PMID-38858523 – Retatrutide for MASLD Phase 2a Trial (Sanyal 2024)
Sanyal AJ, Bedossa P, Fraessdorf M, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine. 2024;30(7):2037-2048. doi: 10.1038/s41591-024-03018-2. PMID: 38858523. NCT04881760.
Quick Reference
| Property | Value |
|---|---|
| PMID | 38858523 |
| DOI | 10.1038/s41591-024-03018-2 |
| ClinicalTrials.gov | NCT04881760 |
| Year | 2024 |
| Journal | Nature Medicine |
| Study Type | RCT (Phase 2a, randomised, double-blind, placebo-controlled) |
| Evidence Level | Ib (Phase 2a with pre-specified primary endpoint) |
| Sample | n=98 MASLD substudy (liver fat ≥10% by MRI-PDFF at baseline; from broader Phase 2 retatrutide obesity trial) |
| Peptide(s) Studied | Retatrutide (triple GLP-1 / GIP / glucagon receptor agonist) |
Key Findings
Liver fat reduction at 24 weeks (MRI-PDFF, relative change from baseline)
| Dose | Liver fat reduction | Normal liver fat achieved (<5% MRI-PDFF) |
|---|---|---|
| Retatrutide 1 mg weekly | −42.9% | 27% |
| Retatrutide 4 mg weekly | −57.0% | 52% |
| Retatrutide 8 mg weekly | −81.4% | 79% |
| Retatrutide 12 mg weekly | −82.4% | 86% |
| Placebo | ~0% | Minimal |
Metabolic and liver-injury biomarkers
- HOMA2-IR: Up to ~50% reduction from baseline at higher retatrutide doses — substantial improvement in insulin sensitivity.
- K-18 (M65, apoptosis/necroptosis marker): −49.6% at 8 and 12 mg doses — consistent with reduction in hepatocellular injury.
- pro-C3 (fibrogenesis biomarker): −26.4% at 12 mg dose — suggests potential anti-fibrogenic signal; histological fibrosis confirmation pending longer-term / Phase 3 data.
- Liver enzymes (ALT, AST): Dose-responsive improvement across retatrutide arms.
- Body weight: Dose-responsive reduction consistent with parent Phase 2 obesity trial findings.
Safety
- Adverse-event profile consistent with prior retatrutide data: gastrointestinal events (nausea, diarrhea, vomiting) are the predominant class; dose-responsive.
- No new unexpected safety signals at the doses studied in this substudy.
Study Design
Substudy of the Phase 2 randomised, double-blind, placebo-controlled trial of retatrutide in adults with obesity (without T2D). Participants with liver fat ≥10% by MRI-PDFF at baseline were included in this MASLD analysis (n=98). They received once-weekly subcutaneous retatrutide (1 mg, 4 mg, 8 mg, or 12 mg with dose escalation) or placebo for 48 weeks. Liver fat was assessed by MRI-PDFF at baseline, 24 weeks, and 48 weeks. Serum biomarkers of hepatocellular injury (K-18), fibrogenesis (pro-C3), and insulin sensitivity (HOMA2-IR) were measured.
Limitations
- Substudy analysis from a broader obesity trial, not specifically powered for MASLD endpoints
- MRI-PDFF is a validated but imperfect surrogate for histological improvement; not all participants had biopsy data
- Relatively short duration for a liver disease trial; 48-week data may not capture long-term fibrosis regression
- The study did not enroll patients with advanced fibrosis (F3-F4) or cirrhosis, limiting applicability to later-stage disease
- Placebo group was small, reducing statistical power for between-group comparisons at lower doses
Clinical Relevance
This study positions retatrutide as potentially the most effective pharmacotherapy for MASLD studied to date. The 82.4% liver fat reduction and 86% normalization rate at 24 weeks (at 12 mg) dramatically exceed results from dedicated MASLD/MASH trials of other agents including resmetirom (MAESTRO-NASH), pioglitazone, and semaglutide (Newsome 2021). The glucagon receptor agonism component of retatrutide may provide a unique advantage in liver disease through direct stimulation of hepatic lipid oxidation and mitochondrial function, effects not achieved by pure GLP-1 RAs. These results have prompted dedicated Phase 3 MASLD programs of retatrutide.
Distinction from Tirzepatide MASH Evidence
The Sanyal-authored retatrutide MASLD paper (this file, PMID: 38858523) is distinct from the Loomba/Sanyal-authored tirzepatide SYNERGY-NASH paper (PMID-38856224 – Sanyal Tirzepatide MASH Phase 2 SYNERGY-NASH, PMID: 38856224). Both are 2024 NEJM-adjacent publications authored with Sanyal AJ's involvement, but:
- Retatrutide MASLD (this paper, Sanyal AJ first author): MRI-PDFF liver fat reduction in MASLD (broader — ≥10% liver fat by imaging); 82.4% reduction at 12 mg; no biopsy-based fibrosis requirement.
- Tirzepatide MASH (Loomba R first author, Sanyal AJ senior): Biopsy-confirmed MASH with F2/F3 fibrosis; 62% MASH resolution at 15 mg; fibrosis improvement as secondary endpoint.
They address overlapping but distinct clinical spaces and populations. Faculty should cite them separately.
Related
- Retatrutide
- NAFLD
- Weight Management
- PMID-38856224 – Sanyal Tirzepatide MASH Phase 2 SYNERGY-NASH (tirzepatide MASH companion — distinct paper)
Orchestrator Notes
- Citation verified 2026-04-19 per repair task; correct first author Sanyal AJ, second author Bedossa P, third author Fraessdorf M (was previously recorded incorrectly as Engel SS).
- NCT04881760 added.
- Primary reference for Retatrutide MASLD evidence in Lesson 5.4 pipeline section.
#research #RCT #phase-2a #retatrutide #masld #nafld #nature-medicine #evidence-level-Ib