Retatrutide

Category: peptide

Aliases: LY3437943, GLP-3, triple agonist

Pharmacological Mechanism

Triple agonist at GLP-1R, GIP-R, and glucagon receptor. 39-residue peptide with Aib substitutions (positions 2 and 20) and a C-20 fatty diacid linker on Lys(17) via a γGlu-2×OEG spacer that binds albumin, extending t½ into once-weekly territory. Glucagon arm drives additional energy expenditure beyond GLP-1/GIP satiety effects.

Half-Life (t½)

SC: 144h

Dosing Guidelines

SC: Typical 4.67 mg (Range: 1–12 mg)

Target Organ Systems

endocrine
digestive

Notes

Receptor EC50 values (Coskun 2022) reflect in vitro cAMP signaling at human-receptor-expressing HEK293 lines: GLP-1R ~3 pM, GIPR ~10 pM, GCGR ~30 pM. Therapeutic plasma (~50–100 ng/mL = ~0.05–0.1 mg/L) is 4–5 orders of magnitude above EC50, so all three receptors saturate within minutes of any dose and remain occupied throughout the week — the OccupancyTile will show 100% across the dosing interval, which is pharmacologically faithful even if visually static.

Pathways It Modulates

AMPK energy sensor (activator) — AMPK (triple GLP-1/GIP/GCG; weight loss → ↑AMPK)
Brown adipose thermogenesis (activator) — GLP-1/GIP/GCG triple agonist; GCG arm may directly increase BAT activity
FXR / TGR5 bile-acid receptor signaling (activator) — TGR5 indirect (GLP-1/GIP/GCG triple)
GI endocrine peptides (activator) — GLP-1R + GIP-R + glucagon-R (triple agonist)
NAFLD / MASH (activator) — GLP-1/GIP/GCG triple — largest weight loss class; MASH program

Chemical Identifiers

Molecular weight: 4731.33 g/mol