Semaglutide is associated with stiffness improvement and broad liver benefits with distinct dose- and weight-linked patterns

Abstract Semaglutide has shown benefit in metabolic dysfunction-associated steatohepatitis (MASH), but real-world evidence across longitudinal liver phenotypes remains limited. Using a de-identified federated electronic health record network, we analyzed 6734 semaglutide-treated patients with pre-existing liver disease. Higher attained semaglutide dose in the pre-landmark period (0–2 years from first prescription) was associated with lower post-landmark (2–4 years) risk of all-cause mortality, steatohepatitis, and alcoholic liver disease. Higher magnitude weight loss during the pre-landmark period was associated with lower post-landmark risk of steatohepatitis, steatotic liver disease, and hepatorenal syndrome. In a complementary longitudinal analysis of 326 adults with repeated non-invasive liver elastography measurements before and after semaglutide initiation, median liver stiffness decreased from 4.85 [3.02–7.20] to 3.9 [2.6–5.8] kPa (median change = −0.38 kPa; p < 0.001), with 194 of 326 patients (59.5%) showing lower post-treatment stiffness. A clinically meaningful reduction of at least 20% was observed in 133 of 326 patients (40.8%), and 69 of 326 (21.2%) shifted to a lower fibrosis stage by prespecified elastography thresholds. Larger improvements were seen in patients with higher baseline stiffness ( p < 0.001), with 80% of patients with cirrhosis-range baseline stiffness (≥12.5 kPa) achieving ≥20% improvement versus 29.5% with minimal baseline disease ( p < 0.001). The proportion achieving at least 20% stiffness improvement was similar across weight-loss strata, and liver stiffness change showed negligible correlation with changes in weight, BMI, hemoglobin A1c, alanine aminotransferase, or aspartate aminotransferase. Single-cell RNA-sequencing analyses demonstrated sparse overall hepatic GLP1R expression in non-parenchymal cell types. Together, this real-world evidence motivates future randomized clinical trials to assess diverse primary or secondary hepatoprotective effects of semaglutide.