Semaglutide for metabolic dysfunction-associated steatotic liver disease in Asian and lean populations

The histologic benefits demonstrated in the phase 3 ESSENCE (Effect of Semaglutide in Subjects with Noncirrhotic Nonalcoholic Steatohepatitis) trial have established semaglutide, a glucagon-like peptide-1 receptor agonist, as a leading pharmacologic option for metabolic dysfunction-associated steatohepatitis. However, the evidence comes predominantly from Western cohorts with high body mass index, raising questions about its generalizability to Asian populations, in whom metabolic dysfunction-associated steatotic liver disease (MASLD) frequently occurs at normal or near-normal body weight (“lean” MASLD). Lean MASLD is a distinct clinical phenotype characterized by visceral adiposity, sarcopenia, and genetic susceptibility rather than generalized obesity; it accounts for a substantial proportion of MASLD in Asia, with a prognosis comparable to or worse than that of non-lean disease. This review synthesizes current evidence for semaglutide in Asian and lean populations with MASLD, examines whether its hepatic benefits depend on weight loss or involve weight-independent mechanisms, and assesses safety considerations specific to lean patients. It identifies the absence of randomized semaglutide trials specifically enrolling Asian patients with biopsy-proven lean MASLD as a central evidence gap and outlines practical approaches to address it, including cohorts assessed with noninvasive endpoints and target trial emulation using national claims data.