Pemafibrate therapy increases serum zinc levels in patients with metabolic dysfunction–associated steatohepatitis: a prospective study

BACKGROUND: Zinc deficiency is common in chronic liver disease and is closely associated with the progression of hepatic fibrosis and metabolic dysfunction. Although pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, has had beneficial effects on lipid metabolism, inflammation, and oxidative stress, its impact on zinc metabolism in patients with metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. METHODS: This prospective study involved patients with biopsy-confirmed MASH complicated by hypertriglyceridemia (fasting triglycerides ≥ 150 mg/dL) who were treated with pemafibrate (0.2 mg twice daily). Serum zinc levels were evaluated at baseline and at 6, 12, 24, and 36 months after initiation of treatment. Subgroup analyses were performed according to cirrhosis status and baseline serum zinc level (< 80 µg/dL vs. ≥80 µg/dL). Changes in liver-related biochemical parameters and albumin levels were also assessed. RESULTS: Twenty-six patients (mean age 56.3 ± 12.6 years; 17 men) were followed for 36 months. Serum zinc levels had increased significantly at 6 months after initiation of pemafibrate and remained significantly elevated through to 36 months. Patients without cirrhosis showed a sustained increase in serum zinc levels throughout the observation period, whereas those with cirrhosis had a delayed and transient response. The serum zinc level increased earlier in patients with zinc deficiency at baseline than in those with a preserved level at baseline. Serum albumin levels increased significantly up to 24 months but not up to 36 months, whereas serum zinc levels remained elevated, suggesting the involvement of albumin-independent mechanisms. Pemafibrate therapy was also associated with significant improvements in triglycerides, liver enzymes, and fibrosis-related markers. CONCLUSIONS: Pemafibrate therapy was associated with a significant and sustained increase in the serum zinc level in patients with hypertriglyceridemia-related MASH, even in the absence of zinc supplementation. However, given the small sample size, the absence of a control group, and the single-arm study design, future large-scale multicenter studies that include a greater number of patients are warranted.