Retatrutide
Also known as: LY3437943, Triple G agonist
Overview
Retatrutide is an investigational first-in-class triple agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. Developed by Eli Lilly, it has demonstrated the most impressive weight loss data of any peptide to date — up to 28.7% body weight reduction in the Phase III TRIUMPH-4 trial at 68 weeks. The addition of glucagon receptor agonism (beyond GLP-1 and GIP) targets the liver directly (which lacks GLP-1/GIP receptors but is rich in glucagon receptors), potentially providing unique benefits for NASH/MAFLD treatment through improved hepatic fat oxidation and antifibrotic effects.
Mechanism of Action
Retatrutide activates three receptors: (1) GLP-1R for appetite suppression and incretin insulin secretion; (2) GIP-R for enhanced metabolic effects and reduced GI side effects; (3) Glucagon-R for hepatic effects including enhanced fatty acid oxidation, improved mitochondrial function in liver, improved bile acid profiles, and direct antifibrotic activity. The glucagon component reduces respiratory quotient more strongly than dual agonists, indicating superior fat oxidation. Studies show strongest effects on body weight, food intake, and metabolic markers compared to semaglutide and tirzepatide.
Potential Benefits
- Up to 28.7% body weight reduction in TRIUMPH-4 Phase III trial
- Expected 30%+ weight loss in the 80-week TRIUMPH-1 trial
- Direct hepatic benefits via glucagon receptor (potential NASH treatment)
- Superior fat oxidation (stronger RQ reduction than tirzepatide)
- Cardiovascular risk factor improvement
- Reduced liver fat, AST, ALT, cholesterol
- Improvements in pain and physical function (TRIUMPH-4)
Dosage Protocols
The following reflects doses used in published research studies. This is not medical advice. Consult a qualified healthcare professional.
| Typical Range | 1-12 mg/week (Phase II range) |
| Beginner | 1 mg/week (titration start) |
| Intermediate | 4-8 mg/week |
| Advanced | 8-12 mg/week (Phase II maximum doses) |
| Cycle Duration | Ongoing therapeutic; weekly dose titration |
| Cycle Off | Not designed for cycling; weight regain after discontinuation |
Phase II used 1 mg/week start, titrated to 2 mg (wk 5), 4 mg (wk 9), then optional up to 8 or 12 mg. Triple agonist mechanism (GLP-1/GIP/glucagon) may produce superior weight loss vs dual agonists.
Use our Reconstitution Calculator to determine exact syringe units for your protocol.
Routes of Administration
Subcutaneous Injection High
Once-weekly subcutaneous injection in all Phase 3 trials; standard injection sites (abdomen, thigh, upper arm). Dose titration schedule: 2 mg start, escalating to 4 mg, 9 mg, 12 mg target doses.
Read our full Routes of Administration Guide for detailed comparison of all delivery methods.
Stacking Protocols
Popular research stacks involving Retatrutide:
Metabolic Health Stack
Combines Retatrutide with MOTS-c (mitochondrial metabolism) and AOD-9604 (lipolysis) for metabolic optimization.
Explore our complete Peptide Stacking Guide for more combinations and safety considerations.
Reconstitution
| Typical Vial Size | Pre-filled pen device (clinical trial) |
|---|---|
| BAC Water | N/A for clinical formulation; research vials use 1-2ml BAC water |
| Storage | Refrigerate at 2-8°C |
| Shelf Life | 24 months unopened |
Need exact syringe measurements?
Amino Acid Sequence
Modified peptide with GLP-1/GIP/glucagon receptor binding domains and C20 fatty diacid for albumin binding (~39 amino acids)
Side Effects & Safety
- Nausea, diarrhea, constipation (similar to GLP-1 class)
- Higher discontinuation rate at highest doses (18.2% at 12 mg)
- Excessive lean mass loss concern at very high doses
- Similar GI adverse events as tirzepatide
Safety & Contraindications
This information is for educational purposes only. Consult a qualified healthcare provider before using any peptide.
Pregnancy / Lactation
Bleeding Disorders
Active Skin Infection at Injection Site
Drug Interactions
- Oral Medications (general):
Pharmacokinetics
| Half-Life | ~6 days (fatty acid C20 chain enables once-weekly dosing via albumin binding) |
|---|---|
| Storage | Refrigerate at 2–8°C; do not freeze; protect from light; clinical formulation in pre-filled pen |
Synergistic Compounds
The following compounds have been studied alongside Retatrutide for potential complementary or synergistic effects:
Learn More
References & Further Reading
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