Retatrutide
Triple agonist (GLP-1/GIP/glucagon) in Phase III trials showing up to 24% body weight reduction.
🔬 Mechanism of Action
Retatrutide (LY3437943) is a triple agonist peptide that simultaneously activates GLP-1, GIP, and glucagon receptors — making it the first triple-action incretin therapy. While GLP-1 and GIP agonism provide the established weight loss mechanisms (appetite suppression, insulin sensitization, gastric slowing), the addition of glucagon receptor activation introduces a third metabolic lever: increased hepatic fatty acid oxidation and energy expenditure.
Phase II trial data demonstrated up to 24.2% body weight reduction at 12 mg, already surpassing semaglutide and tirzepatide. In December 2025, Phase III TRIUMPH-4 results (68 weeks, adults with obesity + knee osteoarthritis) showed 28.7% weight loss at the 12 mg dose and 26.4% at 9 mg — setting a new benchmark for any pharmacological weight loss agent. Retatrutide has a 6-day half-life, supporting once-weekly dosing.
Source: PMID: 37351564 (Phase II)
📜Background & History
Retatrutide (LY3437943) represents the third generation of incretin therapy — a triple agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. Developed by Eli Lilly, Phase II results (NEJM 2023) reported 24.2% weight reduction at 48 weeks with 12 mg dose — the highest ever recorded for a pharmacological agent. The glucagon component uniquely increases hepatic fat oxidation and energy expenditure, a mechanism absent in dual agonists. Phase III TRIUMPH trials are ongoing as of 2026.
🎯 Research Use Cases
- ✓Severe obesity treatment requiring maximum efficacy
- ✓Non-alcoholic fatty liver disease (NAFLD/NASH) — strong hepatic fat reduction
- ✓Type 2 diabetes with metabolic syndrome and cardiovascular risk
- ✓Research protocols seeking superior weight loss vs tirzepatide
💉 Dosing Protocol
| Typical Dose | 1-12 mg/week |
| Frequency | 1× weekly |
| Half-Life | ~144 hours (6 days) |
| Common Vial Sizes | 5 mg, 10 mg |
🧪 Reconstitution Example
⚠️Safety & Considerations
Retatrutide is an investigational drug in Phase III clinical trials (TRIUMPH program). It is not yet FDA-approved. Compounded versions are available through licensed pharmacies. Side effect profile is consistent with other incretin therapies (nausea, diarrhea, decreased appetite — predominantly during dose escalation). Not recommended during pregnancy.
⚡Interactions & Contraindications
Investigational — same MTC/MEN2 contraindications class expected. Glucagon agonism may affect blood glucose more dynamically than GLP-1/GIP alone; closer glucose monitoring required in diabetic patients. Not combined with other incretin agents.
🔗Synergies & Common Stacks
Potential GI tolerability support during aggressive dose escalation protocols.
❓ Frequently Asked Questions
How is retatrutide different from tirzepatide?▼
What is the retatrutide dose escalation?▼
Is retatrutide FDA-approved?▼
📖 References
- Jastreboff AM, et al. “Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial.” N Engl J Med (2023). PMID: 37351564