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Pillar 7 · Research & Future Therapies

MASH research and the therapies coming next

MASH went from no approved drug to two in eighteen months, and the pipeline behind them is dominated by hormone-based therapies. Here is where the leading candidates stand, the push to treat cirrhosis itself, and how to read the trials — including what the endpoints do and don't prove.

Written by Darius A. Schneider, MD, PhD — President & Medical Director, Diabetes & Endocrine Specialists · Board-Certified Endocrinologist (ECNU) · Updated September 2026

Key takeaways

  • Two drugs are approved (resmetirom, 2024; semaglutide, 2025) under accelerated approval — outcome trials must confirm clinical benefit.
  • The leading phase 3 candidates are hormone analogs: FGF21 analogs, dual and triple incretin/glucagon agonists, and pan-PPAR agonists.
  • The biggest unmet need is compensated cirrhosis — trials of several agents are under way.
  • Combination therapy, as in diabetes, is the likely future.

The treatment pipeline

ClassExamplesHow it worksStatus (Sept 2026)
THR-β agonistResmetiromRestores liver thyroid-hormone signaling: fat burning, cholesterol clearanceApproved (F2–F3); cirrhosis outcome trial ongoing
GLP-1 receptor agonistSemaglutideGut hormone: weight loss, insulin sensitivity, less liver fat and inflammationApproved (F2–F3)
GIP/GLP-1 and triple agonistsTirzepatide, retatrutideAdds GIP (and glucagon) signaling for greater weight and liver-fat lossPhase 3 MASH programs
GLP-1/glucagon dual agonistSurvodutideGlucagon increases liver fat burning directlyPhase 3 MASH programs
FGF21 analogsEfruxifermin, pegozafermin, efimosferminAnalogs of a liver-derived metabolic hormone; potent anti-fibrotic signalPhase 3, including compensated cirrhosis
Pan-PPAR agonistLanifibranorInsulin sensitization plus anti-inflammatory and anti-fibrotic effectsPhase 3

Notice the pattern: nearly every leading candidate is a hormone or hormone-receptor drug. The FGF21 analogs are particularly interesting to endocrinologists — FGF21 is a hepatokine, a hormone the liver itself releases to regulate metabolism, and restoring its signal has produced some of the largest fibrosis effects seen in mid-stage trials.

For cliniciansHow to read MASH trials

Accelerated approval rests on two histologic surrogates at 52–72 weeks: resolution of steatohepatitis without fibrosis worsening, and ≥1-stage fibrosis improvement without worsening of steatohepatitis. Placebo response is substantial (10–35%), partly from regression to the mean and inter-pathologist variability — in MAESTRO-NASH the two pathologists' reads differed by several percentage points. Confirmatory endpoints are clinical: progression to cirrhosis, decompensation, transplant, MELD ≥15, and death. Cross-trial comparisons of response rates are unreliable given differing populations (F2 vs F3 mix, diabetes prevalence), durations, and read methodologies. Noninvasive markers (MRI-PDFF, VCTE, ELF) are increasingly used as secondary endpoints and are how we monitor response in practice.

Treating cirrhosis itself

Neither approved drug is indicated for cirrhosis. Patients with compensated MASH cirrhosis have the highest risk of liver events and are the focus of the next wave of trials:

  • Resmetirom — the MAESTRO-NASH OUTCOMES trial in compensated cirrhosis is under way; open-label data have shown reductions in liver stiffness.
  • FGF21 analogs — phase 2 data suggested fibrosis regression in compensated cirrhosis, and phase 3 trials are enrolling.
  • Semaglutide — an earlier phase 2 trial in compensated cirrhosis did not show fibrosis improvement, a reminder that cirrhosis is harder to reverse than earlier fibrosis.

Cirrhosis care, including trial referral, is led by hepatology (see When we refer).

Open questions

  • Outcomes. Will histologic improvement translate into fewer cirrhosis cases, transplants and deaths? Confirmatory trials will tell.
  • Cardiovascular benefit. Semaglutide has proven cardiovascular benefit in high-risk patients; whether liver-directed drugs lower cardiovascular events is unknown.
  • Combination therapy. Pairing a weight-loss drug with a liver-directed one is biologically logical and increasingly common; trial data are limited.
  • Duration. MASH is chronic. What happens after treatment stops is not yet known.
  • Access. The number of people eligible far exceeds current treatment capacity; efficient noninvasive screening in diabetes and primary care is the bottleneck.
Clinical research at our practice. Our physicians also run EndoTrials Clinical Research Center, which conducts studies in diabetes and metabolic disease. Ask us whether a study might fit you.

How we grade evidence. Every intervention carries a plain label — from established, guideline-supported care (A) through moderate (B) and mixed or limited (C) to experimental (D) and insufficient (E). An improvement on a liver biopsy or scan is not the same as fewer cirrhosis cases, heart attacks, or deaths, and we say which we mean.

Questions patients ask

Real questions we hear about new MASH treatments.

Is there a drug that reverses cirrhosis? Grade E
Short answer: Not yet. No drug is approved for MASH cirrhosis; several are in phase 3 trials, and hepatology can advise whether a trial fits.

What the evidence shows

Phase 2 data for FGF21 analogs are encouraging; outcome trials of resmetirom and others in compensated cirrhosis are ongoing.

In our practice

We refer patients with cirrhosis to hepatology and keep treating the metabolic drivers.

EvidenceGrade E
Should I wait for a better drug? Grade B
Short answer: Usually not. Fibrosis can progress, and the approved drugs — and weight loss — work now. New drugs will likely be added to, not replace, today's treatments.

What the evidence shows

Liver-related risk rises steeply from F2 fibrosis; both approved drugs improved fibrosis within about a year to 18 months.

In our practice

We treat with what is proven today and revisit options as new drugs are approved.

EvidenceGrade B

Key references

  1. Rinella ME, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966–1986.
  2. Rinella ME, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797–1835.
  3. Chen VL, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance. Hepatology. 2025;81(1):312–320.
  4. Cusi K, et al. AACE clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings. Endocr Pract. 2022;28(5):528–562.
  5. EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492–542.
  6. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes—2025, Section 4. Diabetes Care. 2025;48(Suppl 1):S59–S85.
  7. Kanwal F, et al. Clinical care pathway for the risk stratification and management of patients with NAFLD. Gastroenterology. 2021;161(5):1657–1669.
  8. Harrison SA, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497–509.
  9. Sanyal AJ, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089–2099.
  10. Loomba R, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299–310.
  11. Loomba R, et al. Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis. Lancet Gastroenterol Hepatol. 2023;8(6):511–522.
  12. Targher G, et al. NAFLD and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(11):903–913.
  13. Mantovani A, et al. NAFLD and risk of incident chronic kidney disease: an updated meta-analysis. Gut. 2022;71(1):156–162.
  14. Mantovani A, et al. NAFLD and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut. 2021;70(5):962–969.
  15. Dulai PS, et al. Increased risk of mortality by fibrosis stage in NAFLD: systematic review and meta-analysis. Hepatology. 2017;65(5):1557–1565.
  16. Lomonaco R, et al. Advanced liver fibrosis is common in patients with type 2 diabetes followed in the outpatient setting. Diabetes Care. 2021;44(2):399–406.
  17. Vilar-Gomez E, et al. Weight loss through lifestyle modification significantly reduces features of NASH. Gastroenterology. 2015;149(2):367–378.
  18. Cusi K, et al. Long-term pioglitazone treatment for patients with NASH and prediabetes or type 2 diabetes mellitus. Ann Intern Med. 2016;165(5):305–315.
  19. Verrastro O, et al. Bariatric–metabolic surgery versus lifestyle intervention plus best medical care in NASH (BRAVES). Lancet. 2023;401(10390):1786–1797.
  20. Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018;14(5):259–269.
Continue across the knowledge base
Treatment → When We Refer → Understanding MASLD → EndoTrials Research →

Questions about new MASH treatments — or a clinical trial?

We follow the research closely and run our own research center. Ask us what fits you.

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