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Retatrutide-Obesity
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling.
Is retatrutide being studied in patients with metabolic dysfunction-associated steatotic liver disease?
Retatrutide is being studied in a phase 3 study to prevent major adverse liver outcomes in adults with high-risk metabolic dysfunction-associated steatotic liver disease (MASLD). The study spans approximately 224 weeks, with an optional 2-year extension.
Content Overview
What is the SYNERGY-Outcomes Phase 3 Study for MASLD?
SYNERGY-Outcomes is an ongoing phase 3 study designed to simultaneously assess retatrutide and tirzepatide treatment for the prevention of major adverse liver outcomes (MALO) in adults with high-risk MASLD. Using a master protocol, participants will be randomly assigned to receive either
- retatrutide,
- tirzepatide, or
- placebo.1
The study will enroll approximately 4,500 adults who have MASLD based on non-invasive tests (NITs), which indicate the participant is more likely to develop MALO. The trial is expected to run for approximately 224 weeks, after which an optional 2-year extension study will be available for eligible participants, who will either remain on active treatment or switch from placebo to retatrutide or retatrutide. Please see SYNERGY-Outcomes Participant Criteria for visual representation.1
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Who is eligible for SYNERGY‑Outcomes?
Inclusion Criteria |
Exclusion Criteria |
Liver biopsy is not needed for study enrollment. |
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Abbreviations: BMI = body mass index; ELF = enhanced liver fibrosis; HbA1c = hemoglobin A1c; kPa = kilopascal; MASLD = metabolic dysfunction-associated steatotic liver disease; VCTE LSM = vibration-controlled transient elastography liver stiffness measurement.
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What are the primary and secondary outcome measures
The primary outcome is the time to first occurrence of any component of the composite endpoint for MALO compared to placebo from baseline up to study completion.1
The composite endpoint includes
- progression to cirrhosis
- development of large esophageal varices, gastric varices, or development of varices needing treatment
- development of ascites
- development of hepatic encephalopathy
- evidence of active or recent variceal hemorrhage
- increase in model for end-stage liver disease (MELD) from ≤12 to ≥15
- liver transplantation, or
- all-cause mortality.1
Secondary outcomes include change from baseline in
- Enhanced Liver Fibrosis (ELF) Score (to Week 104)
- Vibration-Controlled Transient Elastography Liver Stiffness Measurement (VCTE LSM) (to Week 104)
- percent change in liver fat content (to Week 104)
- aspartate aminotransferase (AST) (to study completion)
- alanine aminotransferase (ALT) (to study completion)
- body weight (to study completion), and
- Non-alcoholic steatohepatitis-CHECK Score (NASH-CHECK) (to Week 104).1
In addition, from baseline to study completion, time to
- occurrence of progression to cirrhosis, and
- first occurrence of any component event of the composite endpoint of major adverse cardiovascular events (MACE-3, which includes nonfatal myocardial infarction, nonfatal stroke, cardiovascular death).1
Figure Description: SYNERGY-Outcomes is an ongoing phase 3 study designed to simultaneously assess retatrutide and tirzepatide treatment for the prevention of MALO in adults with high-risk MASLD.
Abbreviations: BMI = body mass index; ELF = enhanced liver fibrosis; HbA1c = hemoglobin A1c; ISA = intervention-specific appendices; kPa = kilopascal; LFC = liver fat content; MALO = major adverse liver outcome; MASLD = metabolic dysfunction-associated steatotic liver disease; MELD = model for end-stage liver disease; NIT = non-invasive test; VCTE LSM = vibration-controlled transient elastography liver stiffness measurement.
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What liver‑fat reductions were observed with retatrutide in participants with MASLD?
A 48-week phase 2a randomized, double-blind, placebo-controlled substudy evaluated the safety and efficacy of retatrutide 1, 4, 8, and 12 mg once weekly compared with placebo in 98 adults with MASLD and ≥10% liver fat (LF). The primary endpoint was mean relative change from baseline in LF at 24 weeks.2
At 24 weeks, participants who received retatrutide had significantly reduced relative LF, with mean relative change from baseline of −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), and −82.4% (12 mg), compared with a 0.3% increase in relative LF for participants who received placebo (p<0.001 for all doses versus placebo).2
Full results are available in the published reference below.
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References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1A master protocol for the randomized, controlled, clinical trial of multiple pharmacologic agents in adults participants with metabolic dysfunction-associated steatotic liver disease who are at increased risk of developing major adverse liver outcomes. ClinicalTrials.gov identifier: NCT07165028. Updated November 5, 2025. Accessed November 21, 2025. https://clinicaltrials.gov/study/NCT07165028
2Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 30, 2037–2048 (2024). https://doi.org/10.1038/s41591-024-03018-2
Date of Last Review: February 23, 2026