Retatrutide

Retatrutide (LY3437943) is a 39-amino-acid triple agonist of the GLP-1, GIP, and glucagon receptors. The peptide carries a fatty-acid moiety for albumin binding and once-weekly pharmacokinetics, and the receptor balance is engineered for substantial agonism at all three targets — distinguishing it from selective GLP-1 agonists and from GIP/GLP-1 dual agonists.

The glucagon receptor arm is the principal mechanistic distinction. Hepatic glucagon receptor activation increases energy expenditure, promotes hepatic fatty acid oxidation, and reduces hepatic steatosis in preclinical models. The combination of glucagon-driven energy expenditure with incretin-driven appetite suppression is the hypothesized basis for the larger weight-loss effects reported in Phase 2 trials.

Receptor potency reports indicate near-equipotent GLP-1 and glucagon activity with somewhat lower GIP potency, though formulations vary across the published literature.

Research Applications

• Triple-incretin receptor pharmacology research in metabolic and hepatic models.
• Glucagon receptor contribution to energy expenditure and hepatic lipid handling.
• Comparative studies against dual agonists (tirzepatide) and selective GLP-1 agonists.
• Hepatic steatosis and NAFLD/MASH translational research.