Dose-dependent efficacy and renal safety of pemafibrate versus fenofibrate in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia: a multicenter randomized controlled, open label trail

Background No randomized controlled trial has directly compared the efficacy of pemafibrate to that of fenofibrate, or evaluated the dose–response relationship of pemafibrate in metabolic dysfunction–associated steatotic liver disease (MASLD). Therefore, we compared the efficacy and safety of high- and low-dose pemafibrate versus fenofibrate over 48 weeks in patients with MASLD and hypertriglyceridemia. Methods This multicenter, open-label, prospective, randomized controlled phase 4 trial (the PRESENT study) included 360 patients with MASLD and hypertriglyceridemia at 29 sites in Japan between December 23, 2020, and March 31, 2026. Participants were randomly assigned (1:1:1) to high-dose pemafibrate (0.4 mg/day; PEM-H), low-dose pemafibrate (0.2 mg/day; PEM-L), or fenofibrate (53.3–106.6 mg/day; FENO) groups. The primary endpoint was change in alanine aminotransferase (ALT) levels at Week 24. Secondary endpoints included liver fibrosis markers, renal parameters, magnetic resonance elastography (MRE), and adverse events. The trial was registered in the Japan Registry of Clinical Trials on December 28, 2020 (jRCTs031200280). Findings At Week 24, PEM-H and PEM-L produced significantly greater ALT reductions than FENO (p < 0.001 and p=0.015, respectively). Exploratory comparison revealed greater reduction for PEM-H than PEM-L (p = 0.018, Holm adjustment), suggesting a dose-dependent effect. Higher baseline ALT levels and lean phenotypes were independently associated with ALT response. At Week 48, Mac-2 binding protein glycosylation isomer decreased significantly in PEM-H and PEM-L compared with a modest reduction in FENO (p < 0.001 and p < 0.001, respectively). MRE demonstrated significant decreases in liver stiffness in PEM-H and PEM-L compared with FENO (p < 0.05 and p=0.02, respectively). Percentage change in serum creatinine levels was lower in PEM-H and PEM-L than in FENO. No treatment-related serious adverse events were observed in any of the three groups. Interpretation Pemafibrate demonstrated greater reductions in ALT levels than fenofibrate, with a notable dose–response relationship and favorable safety profile, suggesting therapeutic potential for patients with MASLD and hypertriglyceridemia. Funding This study was funded by the Kowa Company, Ltd. (Tokyo, Japan).