Retatrutide

Retatrutide is a triple-agonist peptide that activates GIP, GLP-1, and glucagon receptors simultaneously, while tirzepatide is a dual agonist targeting only GIP and GLP-1 receptors. The addition of glucagon receptor agonism in retatrutide is designed to increase hepatic energy expenditure and lipid oxidation, potentially producing greater weight loss and liver fat reduction. Phase II data showed up to 24.2% body weight loss with retatrutide, compared to approximately 22.5% with tirzepatide at similar timepoints.

The Phase II trial published in the New England Journal of Medicine in 2023 showed dose-dependent weight loss of up to 24.2% at 48 weeks in participants with obesity but without diabetes. This exceeded results from all previously reported single-agent anti-obesity therapies. The most common adverse events were gastrointestinal (nausea, diarrhoea, vomiting), consistent with incretin-based mechanisms.

Glucagon receptor activation stimulates hepatic glycogenolysis, lipid oxidation, and thermogenesis, increasing total energy expenditure. This complements the appetite suppression from GLP-1R agonism and the insulin-sensitising effects of GIPR agonism. The glucagon component is particularly relevant for reducing hepatic steatosis (fatty liver), as it directly promotes liver fat catabolism, an effect not achieved by GLP-1 or GIP agonism alone.

Following positive Phase II results, Eli Lilly initiated the Phase III TRIUMPH clinical programme, evaluating retatrutide across obesity, type 2 diabetes, and MASH indications. These large-scale trials are expected to provide the data necessary for regulatory submissions. Retatrutide is administered as a once-weekly subcutaneous injection due to its fatty acid acylation enabling extended plasma half-life.