Pemafibrate Raises Zinc Levels in Fatty Liver Disease Without Supplements

Zinc deficiency is pervasive in chronic liver disease and forms a vicious cycle: depleted zinc impairs antioxidant defenses, accelerates hepatic inflammation and fibrosis, and raises hepatocellular carcinoma risk, while worsening liver function further depletes zinc. In metabolic dysfunction-associated steatohepatitis (MASH), zinc deficiency promotes mitochondrial oxidative stress, iron overload, insulin resistance, and fibrogenesis—making zinc status a clinically meaningful target.

This prospective single-arm study enrolled 26 biopsy-confirmed MASH patients (mean age 56 years; 17 men) with fasting triglycerides ≥150 mg/dL at Toho University Omori Medical Center between July 2021 and December 2023. All patients received oral pemafibrate 0.2 mg twice daily—a selective PPARα modulator approved for hypertriglyceridemia—and were followed with scheduled visits every 3 months for 36 months. Serum zinc was measured at baseline and at 6, 12, 24, and 36 months. Subgroup analyses stratified patients by cirrhosis status and baseline zinc level (deficient <80 µg/dL vs. preserved ≥80 µg/dL). A linear mixed-effects model accounted for repeated within-subject measurements.

At baseline, 11 of 26 patients had zinc deficiency (<80 µg/dL; mean 72.3 µg/dL) and 15 had preserved levels (mean 89.3 µg/dL). The overall cohort showed a statistically significant rise in serum zinc beginning at 6 months (β=5.41, 95% CI 2.05–8.77; P=0.002) and sustained through 36 months (β=7.22, 95% CI 3.87–10.58; P<0.001). Patients without cirrhosis maintained this elevation throughout the observation period, whereas cirrhotic patients showed a delayed and only transient response—consistent with greater hepatic synthetic dysfunction limiting recovery. Interestingly, zinc-deficient patients at baseline responded earlier than those with preserved baseline levels, suggesting a floor effect or greater therapeutic headroom. Serum albumin improved significantly through 24 months but not at 36 months, while zinc remained elevated at 36 months, pointing to albumin-independent mechanisms—possibly involving PPARα-mediated upregulation of zinc transporter expression or reduced urinary zinc losses secondary to improved metabolic health. Pemafibrate also produced significant improvements in triglycerides, AST, ALT, GGT, and fibrosis markers including Mac-2 binding protein glycosylation isomer.

The clinical implication is notable: a single pharmacological agent targeting hypertriglyceridemia in MASH may simultaneously correct zinc deficiency—without zinc supplementation—potentially interrupting the oxidative stress–fibrosis–zinc depletion cycle. This adds a new dimension to pemafibrate's therapeutic profile beyond lipid lowering and anti-inflammatory effects.

Caveats include the small sample size (n=26), single-center setting, absence of a control group, and single-arm design, which preclude causal inference. Mechanistic pathways linking PPARα activation to zinc homeostasis require further elucidation. Large-scale multicenter randomized trials are needed to confirm these findings.