The changing landscape in the management of MAFLD/MASH

23rd November 2025, A/Prof Chee L Khoo

liver fibrosis

Patients used to be given tacit recommendations about lifestyle changes for metabolic dysfunction associated fatty liver disease (MAFLD) because it’s “just a little fat in the liver”. For those of us who have that few patients with those liver as well as non-liver complications, we will remember how horrible these patients fare moving forward. There are a few simple steps for us to perform to predict who is likely to have fibrosis and who doesn’t. We reviewed the topic a few months ago when we looked at the FIB-4 score. It is important to find these patients who has more than just fatty liver. Many of these patients may have significant hepatic fibrosis or metabolic dysfunction associated steatohepatitis (MASH) or both. There aren’t any treatments that will reverse patients with F3 and many patients will progress to F4. Well, up until now.

MAFLD may cause liver injury and inflammation and can lead to liver fibrosis. Liver fibrosis is graded from F0 (no fibrosis) to F1 (mild fibrosis), F2 (significant fibrosis), F3 (advanced fibrosis) and F4 (equivalent to cirrhosis). The gold standard for grading is liver biopsy although we now have non-invasive tests to quantify the fibrosis.

Once MASH (also known has non-alcoholic steatohepatitis (NASH)) progresses to clinically meaningful fibro­sis (stages F2 and F3) the risk of adverse clinical outcomes markedly increases, especially among patients with type 2 diabetes (1-4). Early identification of people at higher risk of adverse liver-related outcomes provides an opportunity for intervention to reduce disease progression and enable referral for specialist hepatology care before liver related complications develop. Aggressive lifestyle measures, management of dyslipidaemia and T2D may prevent development of MAFLD and MASH but once advanced F2 or F3 is present, we don’t have a lot of agents to reverse the fibrosis. Two agents have been demonstrated in Phase 3 trials to reverse F3 to F2 without worsening the fibrosis.

Resmetirom is an oral, liver-directed, thyroid hormone receptor beta (THR-β)–selective agonist in clinical development for the treatment of NASH. In NASH, THR-β function in the liver is impaired, which leads to a reduction in mitochondrial function and β-oxidation of fatty acids in association with an increase in fibrosis. Data from phase 2 and 3 trials have supported the potential efficacy and safety of resmetirom in adults with NASH (5-8).

MAESTRO-NASH is an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2 or F3 (9). 966 eligible patients were randomised to either 80mg resmetiron, 100mg resmetiron or placebo. ~60% of the participants had F3 fibrosis and ~30% were in F2.

NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo).

Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The LDL-C reduced by −13.6% in the 80-mg resmetirom group and −16.3% in the 100-mg resmetirom group compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo).

Resmetiron was approved by the US FDA in March 2024 for treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. It has yet to be approved by the TGA in Australia.

The ESSENCE trial was an ongoing phase 3, multicentre randomised, double-blind, placebo-controlled trial comparing once weekly subcutaneous 2.4 mg semaglutide injection with placebo over 240 weeks in patients with biopsy confirmed MASH and fibrosis stage F2 or F3 (10). After 72 weeks, the planned interim results were published in the NEJM in May 2025. Resolution of NASH without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (P<0.001). A reduction in liver fibrosis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (P<0.001). While the preliminary results looks very promising for semaglutide in the treatment of MASH, especially for reduction of fibrosis, the full results in relation of the regression from F3 to F2 or less has yet to be released.

Resmetiron appears to clearly demonstrate a regression from the stages of fibrosis and improvement in lipid profile but semaglutide has the advantage of other benefits – reduction in HbA1c, body weight, blood pressure, lipids and CRP as well. We also know from other studies on the beneficial effects of semaglutide on cardiovascular (CV) and renal outcomes (11,12). Remember, patients with MAFLD have high CV and chronic kidney disease risks.

Resmetiron may take longer to get TGA approval as it is a new drug while semaglutide 2.4mg is already approved for management of obesity and T2D and may have a significantly shorter path to approval by the TGA.

References:

  1. Dulai PS, Singh S, Patel J, et al. In[1]creased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: sys[1]tematic review and meta-analysis. Hepatology 2017;65:1557-65.
  2. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, associates with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149(2):389-97.e10.
  3. Huang DQ, Wilson LA, Behling C, et al. Fibrosis progression rate in biopsy proven nonalcoholic fatty liver disease among people with diabetes versus people without diabetes: a multicenter study. Gastroenterology 2023;165(2):463-472.e5.
  4. Targher G, Tilg H, Byrne CD. Nonalcoholic fatty liver disease: a multisys[1]tem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol Hepatol 2021;6:578-88.
  5. Taub R, Chiang E, Chabot-Blanchet M, et al. Lipid lowering in healthy volunteers treated with multiple doses of MGL3196, a liver-targeted thyroid hormone receptor-β agonist. Atherosclerosis 2013;230:373-80.
  6. Harrison SA, Taub R, Neff GW, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med 2023;29:2919-28 (https://www.nature.com/articles/s41591-023-02603-1).
  7. Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019;394:2012-24.
  8. Harrison SA, Bashir M, Moussa SE, et al. Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH. Hepatol Commun 2021;5:573-88.
  9. Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024 Feb 8;390(6):497-509.
  10. Sanyal AJ, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025 Jun 5;392(21):2089-2099.
  11. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Dec 14;389(24):2221-2232.
  12. Perkovic V, Tuttle KR, Rossing P, et al; FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024 Jul 11;391(2):109-121.