Non-invasive tests after semaglutide for MASH serve as disease activity readouts, not treatment response biomarkers

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with significant morbidity, often leading to cirrhosis and liver failure. Semaglutide, a GLP-1 receptor agonist, has demonstrated efficacy in MASH, improving histological endpoints like inflammation and ballooning, and sometimes fibrosis. However, the gold standard for diagnosis and monitoring, liver biopsy, is invasive and impractical for routine use. Non-invasive tests (NITs) are increasingly used to identify at-risk MASH, but their utility in monitoring treatment response to agents like semaglutide remains a subject of debate.

This publication is a letter to the editor, offering a critical perspective on the interpretation of non-invasive tests (NITs) following semaglutide treatment for Metabolic dysfunction-associated steatohepatitis (MASH). The authors analyze existing clinical trial data, including insights from the ESSENCE trial (which studied 2.4 mg semaglutide), and the physiological effects of GLP-1 receptor agonism to argue for a nuanced understanding of NIT results in a treated context. They do not present new experimental data but rather provide a conceptual framework for clinical practice.

The authors contend that while semaglutide effectively improves MASH histology, including quantitative fibrosis, non-invasive tests (NITs) may not accurately reflect these specific treatment-induced changes. They argue that NITs, which often rely on markers of inflammation, steatosis, and fibrosis, primarily serve as readouts of disease activity rather than direct biomarkers of treatment response to GLP-1 receptor agonists. This distinction is crucial because GLP-1 agonists like semaglutide exert pleiotropic effects, improving metabolic parameters and reducing lipotoxicity, which might not immediately or directly translate into changes detectable by current NITs designed for untreated MASH.

The letter emphasizes that NITs should be viewed as tools to identify ongoing MASH activity in treated patients, rather than precise measures of how well a specific drug intervention is working to reverse histological damage. They suggest that improvements in quantitative fibrosis histology observed with semaglutide (especially with durations ≥16 weeks) might not always correlate with changes in NIT scores, highlighting a potential disconnect between histological improvement and NIT-based assessment.