Finding the Best Match for MASLD Management
, according to the authors of clinical reviews who offered guidance on the pros and cons of resmetirom and semaglutide.
MASLD has become one of the most common causes of chronic liver disease due to the increased prevalence of diabetes, obesity, and other metabolic disorders, Joanne Lin, DO, an internist in the Division of Gastroenterology and Hepatology at the University of California, San Francisco, and colleagues wrote, in a review published in the Journal of Clinical Gastroenterology.
Its complexity makes MASLD challenging to manage. Metabolic, genetic, and environmental factors are involved in the disease, so patients require multidisciplinary and individualized care, Lin told GI & Hepatology News.
Weight loss, dietary changes, and exercise had long been the only treatment approach clinicians could offer patients. But the approval of two drugs — the thyroid hormone receptor-beta agonist resmetirom and the GLP-1 receptor agonist (RA) semaglutide — for patients whose MASLD has advanced to metabolic dysfunction-associated steatohepatitis (MASH) gives physicians new options for patients with severe disease.
In the review, published online before the official approval of semaglutide, Lin and colleagues proposed an algorithm to guide clinicians in choosing a pharmacological therapy for MASLD. “Resmetirom should be primarily used to reverse fibrosis for patients with MASLD and F2-F3 stages, while GLP-1 RAs are beneficial in managing metabolic comorbidities and weight loss in patients with MASLD,” the researchers concluded.
GLP-1 Power and Potential
In August 2025, the FDA approved semaglutide for MASH and cited evidence from the ESSENCE trial in its decision.
The ESSENCE study, published in The New England Journal of Medicine, showed significantly higher rates of resolution of steatohepatitis without worsening of fibrosis and reduction in liver fibrosis without worsening steatohepatitis in patients with MASH and moderate or advanced liver fibrosis who received 2.4 mg of once-weekly semaglutide compared with patients who received placebo.
The most common adverse events reported with GLP-1 RAs are gastrointestinal-related, including nausea, diarrhea, vomiting, and constipation, and are mainly mild-to-moderate and dose dependent, Lin and colleagues noted in their review.
GLP-1s have some limitations, Lin said. “GLP-1s are great for weight loss and metabolic risk reduction, but studies are still ongoing to determine their effect on liver histology and reversing fibrosis/cirrhosis,” she said. Some patients seeking these medications also have trouble obtaining them because of their popularity for weight loss, she noted.
Resmetirom Shows Success
Resmetirom has demonstrated ability to target hepatocytes and increase the hepatic metabolism of lipids, Lin and colleagues wrote in their review.
Several trials have examined resmetirom as a treatment for MASH, notably the landmark MAESTRO-NASH study , a randomized, placebo-controlled trial of nearly 1000 adults with biopsy-confirmed MASH and stage F2 or F3 fibrosis, which was the basis for the FDA’s approval of the drug in 2024. In the study, 25.9% of the patients treated with 80 mg of resmetirom and 29.9% treated with 100 mg resmetirom achieved MASH resolution with no increase in fibrosis compared with 9.7% of patients treated with placebo. In addition, 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group achieved fibrosis improvement by at least one stage without worsening of MASLD activity scores compared with 14.2% of patients treated with placebo.
The most common reported side effects from resmetirom are diarrhea or constipation, nausea or vomiting, and abdominal pain.
“The limitations of resmetirom include the absence of validated predictors for individual patient response, and no societal guidelines are available to determine when to stop the medication if ineffective,” Lin told GI & Hepatology News. In addition, resmetirom is currently only recommended for a subset of patients with F2-F3 fibrosis, based on the existing trial, she said.
Other limitations include its high cost, which restricts access to the drug for some patients, and lack of long-term safety and efficacy data, Lin added.
Weighing the Options
Comparing the emerging agents in the context of MASLD/MASH is important to help clinicians understand how different patient populations respond and guide evidence-based treatment decisions, said Hazem Ayesh, MD, an endocrinologist at Deaconess Health System, Evansville, Indiana, in an interview.
“The choice of therapy should be individualized based on comorbidities,” said Ayesh, the lead author of a 2024 review published in Biomedicines that compared resmetirom, GLP-1 agonists, and fibroblast growth factor 21 analogs.
“For example, a GLP-1 receptor agonist may be more appropriate for patients with coexisting diabetes or obesity, while resmetirom may be better suited for patients with more advanced liver disease or minimal metabolic comorbidities,” he said.
GLP-1 RAs, such as semaglutide, offer benefits for diabetes, obesity, and metabolic dysfunction in patients with MASLD/MASH and may be more accessible and cost effective, Ayesh told GI & Hepatology News. However, some patients may experience gastrointestinal side effects or be unable to tolerate GLP-1 RAs, he noted.
By contrast, resmetirom may be preferable for patients with low BMI, advanced fibrosis, or an inability to tolerate GLP-1s, as resmetirom directly targets hepatic pathways involved in MASLD/MASH progression, Ayesh said.
Next Steps to Inform Practice
“More research is needed to validate noninvasive biomarkers to monitor response to these medications, determine predictors of efficacy, and evaluate the additive effects, safety, and drug-drug interactions of combination therapy,” Lin said.
Studies are needed to determine both medications’ effects on patients with advanced fibrosis/cirrhosis and special populations, such as individuals with advanced renal disease or posttransplant patients, she added. More studies are expected to inform clinical practice and proper guidelines for the treatment of MASLD, as has been the case with chronic diseases such as hypertension and diabetes, Lin said.
Long-term safety and efficacy data are critical, as most trials of the newly approved medications have had relatively short follow-up periods of approximately 1 year, Ayesh said. “We need real-world evidence and longitudinal studies spanning 3-5 years to confirm sustained efficacy and safety,” he said. Research on cost effectiveness and health-system impacts will be essential to guide policy and ensure equitable access to the medications, he added.
The study by Lin and colleagues received no outside funding. The researchers had no financial conflicts to disclose. Ayesh had no financial conflicts to disclose.
A version of this article appeared on Medscape.com.