DAY 3: The 3S Approach to Managing Metabolic Dysfunction-Associated Steatohepatitis: Screen, Stage, Start Therapy

In the era of targeted therapies for metabolic dysfunction-associated steatohepatitis (MASH), inaction is not an option for healthcare providers who manage patients with this condition, according to Naim Alkhouri, MD, chief academic officer at Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology in Cleveland, Ohio. Patients with MASH deserve the highest standard of care, which includes fibrosis screening and staging, followed by initiation of therapy, when indicated. 

“When we think about the goals of MASH management, we want to improve the liver efficacy endpoints, achieve MASH resolution, fibrosis improvement by one stage, and decreased liver enzymes,” Alkhouri said during a plenary session at the 2025 Annual Scientific Meeting of the American College of Gastroenterology in Phoenix, Arizona. “But it is very important to also understand the impact of any intervention on the components of the metabolic syndrome, including weight, hemoglobin A1c, and lipids. Eventually, we would like to improve outcomes, whether those are liver outcomes or cardiac outcomes, as we know that cardiovascular disease is a major cause of mortality in this population. And we always want to keep cost and adverse events in mind.” 

Two therapies targeting MASH with moderate-to-advanced fibrosis have been approved in the United States, based on histopathologic data showing resolution of MASH on repeat biopsy, as well as fibrosis improvement by one stage, without worsening of MASH. Resmetirom, an oral selective thyroid hormone receptor beta (THR-β) agonist, was the first therapy to gain regulatory approval for this indication, followed by glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide, which entered the MASH armamentarium earlier this year. In the phase 3, placebo-controlled, randomized clinical trial MAESTRO-NASH, 888 patients with biopsy-confirmed MASH and stage 2 or 3 fibrosis were treated with 80 mg or 100 mg resmetirom daily for 52 weeks. Resmetirom proved superior to placebo in achieving MASH resolution and reducing fibrosis by one stage, regardless of dose. The THR-β agonist also decreased the levels of atherogenic lipids, including a reduction in low-density lipoprotein cholesterol by 16% in patients treated with the higher dose. Accelerated approval of resmetirom was based on preliminary results up to 52 weeks. However, Alkhouri noted that the study will continue for up to 5 years, at which point a third liver biopsy will be performed to assess for cirrhosis and outcomes such as liver decompensation and transplantation. 

Semaglutide was initially developed for the management of type 2 diabetes, and subsequently gained approval for the treatment of obesity. Its mechanism of action relies on mimicking the GLP-1 hormone, which can lead to improved glycemic control and weight loss. Semaglutide has also shown benefit in decreasing adverse cardiovascular events in patients with known cardiovascular disease. Accelerated approval of this therapy for MASH was based on results from the phase 3 ESSENCE trial, in which 800 patients were treated with semaglutide for 72 weeks. Repeat biopsy showed that semaglutide, administered as a once-weekly subcutaneous injection (2.4 mg), achieved MASH resolution without worsening of fibrosis and improvements in fibrosis without worsening of steatohepatitis in higher proportions of participants than placebo. The most common adverse events associated with both resmetirom and semaglutide were gastrointestinal disturbances, which were self-limited. Nevertheless, discussing the safety profile with patients is an important step leading up to the initiation of therapy, Alkhouri said. 

Noninvasive tools for identifying and staging liver fibrosis, which were used in both pivotal clinical trials, could guide choice and timing of therapy in clinical practice. Vibration-controlled transient elastography (VCTE) and magnetic resonance elastography, as well as enhanced liver fibrosis (ELF) scores, have been used to develop an algorithm that can help providers identify candidates for either semaglutide or resmetirom therapy, based on fibrosis and liver stiffness values. When the results of noninvasive tests are divergent, clinicians should consider a liver biopsy. 

Patients treated with resmetirom are monitored at 3 months, 6 months, and 12 months after initiation of therapy, to confirm safety and tolerability and assess response to treatment. Treatment should be discontinued if there is evidence of intolerability or presence of another liver disease at 6 months or one year after starting treatment. Noninvasive tests should be used to check for reduction in steatosis, liver enzymes, and fibrosis.