Retatrutide Mechanism of Action

Retatrutide binds to GLP-1R, GIPR, and GCGR with distinct potency profiles. Research indicates it is most potent at the human GIP receptor (EC50: 0.0643 nM), followed by GLP-1R (EC50: 0.775 nM) and glucagon receptor (EC50: 5.79 nM) . The N-terminal segment drives transmembrane domain engagement while the C-terminal segment interacts with extracellular domains, creating a unique binding geometry. This multi-receptor activation leads to cAMP accumulation, delayed gastric emptying, and altered hepatic glucose output in preclinical models. The C20 fatty-diacid acylation enables albumin binding, extending the half-life to approximately 6 days.