Retatrutide (revision 13)
Old revision·04:30, 5 Nov 2024·CagriCass
| 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 |
| 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% |
References
- ^ a b c 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 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.