Triple Agonist
A single molecule designed to activate three different receptor types simultaneously. In the metabolic peptide pipeline, GLP-1/GIP/glucagon triple agonists are in clinical development with the aim of achieving even greater weight loss and metabolic improvements than dual agonists. This approach represents next-generation poly-pharmacology.
Technical Context
Triple agonists targeting GLP-1, GIP, and glucagon receptors simultaneously aim to leverage the glucagon receptor's effects on energy expenditure, hepatic lipid metabolism, and appetite suppression alongside the established benefits of GLP-1 and GIP receptor activation. Retatrutide (LY3437943) is the most advanced triple agonist in clinical development, with Phase II results showing mean weight loss of approximately 24% at 48 weeks — surpassing tirzepatide's results. The glucagon component is hypothesised to increase energy expenditure and promote hepatic fat reduction, potentially benefiting NASH as well as obesity. Balancing the three receptor activities to maximise efficacy while managing safety is a key design challenge.