⚖️Retatrutide (LY3437943)
Triple GIP/GLP-1/glucagon receptor agonist. Phase II trial demonstrated 24.2% body weight reduction at 48 weeks — the highest ever recorded for a pharmacological agent.
GIP/GLP-1/Glucagon triple agonistWhat 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
- Jastreboff AM et al. "Triple-Hormone-Receptor Agonist Retatrutide for Obesity." N Engl J Med, 2023;389(6):514–526.
- Rosenstock J et al. "Retatrutide for type 2 diabetes." Lancet, 2023;402:529–544.
Frequently Asked Questions
Tirzepatide is a dual GIP/GLP-1 receptor agonist; retatrutide adds a third mechanism — glucagon receptor (GCGR) agonism — studied for its additional energy-expenditure effects via brown-fat thermogenesis, on top of the appetite-suppressing incretin effects both compounds share.
As of the most recently published data, retatrutide has completed Phase 2 trials (reported in NEJM and The Lancet, 2023) with the 24.2% body-weight-reduction result. It remains a Lilly investigational compound, not an approved medication.
Glucagon receptor agonism increases resting energy expenditure through brown-adipose-tissue thermogenesis (via UCP-1) and promotes hepatic fat mobilisation — mechanisms distinct from simple appetite suppression, which is the main scientific rationale for studying triple agonists like retatrutide versus dual or single agonists.