Retatrutide
aka LY3437943
Class Triple GLP-1 / GIP / Glucagon receptor agonist
Status Research-only — Phase 3 complete, NDA expected late 2026, launch ~2027
TL;DR
Most potent pharmacological obesity intervention ever recorded. 28.7% mean body weight loss in Phase 3 — matches bariatric surgery without surgery. The glucagon (GCGR) component is the differentiator: it actively prevents the adaptive thermogenesis that causes plateaus with GLP-1 mono-agonists. Also holds the record for MASLD resolution: 86% liver fat reduction at 12 mg.
Key Facts
| Weight loss | 28.7% mean (Phase 3 TRIUMPH-4, 12 mg, 68 wks) |
| Liver fat reduction | 86% at 12 mg — best MASLD data ever |
| Mechanism | GLP-1R + GIPR + GCGR simultaneous agonism |
| Dosing | SubQ weekly, slow titration: 0.5 → 1 → 2 → 3 → 4 → 6 mg |
| Key risk | +5–10 bpm resting HR; dysesthesia 20.9% at 12 mg |
| Critical stack need | GHK-Cu (skin laxity); XW4475/bimagrumab (lean mass) |
Triple Receptor Pharmacology
| Receptor | Potency vs. endogenous | Primary role |
|---|---|---|
| GIPR | ~8.9× more potent | Insulin synergy, adipose lipid buffering |
| GLP-1R | ~0.4× endogenous | Appetite suppression, satiety, gastric delay |
| GCGR | ~0.3× endogenous | Thermogenesis, hepatic lipolysis — the anti-plateau axis |
Mechanism
- GLP-1R: Hypothalamic appetite suppression; delayed gastric emptying
- GIPR: Subcutaneous adipocyte lipid buffering; prevents ectopic fat deposition
- GCGR: Direct hepatic lipolysis + β-oxidation; increased REE — prevents adaptive metabolic slowdown
- The GCGR axis is why this has no weight-loss plateau
Clinical Highlights
- TRIUMPH-4 (Phase 3): 28.7% weight loss at 12 mg; 39.4% achieved ≥30% loss; 74% knee pain reduction (OA comorbidity)
- MASLD Phase 2a: 93% achieved normal liver fat (<5%) at 12 mg/48 wks
- Lean mass: Preserved proportionally to other GLP-1 agents — lean loss is real. See Retatrutide Lean Mass Preservation for the retatrutide-specific protocol (protein targets, training cadence, catabolism signals, evidence grades). See also Protein Intake GLP-1 Glucagon for the broader GLP-1 class protein intake framework.
- Dysesthesia signal: 20.9% at 12 mg — tingling/numbness on normal touch; under regulatory scrutiny
Stacks
| Partner | Rationale |
|---|---|
| GHK-Cu | Essential — prevents skin laxity from rapid fat loss |
| SLU-PP-332 | GCGR-liberated fatty acids → SLU-PP-332 oxidizes them; endurance without exercise |
| Melanotan II PT-141 | Separate appetite axis (MC4R); counters libido decline during caloric restriction |
| BPC-157 | Angiogenesis support; counteracts NSAID/steroid use for joint pain |
| XW4475 | CRF2 agonist provides chemical anabolism (mTORC1); protects myocardium from catabolic stress during extreme weight loss |
| TB-500 | Anti-sarcopenia: counters 25–45% lean mass loss during GLP-1-driven caloric deficit |
| Berberine | Complementary GLP-1 effect (↑endogenous GLP-1 secretion); monitor for additive glucose-lowering and GI overlap; bradycardia risk is rare but real; Retatrutide note |
| Cannabis | Goal conflict — THC ↑ appetite via CB1; reduces Retatrutide satiety signaling |
Links
- Peptides MOC
- GLP-1 GIP Glucagon (mechanism note)
- XW4475 (CRF2 — ultimate recomposition stack)
- TB-500 (anti-sarcopenia stack)
- Protein Intake GLP-1 Glucagon — Protein intake protocol, DXA monitoring, BUN/urea compliance check, and GLP-1-specific protein targets (1.8–2.2 g/kg); see also mTOR AMPK Muscle Catabolism for the catabolism mechanism
- BPC-157 (tissue repair)
- Cannabis peptide interactions
Source: Gemini Deep Research · TRIUMPH-4 Phase 3 · MASLD Phase 2a · PeptideDosages.com 2026-03-20