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Editorially reviewed · Last updated September 8, 2026 · How we review

SYNERGY-OUTCOMES: Retatrutide & Tirzepatide MASH Phase 3 Trial

SYNERGY-OUTCOMES: Retatrutide & Tirzepatide MASH Outcomes Trial

Trial registered: September 2025 · Phase 3 master protocol · 4,500 participants · MASLD/MASH
SYNERGY-OUTCOMES is an ongoing Phase 3 master protocol testing whether retatrutide and tirzepatide can reduce major adverse liver outcomes in adults with high-risk MASLD. The registry record, NCT07165028, lists a retatrutide subprotocol and a tirzepatide subprotocol, each with its own placebo arm. It does not establish a direct retatrutide-versus-tirzepatide comparison.
No clinical outcome results are posted. The primary completion date is estimated at August 2030, so liver-fat reductions from earlier trials should not be presented as proof that this study has prevented cirrhosis or liver failure.

Headline Facts

PropertyValue
Trial nameSYNERGY-OUTCOMES
SponsorEli Lilly and Company
NCT IDNCT07165028
Phase3
DesignMaster protocol — separate retatrutide and tirzepatide comparisons with placebo
IndicationHigh-risk MASLD / MASH
Enrollment target~4,500 participants
Treatment duration~224 weeks (~4.3 years)
Primary endpointPrevention of Major Adverse Liver Outcomes (MALO)
StatusRecruiting
Estimated primary completionAugust 2030
Estimated study completionAugust 2032

Why This Trial Is Different

1. It measures clinical outcomes. The primary endpoint is time to the first event in a composite that includes progression to cirrhosis, serious liver complications, transplantation, and all-cause death. A change in MRI-measured liver fat is a different outcome.
2. The two medicines have separate placebo comparisons. The registry lists tirzepatide and placebo under TZ01, and retatrutide and placebo under RT01. Readers should not assume that a shared master protocol makes this a head-to-head trial.
3. Follow-up takes years. The planned enrollment is 4,500 participants, with the primary outcome followed for about 224 weeks. The dates are estimates and can change.
4. The question is whether fewer serious events occur. Current treatment options already include FDA-approved medicines for selected adults with MASH and fibrosis. In particular, Wegovy received a MASH indication in August 2025, after resmetirom's 2024 approval. SYNERGY-OUTCOMES will address a different question from an early liver-fat study.

Where SYNERGY-OUTCOMES Fits

Retatrutide's liver evidence chain is:

  • Phase 2 MASLD sub-study — completed; 82.4% mean relative liver fat reduction at 24 weeks with 12 mg on MRI-PDFF (see fatty liver page).
  • SYNERGY-OUTCOMES / NCT07165028 — the Phase 3 multi-agent MASLD master protocol that includes retatrutide (and tirzepatide), using clinical event endpoints (MALO) rather than histology alone.
There is no numbered TRIUMPH liver-disease trial. TRIUMPH-5 is the head-to-head obesity efficacy study of retatrutide vs tirzepatide (NCT06662383). Long-term cardiovascular/kidney outcomes are studied separately in TRIUMPH-Outcomes (NCT06383390).
For full MASH/MASLD context, see our Retatrutide & Fatty Liver Disease page.

What's Expected from the Phase 2 MASH Data

The relevant human evidence is the Phase 2a MASLD substudy published in Nature Medicine in 2024. It included 98 participants from the obesity trial with at least 10% liver fat at baseline. At 24 weeks, the 12 mg group had an 82.4% mean relative reduction in liver fat.

That study measured liver fat by MRI. It did not establish that retatrutide reverses biopsy-confirmed MASH, repairs fibrosis, or prevents liver-related clinical events. SYNERGY-OUTCOMES is designed to investigate longer-term outcomes.

How SYNERGY-OUTCOMES Compares to Other Liver Trials

The Phase 2 retatrutide MASLD study used MRI-measured liver fat as its primary endpoint. SYNERGY-OUTCOMES instead measures time to major adverse liver outcomes. These are complementary kinds of evidence, not interchangeable measures of success.
Biopsy endpoints, such as MASH resolution or fibrosis improvement, are another category. The FDA's Wegovy MASH decision describes both histological findings and the need for ongoing confirmation of clinical benefit.

What to Watch

  • Registry updates: recruitment, estimated completion dates, and any posted results.
  • Separate treatment comparisons: whether retatrutide or tirzepatide reduces the composite endpoint against its assigned placebo control.
  • Endpoint components: a positive composite result would still need to be read alongside its individual liver outcomes and safety data.
For broader retatrutide trial tracking, see our Clinical Trials page.

Frequently Asked Questions

What is SYNERGY-OUTCOMES?

A Phase 3, event-driven master-protocol clinical trial evaluating both retatrutide and tirzepatide versus placebo for the prevention of Major Adverse Liver Outcomes (MALO) in adults with high-risk MASLD/MASH. NCT07165028. ~4,500 participants, ~4.3 years duration.

When did SYNERGY-OUTCOMES start?

The trial was first posted on September 10, 2025, and began on October 15, 2025. The August 2026 registry update lists it as recruiting. Estimated primary completion is August 2030, with study completion estimated in August 2032.

Is SYNERGY-OUTCOMES the same as TRIUMPH-5?

No. TRIUMPH-5 (NCT06662383) is a Phase 3 head-to-head obesity trial of retatrutide vs tirzepatide with a body-weight primary endpoint. SYNERGY-OUTCOMES (NCT07165028) is a separate multi-agent MASLD master protocol using clinical event endpoints (MALO). Long-term CV/kidney outcomes are yet another trial: TRIUMPH-Outcomes (NCT06383390).

Will SYNERGY-OUTCOMES affect retatrutide's FDA approval?

Lilly has described a planned Q1 2027 U.S. submission supported by its obesity program. SYNERGY-OUTCOMES has an estimated primary completion in 2030 and could inform a future liver indication if its results support one. Neither a label expansion nor initial approval is guaranteed.

Sources

Medical disclaimer: Retatrutide and tirzepatide are not FDA approved for MASH. This page is informational only, not medical advice. Always consult a qualified healthcare provider before making decisions about medications. glp3.wiki is not affiliated with Eli Lilly or any pharmaceutical company.
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What this is
Educational information, not medical advice. It reports published research — it doesn’t recommend that you use, obtain, or supply anything.
Regulatory status
Retatrutide and similar peptides are investigational — not approved by the FDA or any regulator. Semaglutide and tirzepatide are prescription-only medicines, available only through a licensed prescriber.
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Grounded in primary sources
NEJMThe LancetJAMAFDAClinicalTrials.gov

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