Encyclopedia

Retatrutide is an investigational triple hormone receptor agonist, developed by Eli Lilly, that simultaneously activates the GIP, GLP-1, and glucagon receptors. It produced the largest pharmacological weight loss recorded to date in a phase 2 trial (24.2% at 48 weeks). It is NOT yet FDA-approved -- it remains in phase 3 (the TRIUMPH program) as of this review, and claims of approval circulating in some vendor/marketing material are inaccurate.

Retatrutide (LY3437943) is a synthetic ~39-amino-acid peptide built on a GIP receptor agonist backbone, engineered to also activate the GLP-1 and glucagon receptors, making it the first-in-class 'triple G' (GIP/GLP-1/glucagon) agonist. It binds human GCGR, GIPR, and GLP-1R with reported EC50 values of 5.79, 0.0643, and 0.775 nM respectively. Unlike dual GIP/GLP-1 agonists such as tirzepatide, the added glucagon receptor activity contributes a thermogenic and energy-expenditure component: despite glucagon receptor activation normally raising blood glucose, retatrutide produces net glucose lowering because the GLP-1 and GIP effects predominate. A phase 2 trial (NEJM 2023) reported up to 24.2% mean body weight loss at 48 weeks (12 mg dose) -- the most substantial pharmacological weight loss recorded to date, with weight curves still declining at study end; newer 68-week data have reported up to 28.7% loss at the highest dose. As of this review, retatrutide is still completing phase 3 trials (the TRIUMPH program) and has NOT received FDA approval; some vendor/marketing sources inaccurately state it is FDA-approved, which should be disregarded.

Mechanism of Action

Simultaneous agonist at three G-protein-coupled receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). GLP-1R activity slows gastric emptying, enhances satiety, and reduces appetite; GIPR activity enhances glucose-dependent insulin secretion and supports beta-cell function; GCGR activity adds a thermogenic, energy-expenditure-raising component not present in dual GIP/GLP-1 agonists. The combined GLP-1/GIP insulinotropic effect outweighs glucagon's glucose-raising tendency, producing net glucose lowering.