SYNERGY-OUTCOMES: Retatrutide & Tirzepatide MASH Outcomes Trial

Q: 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).

Trial registered: September 2025 · Phase 3 master protocol · 4,500 participants · MASLD/MASH

SYNERGY-OUTCOMES is the first event-driven Phase 3 trial designed to test whether incretin-based therapies can prevent Major Adverse Liver Outcomes (MALO) in adults with high-risk metabolic dysfunction-associated steatotic liver disease (MASLD), including those with metabolic dysfunction-associated steatohepatitis (MASH). First posted in September 2025 under NCT07165028, it is one of the most ambitious liver disease trials ever designed — evaluating both retatrutide and tirzepatide versus placebo in the same master protocol.

Headline Facts

Property	Value
Trial name	SYNERGY-OUTCOMES
Sponsor	Eli Lilly and Company
NCT ID	NCT07165028
Phase	3
Design	Master protocol — retatrutide vs. tirzepatide vs. placebo
Indication	High-risk MASLD / MASH
Enrollment target	~4,500 participants
Treatment duration	~224 weeks (~4.3 years)
Primary endpoint	Prevention of Major Adverse Liver Outcomes (MALO)
Status	Recruiting
Estimated primary completion	August 2030
Estimated study completion	August 2032

Why This Trial Is Different

1. First event-driven MASLD outcomes trial. Previous MASLD/MASH drug trials have relied on histological surrogates — liver biopsy changes in steatosis, inflammation, or fibrosis scores. SYNERGY-OUTCOMES is the first to use clinical events (decompensation, liver-related death, transplant) as the primary endpoint. This is the gold standard for outcomes research.

2. Head-to-head with tirzepatide. Most Phase 3 trials test a single drug against placebo. SYNERGY-OUTCOMES tests both retatrutide (triple agonist) and tirzepatide (dual agonist) in the same trial, with placebo control. This will produce one of the first apples-to-apples comparisons of dual vs. triple agonist efficacy on long-term liver outcomes.

3. Massive enrollment, long duration. 4,500 participants over ~4 years gives the trial statistical power to detect rare events. MASLD affects ~25-30% of adults globally, but only a fraction develop the serious liver outcomes (cirrhosis, hepatocellular carcinoma, liver-related death) that the trial measures.

4. Could reshape standard of care. If either drug reduces MALO, it would be the first incretin-based therapy with formal outcomes data in MASLD. Currently, the only FDA-approved MASH drug (resmetirom, Madrigal's Rezdiffra, approved March 2024) acts solely on the liver via THR-β agonism. Retatrutide and tirzepatide would address both obesity and liver disease simultaneously, attacking the underlying metabolic driver.

Where SYNERGY-OUTCOMES Fits

Retatrutide's liver evidence chain is:

Phase 2 MASLD sub-study — completed; up to ~82% liver fat reduction 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 mechanistic case for retatrutide in MASLD is unusually strong:

Phase 2 obesity trial: Retatrutide reduced liver fat by up to 82% at 48 weeks in participants with MASLD at baseline (Jastreboff et al., NEJM 2023, secondary analysis).
Preclinical: A February 2026 paper in Obesity (Briand et al.) showed retatrutide reduced hepatic triglycerides by ~50% in diet-induced obese MASH mouse and hamster models, alongside 31% weight loss and improved insulin resistance.

These are among the largest liver fat reductions reported for any drug class. The unanswered question is whether such large reductions translate to fewer real-world liver events over years of treatment — which is exactly what SYNERGY-OUTCOMES is built to answer.

How SYNERGY-OUTCOMES Compares to Other Liver Trials

Trial	Drug	Endpoint	Population	Duration
MAESTRO-NASH	Resmetirom (Madrigal)	Histology (MASH resolution + fibrosis)	Biopsy-confirmed MASH	52 weeks
Phase 2 MASLD sub-study	Retatrutide (Lilly)	MRI-PDFF liver fat	MASLD (obesity parent trial)	24–48 weeks
LIVERAGE	Survodutide (BI / Lilly)	Histology	MASH (Breakthrough Therapy)	~52 weeks
SYNERGY-OUTCOMES	Retatrutide + Tirzepatide (multi-agent master)	Clinical events (MALO)	High-risk MASLD/MASH	~224 weeks

What to Watch

First interim analysis likely 2027-2028 as enrollment completes and follow-up accumulates.
Retatrutide vs. tirzepatide differential within SYNERGY-OUTCOMES will be one of the most-watched data signals in incretin medicine.
TRIUMPH-5 (separate from this liver program) is the head-to-head obesity trial vs tirzepatide and will answer weight-loss ranking.

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 ClinicalTrials.gov in September 2025 and is currently 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?

Not directly. The expected 2026 retatrutide FDA filing is supported by the obesity (TRIUMPH-1, -2, -3, -4) and diabetes (TRANSCEND-T2D-1) trials. SYNERGY-OUTCOMES would generate long-term liver outcomes data to support post-approval labeling expansions and reinforce the cardiometabolic/liver positioning.

Sources

ClinicalTrials.gov: NCT07165028 — SYNERGY-OUTCOMES
Briand, F., et al. (February 25, 2026). Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models. Obesity. DOI: 10.1002/oby.70155
Jastreboff, A.M., et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. DOI: 10.1056/NEJMoa2301972

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.

How we keep this honest

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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Sources