Retatrutide (revision 6)

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]

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]