Retatrutide (LY3437943)

What Is Retatrutide?

Retatrutide (LY3437943) is a synthetic acylated peptide engineered by Eli Lilly as the world’s first GIP/GLP-1/glucagon triple receptor agonist. It simultaneously activates GIPR, GLP-1R, and GCGR — adding the energy-expenditure-boosting glucagon receptor mechanism to the proven appetite-suppressing dual incretin approach of tirzepatide.

Key Mechanisms

• GLP-1R agonism — suppresses NPY/AgRP in hypothalamus; slows gastric emptying; drives glucose-dependent insulin secretion
• GIPR agonism — amplifies GLP-1R weight loss effects; modulates bone, kidney, cardiovascular biology
• GCGR agonism — increases resting energy expenditure via BAT thermogenesis (UCP-1); drives hepatic fat mobilisation; key differentiator from dual agonists

Clinical Trial Results

• 24.2% body weight reduction at 12mg weekly over 48 weeks (Phase II, NEJM 2023)
• Responder rate ≥5% loss at 12mg: >96%
• HbA1c −2.02% vs −0.27% placebo in T2D (Lancet 2023)
• Significant NASH/liver fat reduction (Phase II EASL 2023)

Key References

1. Jastreboff AM et al. “Triple-Hormone-Receptor Agonist Retatrutide for Obesity.” N Engl J Med, 2023;389(6):514–526.
2. Rosenstock J et al. “Retatrutide for type 2 diabetes.” Lancet, 2023;402:529–544.