The future of MASLD treatments

Future hepatologists could have numerous drugs for MASLD control and treatment. Promising results from recent trials were presented at EASL 2024.

During the seminar, emphasis was also placed on the need to address MASLD with a multidisciplinary team that deals not only with metabolic-based liver disease but also, together, with other metabolic-based dysfunctions that the patient might present with.


Steatotic liver disease is due to excessive lipid accumulation in hepatocytes. Metabolic dysfunction-associated liver disease (MASLD) includes simple fatty infiltration (a benign condition called steatotic liver disease), while metabolic dysfunction-associated steatohepatitis (MASH) is defined as the presence of fat leading to lipotoxicity and inflammatory damage of hepatocytes.

A major factor in MASLD is hepatic triglyceride overload from expanded and inflamed adipose tissue in the context of insulin resistance, along with increased de novo lipogenesis in the liver. This leads to the formation of lipotoxic species and hepatic damage through endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis.

GLP-1 receptor agonists (GLP-1 RA) for liver diseases

GLP-1 receptor agonists are excellent compounds that increase satiety by reducing food intake and body weight, delay gastric emptying, improve pancreatic beta cell function, and reduce hepatic glucose production. They also offer renal and cardiovascular protection.

In a trial to test Semaglutide (a 72-week Phase 2 study of 320 participants with MASH, fibrosis stage 1, 2 or 3 - interventions: placebo vs semaglutide 0.1, 0.2 or 0.4 mg once-daily subcutaneous), the primary endpoint was resolution of MASH without worsening liver fibrosis, achieved in nearly 60% of patients with high doses of Semaglutide. However, the secondary endpoint of improvement of liver fibrosis without worsening of MASH could not be achieved. The side effects of Semaglutide are well known and are gastrointestinal: nausea, constipation, decreased appetite, but still no serious adverse events.1

Twincretin, which combines the effect of GLP-1 with that of glucagon or GIP, represents another promising therapy for MASLD. The dual GIPR/GLP-1R receptor agonist, Tirzepatide, showed increased resolution of MASH in up to 74% of patients in a Phase 2b trial (patients with biopsy confirmed MASH F2-F3 were randomized 1:1:1 to receive once-weekly subcutaneous injections of placebo or Tirzepatide 5, 10 or 15 mg).2 In another trial, the glucagon/GLP-1 receptor agonist, Survodutide, achieved MASH resolution in 83% of patients at a dose of 4.8 mg (patients with biopsy-confirmed MASH F2-F3 were randomized 1:1:1 to receive once-weekly subcutaneous injections of placebo or Survodutide 2.4, 4.8 or 6 mg).3

Resmetirom, a THR-β agonist approved by FDA for the treatment of MASH F2-F3

Resmetirom is a thyroid hormone receptor beta agonist approved by the FDA for the treatment of MASH F2 and F3. It reduces hepatic fat, resolves MASH, lowers LDL cholesterol and triglycerides, and improves mitochondrial function and reduces damage. In the MAESTRO-NASH trial,4 resolution of MASH with Resmetirom was achieved in up to 30% of patients. Resmetirom is very well tolerated. The most common adverse event is generally mild and transient diarrhea, especially at the beginning of therapy.

Lanifibranor is a Pan-PPAR (PPAR α/δ/γ) agonist

Lanifibranor increases fatty acid oxidation and reduces collagen production from hepatic stellate cells, with anti-inflammatory and antifibrotic action. In the NATIVE Phase 2b trial, Lanifibranor resulted in resolution of MASH in 50% of patients and improvement of fibrosis in 42% (a 24-week, Phase 2b study of 247 participants with MASH and SAF activity ≥2 - interventions: placebo vs pan-PPAR agonist Lanifibranor 800 and 1,200 mg/day oral).5

Fibroblast growth factor 21 pathway

FGF21 regulates energy expenditure and glucose and lipid metabolism. Reduces liver fat by action within liver and from periphery. Impacts liver fibrosis via metabolic pathway and upregulation of adiponectin homeostasis. The pleiotropic effects of FGF21 are mediated by its direct actions in hepatocytes and cardiomyocytes, and/or indirect mechanism through adipocyte-secreted adiponectin or brain-liver crosstall. Native FGF21 has a short half life of < 2 hours.6

Pegozafermin, a long-acting Fc FGF21 fusion protein, showed improvements in fibrosis in 27% of patients (a 24-week RCT in MASH and F2-F3 fibrosis - placebo vs pegozafermin 15 vs 30 mg weekly vs 44 mg every 2 weeks). Efruxifermin, a long-acting FGF21 analog, in the Phase 2b HARMONY trial achieved resolution of MASH in 62% of patients.7

Conclusion: MASLD and MASH treatment in the future

The hepatic and cardiometabolic effects of drugs in late-stage clinical trials show promising results for the treatment of MASLD and MASH, with significant health benefits for patients.

By 2030, in addition to Resmetirom, we are likely to have new drugs for the treatment of MASLD, such as Semaglutide, Lanifibranor, FGF-21 compounds, and twincretin. Interdisciplinary management, including pharmacological management, will be critical, as MASLD and MASH can exacerbate the consequences of metabolic syndrome, leading to type 2 diabetes, cardiovascular disease, and chronic kidney disease.

Professor Bugianesi concluded her seminar by focusing on weight loss. Weight loss, achieved with GLP-1 receptor agonists and FGF-21 compounds for example, is crucial in MASLD therapy, but it is essential to maintain weight loss over the long term. The beneficial effects on the liver are most clearly seen after several years, as demonstrated by bariatric surgery.8

  1. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA; NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021 Mar 25;384(12):1113-1124. doi: 10.1056/NEJMoa2028395. Epub 2020 Nov 13. PMID: 33185364.
  2. 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 Jun 8. doi: 10.1056/NEJMoa2401943. Epub ahead of print. PMID: 38856224.
  3. Sanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E, Anstee QM, Hussain SA, Newsome PN, Ratziu V, Hosseini-Tabatabaei A, Schattenberg JM, Noureddin M, Alkhouri N, Younes R; 1404-0043 Trial Investigators. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. 2024 Jun 7. doi: 10.1056/NEJMoa2401755. Epub ahead of print. PMID: 38847460.
  4. 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 Feb 8;390(6):497-509. doi: 10.1056/NEJMoa2309000. PMID: 38324483.
  5. Sven M F, Pierre B, Manal F A, Quentin M A, Elisabetta B, Vlad R, Philippe HM, Bruno S, Jean-Louis J, Pierre B, Jean-Louis A. A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study. Contemp Clin Trials. 2020 Nov;98:106170. doi: 10.1016/j.cct.2020.106170. Epub 2020 Oct 8. PMID: 33038502.
  6. Loomba R, Sanyal AJ, Kowdley KV, Bhatt DL, Alkhouri N, Frias JP, Bedossa P, Harrison SA, Lazas D, Barish R, Gottwald MD, Feng S, Agollah GD, Hartsfield CL, Mansbach H, Margalit M, Abdelmalek MF. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH. N Engl J Med. 2023 Sep 14;389(11):998-1008. doi: 10.1056/NEJMoa2304286. Epub 2023 Jun 24. PMID: 37356033; PMCID: PMC10718287.
  7. Harrison SA, Frias JP, Neff G, Abrams GA, Lucas KJ, Sanchez W, Gogia S, Sheikh MY, Behling C, Bedossa P, Shao L, Chan D, Fong E, de Temple B, Shringarpure R, Tillman EJ, Rolph T, Cheng A, Yale K; HARMONY Study Group. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2023 Dec;8(12):1080-1093. doi: 10.1016/S2468-1253(23)00272-8. Epub 2023 Oct 3. PMID: 37802088.
  8. Source: Bugianesi E. Treatment of MASLD in 2030: breaking the frontier?. EASL 2024. Thursday, 6 Jun, 08:30 - 09:45 CEST