Retatrutide (LY3437943) is a novel investigational triple-hormone receptor agonist developed by Eli Lilly that activates the GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and glucagon receptors. It represents the next generation of incretin-based therapies beyond dual agonists like tirzepatide (GIP/GLP-1). By combining three complementary mechanisms—GLP-1 for appetite suppression and glucose control, GIP for enhanced metabolic effects and insulin sensitivity, and glucagon for increased energy expenditure and fat oxidation—retatrutide produces profound weight loss that exceeds current approved obesity medications. In Phase 2 clinical trials (2023), retatrutide achieved up to 24% body weight reduction in obese adults over 48 weeks, making it one of the most effective weight-loss medications ever tested. It is currently in Phase 3 development for obesity and type 2 diabetes. Retatrutide is administered once weekly via subcutaneous injection and is designed for long-term chronic use.
5-7 days
Subcutaneous injection
4
~4700 Da (estimated)
Retatrutide works through coordinated activation of three hormone receptors: (1) GLP-1 receptor agonism: Stimulates glucose-dependent insulin secretion from pancreatic beta cells, suppresses glucagon release, slows gastric emptying, and acts on hypothalamic appetite centers to reduce hunger and food intake; (2) GIP receptor agonism: Enhances insulin secretion in a glucose-dependent manner, improves insulin sensitivity, modulates adipose tissue function, and may have neuroprotective effects on appetite regulation; (3) Glucagon receptor agonism: Increases energy expenditure, stimulates lipolysis (fat breakdown) and fatty acid oxidation in liver and adipose tissue, enhances thermogenesis, and promotes hepatic glucose output reduction under fed conditions. The combination of these three mechanisms creates a synergistic effect: GLP-1 and GIP components drive appetite suppression and metabolic optimization, while glucagon component increases energy expenditure and fat burning. This triple action results in greater weight loss than GLP-1 or dual GIP/GLP-1 agonists alone. Retatrutide is engineered for once-weekly dosing with a long half-life achieved through modifications that resist enzymatic degradation and enhance albumin binding.
Retatrutide is in active Phase 3 clinical development by Eli Lilly (2023-2025). Phase 2 trials published in high-impact journals (Lancet, NEJM) demonstrated exceptional efficacy for weight loss (up to 24%) and glycemic control. Safety profile consistent with GLP-1 class. Phase 3 trials (TRIUMPH program) ongoing for obesity and type 2 diabetes. Expected regulatory submission 2025-2026 if trials successful. Represents cutting-edge obesity pharmacotherapy research.
Synthetic peptide with modifications for prolonged half-life