Retatrutide (development code: LY3437943) is an investigational peptide therapeutic developed by Eli Lilly and Company. It is classified as a triple receptor agonist because it simultaneously activates three distinct G protein-coupled receptor systems: the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GcgR).
How It Differs from Existing Agents
Semaglutide (Ozempic, Wegovy) is a GLP-1 receptor monoagonist. Tirzepatide (Mounjaro, Zepbound) is a dual GLP-1/GIP receptor agonist. Retatrutide adds glucagon receptor agonism to this combination, making it the first triple agonist to reach Phase 3 clinical development in humans.
Mechanism of Action
GLP-1 receptor agonism suppresses appetite via central hypothalamic pathways, slows gastric emptying, and stimulates glucose-dependent insulin secretion. This is the primary mechanism shared with semaglutide and tirzepatide.
GIP receptor agonism potentiates insulin secretion in a glucose-dependent manner, reduces glucagon secretion, and may enhance adipose tissue metabolism and fat oxidation. This mechanism is shared with tirzepatide.
Glucagon receptor agonism is unique to retatrutide among approved or late-stage agents. Glucagon receptor activation increases hepatic glucose production, stimulates thermogenesis, and increases resting energy expenditure. It also promotes hepatic fat oxidation, which may explain the pronounced effects on liver fat observed in early studies.
Development Status
Retatrutide is currently in Phase 3 clinical development under the TRIUMPH trial program. It is not FDA approved and is not commercially available. It is investigational only.