Post Hoc Analysis of a Phase 2 Randomized Trial of Pemafibrate in Metabolic Dysfunction–associated Steatotic Liver Disease: Associations With Platelet Count, Liver Stiffness, and Spleen Volume

Background Portal hypertension is a major complication in metabolic dysfunction-associated steatotic liver disease (MASLD). In the PEMA-FL phase 2 trial, this post-hoc analysis examined associations between pemafibrate, a selective peroxisome proliferator–activated receptor alpha modulator, and noninvasive markers related to portal hypertension–related hemodynamic stress, including platelet count, liver stiffness, and spleen volume. Methods This 72-week, multicenter, randomized, double-blind, placebo-controlled phase 2 study enrolled 118 patients with high-risk MASLD, randomized 1:1 to pemafibrate 0.4 mg/day or placebo. Platelet count, liver stiffness, and spleen volume were assessed at baseline and during follow-up. Percent changes and parameter associations were evaluated in an exploratory post-hoc analysis. Results Pemafibrate administration was associated with an early and sustained increase in platelet count during follow-up. Liver stiffness showed a gradual decline from week 24 in the pemafibrate group and stabilized after week 48. At week 72, spleen volume decreased in the pemafibrate group, whereas no reduction was observed in the placebo group. In patients with metabolic dysfunction-associated steatohepatitis (MASH), changes in platelet count, liver stiffness, and spleen volume were more pronounced than in those without MASH. At week 72, changes in spleen volume correlated positively with changes in liver stiffness and negatively with platelet count, with a stronger association observed for liver stiffness. In contrast, platelet count changes did not correlate with liver stiffness. Conclusions In this exploratory post-hoc analysis, pemafibrate was associated with sustained increases in platelet count and reductions in spleen volume in patients with MASLD, accompanied by a decline in liver stiffness. While platelet count changes likely reflect mechanisms independent of portal pressure, concordant changes in spleen volume and liver stiffness may represent a coherent noninvasive signal of improvement in portal hypertension–related hemodynamic stress. These hypothesis-generating findings warrant prospective validation using direct hemodynamic assessments and clinical outcomes in MASLD/MASH. ClinicalTrials.gov identifier: NCT03350165.