Semaglutide in MASH with F2-F3 fibrosis: a holistic perspective on the ESSENCE phase 3 trial

Metabolic dysfunction-associated steatohepatitis (MASH) with significant fibrosis (F2-F3) is a critical stage of metabolic dysfunction-associated steatotic liver disease (MASLD), during which intervention may avert transition to cirrhosis, hepatocellular carcinoma, and liver-related death. The phase 3 ESSENCE trial (NCT04822181) evaluated once-weekly subcutaneous semaglutide 2.4 mg vs. placebo over 240 weeks in adults with biopsy-confirmed MASH and F2-F3 fibrosis. A prespecified interim histologic assessment was performed at week 72 among the first 800 randomized participants. Semaglutide increased MASH resolution without worsening fibrosis and significantly increased the proportion of individuals achieving ≥ 1-stage fibrosis improvement compared with placebo, with a clinically meaningful number needed to treat. These histologic effects coincided with substantial weight reduction (~10%-11% vs. ~2% with placebo) and broad improvements in cardiometabolic risk profiles, including glycemia, blood pressure, lipid levels, and inflammatory biomarkers. Favorable shifts were also observed in non-invasive assessments, including the enhanced liver fibrosis score, vibration-controlled transient elastography, N-terminal type III Collagen Propeptide (PRO-C3), FibroScan-AST (FAST) score, and aminotransferases. Safety outcomes were consistent with the established semaglutide profile in type 2 diabetes and obesity. Here, we critically appraise ESSENCE from clinical and translational perspectives and consider the relative contributions of weight loss vs. potential weight-independent mechanisms. Semaglutide was also situated among emerging latestage therapies, including resmetirom, a thyroid hormone receptor β agonist with demonstrated antifibrotic and antisteatohepatitic activity. Finally, we outline the implications of adopting semaglutide as a disease-modifying agent in MASH with F2-F3 fibrosis, note the study limitations and remaining questions, and argue that combinatorial approaches targeting complementary metabolic and hepatocentric pathways may define the next phase of MASLD management.