Retatrutide Protocol Guide
Retatrutide (LY3437943) is Eli Lilly's investigational triple-receptor agonist that simultaneously activates GIP, GLP-1, and glucagon receptors. In Phase 2 trials (JAMA 2023), participants achieved up to 24.2% body weight loss at 48 weeks — the highest weight loss demonstrated by any anti-obesity peptide. The glucagon receptor component provides unique benefits including enhanced hepatic fat oxidation (up to 86% liver fat reduction), increased energy expenditure, and thermogenesis. This protocol covers the 1-12mg weekly titration, GI management, metabolic monitoring, and stacking considerations.
Protocol Overview
- Compound
- Retatrutide (LY3437943)
- Category
- Triple Incretin / Glucagon Receptor Agonist
- Mechanism
- GIP receptor agonism (insulin sensitization), GLP-1 receptor agonism (appetite suppression, glucose regulation), glucagon receptor agonism (hepatic fat oxidation, thermogenesis, energy expenditure)
- Half-Life
- ~6 days (weekly dosing)
- Route
- Subcutaneous
- Frequency
- Once weekly
- Cycle
- Ongoing (with titration over 16-20 weeks)
Dosing — Titration Schedule
| Phase | Weeks | Dose | Notes |
|---|---|---|---|
| Initiation | 1-4 | 1 mg/week | Establish GI tolerance |
| Escalation 1 | 5-8 | 2 mg/week | Moderate appetite suppression begins |
| Escalation 2 | 9-12 | 4 mg/week | Significant weight loss phase |
| Escalation 3 | 13-16 | 8 mg/week | Enhanced metabolic effects |
| Maintenance | 17+ | 8-12 mg/week | Maximum efficacy dose; 12mg showed 24.2% loss |
Inject subcutaneously in abdomen, thigh, or upper arm. Same day each week. Slow titration is critical — extend any phase by 2-4 weeks if GI side effects are not tolerable. Do not skip titration steps.
Timeline
Side Effects & Stacking
Side Effects
- Nausea (most common, dose-dependent, improves with time)
- Diarrhea, especially during titration
- Vomiting (less common with slow titration)
- Decreased appetite (therapeutic effect)
- Constipation (alternating with diarrhea in some)
- Injection site reactions (mild)
- Monitor for pancreatitis (rare but serious)
Stacking
- BPC-157: GI protection and healing during GI side effects
- MOTS-C: Additional metabolic and mitochondrial support
- Tesamorelin: Visceral fat synergy (use cautiously)
- NAD+: Metabolic and cellular energy support
- Note: Do NOT stack with other GLP-1 agonists (semaglutide, tirzepatide)
Blood Work
| Panel | Markers | Timing |
|---|---|---|
| Metabolic | Fasting glucose, HbA1c, fasting insulin, HOMA-IR | Baseline, Week 8, 16, 24 |
| Liver | ALT, AST, GGT, liver ultrasound/FibroScan | Baseline, Week 12, 24 |
| Lipids | Full lipid panel, ApoB, triglycerides | Baseline, Week 12, 24 |
| Pancreatic | Lipase, amylase | Baseline, if symptoms arise |
| Basic | CBC, CMP, thyroid panel | Baseline, Week 12 |
