New Therapies Expanding the MASH Treatment Landscape

One year after the first therapy for patients with liver scarring due to fatty liver disease was approved by the FDA, a new review argues the treatment of metabolic dysfunction–associated steatohepatitis (MASH) is likely to shift in important ways. The report was published in the International Journal of Endocrinology.¹

Both MASH and the less-severe metabolic dysfunction–associated steatotic liver disease (MASLD) are common and complicated diseases, the authors said. MASLD, which was previously known as nonalcoholic fatty liver disease, affects an estimated 30% of the global population, they noted.² Additionally, patients with the disease often have other metabolic comorbidities, including obesity, diabetes, and high blood pressure. MASH (long known as NASH) is a more serious form of the disease. Liver damage associated with MASH can lead to fibrosis, cirrhosis, or hepatocellular carcinoma, the authors explained.

The FDA approval of resmetirom approval has “profound implications” for the care of MASLD and MASH because it allows those conditions to be managed with a liver-specific therapy in addition to lifestyle modifications. | Image credit: Nisit - stock.adobe.com

One well-documented way to manage the diseases is through lifestyle changes and weight loss, but pharmaceutical approaches have taken on greater importance in recent years given the difficulty of achieving sustained weight loss and the availability of new therapies.

For instance, glucagon-like peptide-1 (GLP-1) receptor agonists, which have made waves as therapies for diabetes and obesity, appear to hold promise for patients with MASLD and MASH, the authors said. One study found that 59% of patients with NASH who received semaglutide (Ozempic or Wegovy; Novo Nordisk) at a dose of 0.4 mg saw their NASH resolve without worsening fibrosis at 72 weeks, compared with 17% in the placebo group.³ Forty-three percent of patients in the therapeutic group saw their fibrosis stage improve.

Another approach is dual and triple agonists targeting multiple metabolic pathways, the authors said, including tirzepatide (Mounjaro; Eli Lilly), a GLP-1/gastric inhibitory polypeptide (GIP) dual receptor agonist, and retatrutide, a GLP-1/GIP/glucagon receptor agonist. Research suggests both therapies may prove beneficial in patients with MASH.

The investigators noted that peroxisome proliferator-activated receptor agonists—which work by modulating lipid metabolism, insulin sensitivity, and fibrosis progression—are also valuable in MASH therapy. Fibroblast growth factor analogs and sodium glucose transport protein 2 inhibitors have also emerged as potential therapeutic options, they noted.

However, the most significant advance in recent years may be the FDA approval of resmetirom (Rezdiffra; Madrigal Pharmaceuticals) in 2024. The therapy is a thyroid hormone receptor beta agonist that works by stimulating lipid metabolism, thereby reducing lipid accumulation and fibrosis.

In the pivotal phase 3 trial of resmetirom, patients with biopsy-confirmed NASH and stage F1B, F2, or F3 fibrosis were given the therapy or placebo. Approximately one-quarter of patients in both the 80-mg therapy group and the 100-mg therapy group had fibrosis improvement of at least 1 stage without worsening of NASH, compared to 14.2% in the placebo group.⁴

The resmetirom approval has “profound implications” for the care of MASLD and MASH because it allows those conditions to be managed with a liver-specific therapy in addition to lifestyle modifications, the authors explained.

“By reducing hepatic fat content, resmetirom aims to resolve NASH and mitigate fibrosis, which is expected to significantly improve patient outcomes,” they wrote. “For those with advanced fibrosis, the drug may reduce the need for liver transplants and other invasive interventions.”

The investigators said resmetirom may also lower the overall cost of care for patients with MASH; however, they said that will depend in part on the drug’s pricing and reimbursement policies.

“The approval’s implications extend into health care policy, diagnostic practices, and ongoing research, underscoring resmetirom’s role in managing NASH and potentially influencing the future landscape of metabolic disease treatment,” they concluded.

References

1. Polyzos SA, Targher G. Hepatic thyroid hormone receptor-β signalling: mechanisms and recent advancements in the treatment of metabolic dysfunction-associated steatohepatitis. Diabetes Obes Metab. 2025;27(4):1635-1647. doi:10.1111/dom.16117
2. Amini-Salehi E, Letafatkar N, Norouzi N, et al. Global prevalence of nonalcoholic fatty liver disease: an updated review meta-analysis comprising a population of 78 million from 38 countries. Arch Med Res. 2024;55(6):103043. doi:10.1016/j.arcmed.2024.103043
3. Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. doi:10.1056/NEJMoa2028395
4. Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000