for an approved molecule.[4]
Nothing here should be read as an evaluation of any supplier's material, and this wiki does not represent investigational compounds as suitable for human use.
See also
References
- ^ a b c d 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." Cell Metabolism 34(9):1234–1247 (2022). DOI:10.1016/j.cmet.2022.07.013. PMID 35985340.
- ^ a b c d Jastreboff AM, Kaplan LM, Frías JP, et al. "Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial." New England Journal of Medicine 389(6):514–526 (2023). DOI:10.1056/NEJMoa2301972. PMID 37366315.
- ^ United States Pharmacopeia, General Chapter <1503>, Quality Attributes of Synthetic Peptide Drug Substances.
- ^ PeptidePedia Wiki community test-report tally, 2024–2026 (self-reported; see Project:Sourcing guidelines).
External links
- Retatrutide phase 2 — NCT04881760 — Registry record for the phase 2 obesity trial.