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Scientific deep-dive

Retatrutide for MASH and MASLD: What the Phase 2a Liver-Fat Data Show

Retatrutide is NOT FDA-approved. Only human MASLD data is a Phase 2a substudy (Sanyal 2024 Nat Med, n=98) by MRI-PDFF: -82.4% mean liver-fat reduction at 12 mg vs +0.3% placebo at 24 wk, 86% normalized. No Phase 3 trial. Framed vs Rezdiffra (MAESTRO-NASH) and Wegovy (ESSENCE).

By Eli Marsden · Founding Editor
Editorially reviewed & fact-checked against primary sources · How we verify contentLast reviewed
13 min read·11 citations

The honest answer: Retatrutide is not FDA-approved for MASH, MASLD, or anything else. The only human data in fatty liver disease is a single Phase 2a substudy (n=98) measuring liver fat by MRI-PDFF at 24 weeks [1]. There is no Phase 3 retatrutide-in-MASH trial reported as of {article.lastUpdated ?? article.publishedDate}.

At a glance

  • Retatrutide is Eli Lilly’s investigational triple GIP/GLP-1/glucagon receptor agonist. It is not approved for any indication, including MASH/MASLD.
  • The only human MASLD data is Sanyal et al., Nat Med 2024 (PMID 38858523) — a 48-week Phase 2a substudy in 98 adults with obesity and ≥10% liver fat[1].
  • At 24 weeks, mean relative liver-fat reduction was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), −82.4% (12 mg) vs +0.3% placebo (all P < 0.001)[1].
  • Liver fat normalization (<5%) at 24 weeks: 27% / 52% / 79% / 86% across the four doses vs 0% placebo[1].
  • The Sanyal Phase 2a used MRI-PDFF, not biopsy. MASH resolution and fibrosis improvement endpoints were not assessed.
  • The current FDA-approved option for biopsy-confirmed MASH with F1B–F3 fibrosis is Rezdiffra (resmetirom), approved March 2024[11]. Semaglutide (Wegovy) was approved for MASH in August 2025 based on ESSENCE Phase 3 [3].
  • Compounded retatrutide for MASH is not a legitimate pathway — it is not on the FDA bulk substances list, has no FDA-reviewed safety package, and is in active investigation.

What MASH and MASLD mean

MASLD (metabolic dysfunction-associated steatotic liver disease) is the 2023 nomenclature for what used to be called NAFLD — excess fat accumulation in the liver (≥5% of hepatocytes) in a patient with at least one cardiometabolic risk factor (overweight/obesity, type 2 diabetes, hypertension, dyslipidemia). MASH (metabolic dysfunction-associated steatohepatitis) is the more advanced form: fatty liver plus inflammation and hepatocyte injury (ballooning) on biopsy. MASH can progress through fibrosis stages F1 → F2 → F3 → F4 (cirrhosis), with higher-stage fibrosis driving the liver-related mortality risk. See our Wegovy MASH evidence review for the terminology change in detail and the ESSENCE Phase 3 results.

Where retatrutide stands

Retatrutide is investigational. The Phase 3 obesity program (TRIUMPH) is in flight; TRIUMPH-4 read out in December 2025 for obesity + knee osteoarthritis. There is no dedicated Phase 3 retatrutide-in-MASH trial publicly disclosed as of {article.lastUpdated ?? article.publishedDate}. The only human MASLD evidence is the Sanyal Phase 2a substudy nested within the parent obesity Phase 2 program[1]. For the broader retatrutide evidence base (Phase 2 weight loss, TRIUMPH-4, mechanism, and access considerations), see our retatrutide triple-agonist evidence review and the TRIUMPH-1 before-and-after evidence.

What Sanyal Phase 2a showed

Sanyal et al., Nat Med 2024 (PMID 38858523), reported a randomized, double-blind, placebo-controlled Phase 2a substudy of once-weekly subcutaneous retatrutide in adults with obesity-related MASLD[1]. Verified design and results:

  • Sample size: n = 98 (substudy of the 48-week Phase 2 obesity trial in participants with MASLD and ≥10% liver fat)
  • Doses: 1 mg, 4 mg, 8 mg, 12 mg subcutaneously once weekly, or placebo
  • Duration: 48 weeks of dosing
  • Primary endpoint: mean relative change from baseline in liver fat by MRI-PDFF at 24 weeks

Mean relative change in liver fat at 24 weeks was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), −82.4% (12 mg) versus +0.3% with placebo (all P < 0.001 vs placebo)[1]. Liver-fat normalization (defined as <5%) at 24 weeks was achieved by 27% / 52% / 79% / 86% of participants across the four reta arms versus 0% on placebo[1].

Magnitude comparison

Mean relative change in liver fat (MRI-PDFF) from baseline at 24 weeks — retatrutide Phase 2a MASLD substudy (Sanyal 2024, Nat Med, n=98). Values are absolute magnitude of percent change. All retatrutide arms P < 0.001 vs placebo. Note: placebo arm showed a +0.3% increase (rendered here as 0.3 for chart legibility).[1]

  • Placebo0.3 % LF change
    +0.3% (slight increase)
  • Retatrutide 1 mg42.9 % LF reduction
  • Retatrutide 4 mg57 % LF reduction
  • Retatrutide 8 mg81.4 % LF reduction
  • Retatrutide 12 mg82.4 % LF reduction
    highest dose; 86% achieved <5% LF
Mean relative change in liver fat (MRI-PDFF) from baseline at 24 weeks — retatrutide Phase 2a MASLD substudy (Sanyal 2024, Nat Med, n=98). Values are absolute magnitude of percent change. All retatrutide arms P < 0.001 vs placebo. Note: placebo arm showed a +0.3% increase (rendered here as 0.3 for chart legibility).

Two important caveats: (1) the primary endpoint was measured by MRI-PDFF, an imaging biomarker for liver fat content, not by paired liver biopsy. MASH resolution and fibrosis improvement — the histologic endpoints the FDA has used to approve resmetirom and semaglutide for MASH — were not assessed. (2) The Phase 2a abstract does not break out adverse-event or discontinuation rates within the MASLD substudy specifically; safety data for the parent obesity Phase 2 are in Jastreboff 2023 NEJM (PMID 37366315).

FDA-approved comparator: resmetirom (Rezdiffra), MAESTRO-NASH

On March 14, 2024 the FDA granted accelerated approval to resmetirom (Rezdiffra), a thyroid hormone receptor-beta agonist, as the first drug ever approved for MASH[11]. Approval was based on MAESTRO-NASH (Harrison et al., NEJM 2024, PMID 38324483; NCT03900429), a Phase 3 trial of 966 adults with biopsy-confirmed MASH and F1B, F2, or F3 fibrosis[2].

  • NASH resolution with no worsening of fibrosis at week 52: 25.9% (80 mg) / 29.9% (100 mg) vs 9.7% placebo (P < 0.001 for both)[2]
  • Fibrosis improvement ≥1 stage with no worsening of NAFLD activity score: 24.2% (80 mg) / 25.9% (100 mg) vs 14.2% placebo (P < 0.001 for both)[2]

Resmetirom is currently the only drug approved on a histologic MASH endpoint via paired biopsy. It is indicated for adults with non-cirrhotic MASH and moderate-to-advanced (F2/F3) fibrosis.

Cross-trial vs semaglutide ESSENCE Phase 3

Sanyal et al., NEJM 2025 (ESSENCE, PMID 40305708), reported the 72-week interim analysis of Phase 3 semaglutide 2.4 mg weekly in adults with biopsy-confirmed MASH and F2/F3 fibrosis [3]. Verified key findings:

  • Resolution of steatohepatitis without worsening of fibrosis: 62.9% semaglutide vs 34.3% placebo (estimated difference 28.7 percentage points; 95% CI 21.1–36.2; P < 0.001)[3]
  • Reduction in fibrosis without worsening of steatohepatitis: 36.8% vs 22.4% (difference 14.4 pp; P < 0.001)[3]
  • Mean body-weight change: −10.5% vs −2.0% placebo [3]

ESSENCE supported the August 2025 FDA approval of Wegovy for non-cirrhotic MASH with moderate-to-advanced fibrosis — the first GLP-1 with an FDA-approved liver indication.

Cross-trial vs tirzepatide SYNERGY-NASH Phase 2

Loomba et al., NEJM 2024 (SYNERGY-NASH, PMID 38856224), reported the 52-week Phase 2 trial of tirzepatide in 190 adults with biopsy-confirmed MASH and F2/F3 fibrosis[4]. Verified primary endpoint:

  • MASH resolution without worsening of fibrosis : 44% (5 mg) / 56% (10 mg) / 62% (15 mg) vs 10% placebo (P < 0.001 for all)[4]

Tirzepatide has not yet received an FDA-approved MASH indication; a Phase 3 program is ongoing.

How retatrutide’s liver-fat signal sits in context

The retatrutide Phase 2a numbers are striking on the MRI-PDFF endpoint — up to 82.4% mean relative liver-fat reduction at the 12 mg dose, with 86% of participants reaching the <5% normalization threshold by 24 weeks[1]. But MRI-PDFF reduction is not the same endpoint as the histologic MASH-resolution and fibrosis-improvement endpoints the FDA uses to approve MASH drugs. Resmetirom, semaglutide, and tirzepatide all carry biopsy-based readouts; retatrutide has only an imaging biomarker in MASLD so far. Whether the Phase 2a liver-fat signal will translate into histologic MASH resolution and fibrosis improvement in a Phase 3 trial is currently unknown.

Preclinical mechanism support

Two recent animal studies support a plausible biological rationale for retatrutide in MASH:

  • Viebahn 2025 (Am J Physiol Gastrointest Liver Physiol, PMID 41056349): in an accelerated mouse model of diet-induced steatohepatitis with a fructose binge, retatrutide improved steatohepatitis histology[5].
  • Briand 2026 (Obesity, PMID 41741376): in two-species (mouse and hamster) diet-induced obese MASH models, retatrutide produced multiple metabolic benefits[6].

These are preclinical findings. They establish biological plausibility but do not predict efficacy in humans. Reviews of the broader anti-obesity-drug landscape in MASLD (Concepción- Zavaleta 2025[7]), GLP-1-based medications (Son 2026 [8]), glucagon-receptor pharmacology (Elmendorf 2026 [9]), and engineered multi-agonist design (Cho 2026 [10]) all flag retatrutide as a high-interest candidate but consistently note the absence of Phase 3 MASH outcome data.

What is not yet known

  1. No Phase 3 retatrutide-in-MASH trial has been reported as of {article.lastUpdated ?? article.publishedDate}.
  2. No biopsy-confirmed histologic endpoint. The Sanyal Phase 2a used MRI-PDFF only. MASH resolution and fibrosis improvement — the endpoints the FDA has consistently required for MASH drug approval — have not been assessed for retatrutide.
  3. No liver-outcome data. There is no published retatrutide data on cirrhosis development, hepatocellular carcinoma, liver transplantation, or all-cause mortality in MASH patients.
  4. No head-to-head trial. There is no randomized comparison of retatrutide vs resmetirom, semaglutide, or tirzepatide in MASH.
  5. Safety in MASH-specific populations. The Sanyal Phase 2a was nested in the obesity trial. Glucagon receptor agonism raises mechanistic questions specifically relevant to hepatic and glycemic safety that will need dedicated MASH-population characterization.

Practical takeaway

For a patient with biopsy-confirmed MASH and moderate-to-advanced fibrosis (F1B–F3) who wants pharmacologic treatment today, the FDA-approved options are resmetirom (Rezdiffra) — approved specifically on a MASH histologic endpoint — and semaglutide 2.4 mg (Wegovy), approved August 2025 for non-cirrhotic MASH with moderate-to-advanced fibrosis based on ESSENCE Phase 3[3]. Tirzepatide has promising Phase 2 SYNERGY-NASH data but is not yet FDA-approved for MASH[4].

Retatrutide is investigational and not currently prescribable for MASH. Compounded retatrutide is not a legitimate access pathway — it is not on the FDA bulk substances list, has not been through FDA review, and is in active clinical investigation. Patients interested in retatrutide for fatty liver disease should discuss enrolling in a clinical trial with a hepatologist rather than seeking compounded supply.

Patients worried about GLP-1 effects on the liver should also see our review of the question do GLP-1s cause liver damage — the trial evidence consistently shows reduced liver fat and improved liver enzymes, not harm.

Further reading

Key terms, explained

New to GLP-1s? Tap any term for a quick, plain-English definition.

Frequently Asked Questions

No. Retatrutide is investigational and not FDA-approved for any indication, including MASH or MASLD. The only human MASLD data is a Phase 2a substudy (Sanyal et al., Nat Med 2024, PMID 38858523) in 98 adults using MRI-PDFF as the endpoint. There is no Phase 3 retatrutide-in-MASH trial reported as of 2026. Talk to a hepatologist about FDA-approved options.
Sanyal 2024 (PMID 38858523) randomized 98 adults with obesity and at least 10% liver fat to once-weekly retatrutide at 1, 4, 8, or 12 mg or placebo for 48 weeks. The primary endpoint was mean relative change in liver fat (MRI-PDFF) at 24 weeks: -42.9% / -57.0% / -81.4% / -82.4% across the four doses vs +0.3% placebo (all P < 0.001). Liver fat normalization (<5%) was achieved by 27% / 52% / 79% / 86% of participants. MASH resolution and fibrosis improvement were not assessed because biopsy endpoints were not part of the substudy. Treatment decisions should be made with your prescriber based on FDA-approved options.
MRI-PDFF (proton density fat fraction) is an imaging biomarker that quantifies liver fat content non-invasively. A liver biopsy assesses steatosis, inflammation, hepatocyte ballooning, and fibrosis stage histologically. The FDA has consistently required biopsy-based endpoints (MASH resolution and fibrosis improvement) to approve drugs for MASH. The Sanyal Phase 2a used MRI-PDFF only, which is why retatrutide's striking liver-fat numbers cannot be directly translated into the FDA-relevant MASH-resolution endpoint. Ask your hepatologist which endpoint applies to your situation.
Two: resmetirom (Rezdiffra), approved March 2024 for non-cirrhotic MASH with moderate-to-advanced fibrosis (F1B-F3) based on the MAESTRO-NASH Phase 3 trial (Harrison 2024 NEJM, PMID 38324483); and semaglutide 2.4 mg (Wegovy), approved August 2025 for the same indication based on the ESSENCE Phase 3 trial (Sanyal 2025 NEJM, PMID 40305708). Discuss eligibility, side effects, and access with your prescriber.
Cross-trial comparisons are not head-to-head and use different endpoints. Retatrutide Phase 2a showed up to 82.4% mean liver fat reduction by MRI-PDFF at 24 weeks (Sanyal 2024). Semaglutide ESSENCE Phase 3 showed 62.9% MASH resolution by biopsy at 72 weeks vs 34.3% placebo (Sanyal 2025 NEJM). Tirzepatide SYNERGY-NASH Phase 2 showed 44 to 62% MASH resolution by biopsy at 52 weeks vs 10% placebo (Loomba 2024 NEJM). These are different populations, different endpoints, and different durations — not a head-to-head efficacy ranking. Your prescriber can weigh the evidence in context of your medical history.
Compounded retatrutide is not a legitimate pathway for treating MASH or MASLD. Retatrutide is in active clinical investigation, is not on the FDA bulk substances list, and has not been through FDA safety review. Patients interested in retatrutide for fatty liver disease should discuss clinical-trial enrollment with a hepatologist rather than seeking compounded supply.
Eli Lilly has not publicly announced a dedicated Phase 3 retatrutide-in-MASH trial as of 2026. Any approval would require a Phase 3 trial with biopsy-confirmed histologic endpoints (MASH resolution, fibrosis improvement), followed by FDA review. No timeline is publicly available. Discuss current treatment options with your prescriber.
Not directly. A large reduction in MRI-PDFF measured liver fat is mechanistically encouraging but does not by itself prove the histologic MASH resolution and fibrosis improvement endpoints that the FDA has used to approve resmetirom and semaglutide for MASH. The relationship between MRI-PDFF reduction and histologic outcomes is being studied; a Phase 3 retatrutide-in-MASH trial with paired biopsies would be required to establish efficacy on the FDA-relevant endpoint. Talk to your hepatologist about what endpoint matters for your situation.
The Sanyal Phase 2a abstract does not break out adverse-event or discontinuation rates specifically within the MASLD substudy. Safety data for the parent Phase 2 obesity program are in Jastreboff 2023 NEJM (PMID 37366315) and were predominantly gastrointestinal, mild to moderate, and dose-dependent — consistent with the incretin drug class. Full Phase 3 retatrutide safety data are still being assembled; discuss any specific concerns with your prescriber.
Retatrutide is a triple GIP/GLP-1/glucagon receptor agonist, and the glucagon-receptor component is a leading mechanistic reason it is of interest for fatty liver: glucagon-receptor agonism is thought to increase hepatic fat oxidation and energy expenditure, on top of the substantial weight loss driven by the GLP-1 and GIP arms. In the Phase 2a MASLD substudy (Sanyal 2024, PMID 38858523) this translated into large MRI-PDFF liver-fat reductions of up to ~82% at 24 weeks, and preclinical MASH models are directionally consistent. Importantly this remains investigational and mechanism-level — reducing imaging-measured liver fat is not the same as the biopsy-confirmed MASH resolution the FDA requires, and glucagon-receptor agonism also raises hepatic and glycemic safety questions that dedicated MASH trials still need to answer. Discuss FDA-approved options with a hepatologist.

References

  1. 1.Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, Harris C, Schloot NC, Du Y, Mather KJ, Haupt A, Hartman ML. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024. PMID: 38858523.
  2. 2.Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, Labriola D, Moussa SE, Neff GW, Rinella ME, Anstee QM, Abdelmalek MF, Younossi Z, Baum SJ, Francque S, Charlton MR, Newsome PN, Lanthier N, Schiefke I, Mangia A, Pericàs JM, Patil R, Sanyal AJ, Noureddin M, Bansal MB, Alkhouri N, Castera L, Rudraraju M, Ratziu V; MAESTRO-NASH Investigators. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024. PMID: 38324483.
  3. 3.Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, Cali AMG, Bugianesi E, Rinella ME, Roden M, Ratziu V; ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025. PMID: 40305708.
  4. 4.Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, Yoneda M, Behling C, Cummings OW, Tang Y, Brouwers B, Robins DA, Nikooie A, Bunck MC, Haupt A, Sanyal AJ; SYNERGY-NASH Investigators. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024. PMID: 38856224.
  5. 5.Viebahn GK, Hartmann P, Schaefer L, Roeb E, Roderfeld M. Retatrutide improves steatohepatitis in an accelerated mouse model of diet-induced steatohepatitis with a fructose binge. Am J Physiol Gastrointest Liver Physiol. 2025. PMID: 41056349.
  6. 6.Briand F, Sulpice T. Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models. Obesity (Silver Spring). 2026. PMID: 41741376.
  7. 7.Concepción-Zavaleta MJ, Quiroz-Aldave JE, Coronado-Arroyo JC, Concepción-Urteaga LA, Paz-Ibarra J. Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review. World J Gastroenterol. 2025. PMID: 41025003.
  8. 8.Son JW. Novel GLP-1-based Medications for Type 2 Diabetes and Obesity. Endocr Rev. 2026. PMID: 41054801.
  9. 9.Elmendorf AJ, Hodson DJ, Tomas A. IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes. Pharmacol Res. 2026. PMID: 41478576.
  10. 10.Cho YK, Lee YH. Engineered nutrient-stimulated hormonal multi-agonists for precision targeting of obesity and metabolic disorders. Clin Mol Hepatol. 2026. PMID: 41297910.
  11. 11.U.S. Food and Drug Administration. FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease (Rezdiffra / resmetirom). FDA Press Announcement, March 14, 2024. 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease

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