Retatrutide (revision 23)
Old revision·00:45, 26 Apr 2025·ManualOfStyleMo
| 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}}
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.