SYNERGY-OUTCOMES: Retatrutide & Tirzepatide MASH Outcomes Trial

Trial registered: February 2026 · 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). Registered in February 2026 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

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

This is one of two retatrutide Phase 3 liver-disease efforts:

• TRIUMPH-5 — Lilly's dedicated retatrutide Phase 3 trial in MASH using histological endpoints (biopsy-based MASH resolution and fibrosis improvement). Smaller, shorter, supports an initial MASH indication filing.
• SYNERGY-OUTCOMES — The follow-on event-driven trial that would generate long-term outcomes data, supporting confirmation of the histology benefits and expanded labeling.

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

What to Watch

• First interim analysis likely 2027-2028 as enrollment completes and follow-up accumulates.
• TRIUMPH-5 readout (histology-based) is the more immediate retatrutide MASH milestone — supporting Lilly's initial MASH indication filing.
• Retatrutide vs. tirzepatide differential within SYNERGY-OUTCOMES will be one of the most-watched data signals in incretin medicine.

For broader retatrutide trial tracking, see our Clinical Trials page.

Frequently Asked Questions

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.