Retatrutide

Retatrutide (LY3437943) is a single-molecule triple agonist that simultaneously activates three incretin and metabolic hormone receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). This triple mechanism differentiates it from dual agonists like tirzepatide, which target only GIP and GLP-1 receptors.

GLP-1R activation suppresses appetite centrally via hypothalamic signalling, slows gastric emptying, and enhances glucose-dependent insulin secretion from pancreatic beta cells. GIPR co-agonism amplifies the insulinotropic and appetite-suppressive effects while potentially improving beta-cell function and lipid metabolism. The addition of glucagon receptor agonism recruits a third axis: hepatic energy expenditure. Glucagon stimulates hepatic glycogenolysis and gluconeogenesis, but critically also promotes lipid oxidation and thermogenesis in both liver and brown adipose tissue, increasing total energy expenditure beyond what appetite suppression alone can achieve.

The peptide is acylated with a C20 fatty acid moiety that enables albumin binding, extending its plasma half-life to support once-weekly dosing. The balanced activity ratios across all three receptors are engineered to maximise weight loss efficacy while maintaining glycaemic safety.

Retatrutide was developed by Eli Lilly and Company as a next-generation metabolic peptide therapy. The rationale for triple agonism emerged from the clinical success of tirzepatide (a GIP/GLP-1 dual agonist), combined with preclinical evidence that adding glucagon receptor agonism could enhance energy expenditure and hepatic lipid metabolism beyond what dual agonism achieved.

The first-in-human Phase I trial was completed in 2022, demonstrating dose-dependent weight loss and acceptable tolerability. In 2023, the pivotal Phase II trial (published in the New England Journal of Medicine) reported that retatrutide produced up to 24.2% body weight loss at 48 weeks at the highest dose, which exceeded results from all previously studied single-agent anti-obesity therapies. The trial also demonstrated significant improvements in glycaemic control, hepatic steatosis (fatty liver), and cardiometabolic risk markers. Phase III trials (TRIUMPH programme) were initiated in late 2023 to evaluate retatrutide across obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH).