Pemafibrate significantly reduces fasting glucose, insulin, and HOMA-IR while increasing FGF21 levels.

Despite advancements, effective treatments for metabolic dysfunction-associated steatohepatitis (MASH) and broader glucose dysregulation remain limited, with only a few drugs approved. Peroxisome proliferator-activated receptor alpha (PPARα) modulators like Pemafibrate are promising, as PPARα activation plays a crucial role in lipid metabolism and glucose homeostasis by enhancing fatty acid oxidation and mitochondrial biogenesis. However, Pemafibrate's precise impact on key metabolic biomarkers, including insulin sensitivity and the hormone fibroblast growth factor 21 (FGF21), needed comprehensive evaluation to clarify its therapeutic potential.

Researchers conducted a systematic review and meta-analysis of 14 randomized controlled trials (RCTs), encompassing 4084 participants, to assess Pemafibrate's effects on glucose metabolism and FGF21. A comprehensive literature search was performed across PubMed, Web of Science, SCOPUS, and Embase databases from their inception until November 2025. The study included RCTs evaluating Pemafibrate's impact on fasting blood glucose (FBG), insulin, HbA1c, HOMA-IR, and FGF21. Weighted mean differences (WMD) for each outcome were calculated using a random-effects model.

Pemafibrate demonstrated significant improvements across several key metabolic parameters. It significantly reduced FBG by -0.47 mmol/L (11 studies, 3273 patients, 95% CI: -0.70 to -0.24), insulin levels by -30.72 pmol/L (7 studies, 2102 patients, 95% CI: -42.08 to -19.36), and HOMA-IR by -1.60 (8 studies, 2381 patients, 95% CI: -2.27 to -0.93). Additionally, FGF21 levels were significantly increased by 3.30 pg/mL (7 studies, 2178 patients, 95% CI: 2.57 to 4.04). The effect on HbA1c was marginally non-significant, showing a WMD of 0.02% (10 studies, 3065 patients, 95% CI: 0.00 to 0.05). Subgroup analysis revealed that shorter durations of Pemafibrate intake were linked to more pronounced FBG improvements, while higher doses (> 0.2 mg/day) showed greater effects on FGF21 and glucose metabolism. Meta-regression indicated a positive correlation between treatment duration and reductions in insulin levels. The overall GRADE quality assessment was rated as very good.

Pemafibrate significantly improved insulin sensitivity, reducing HOMA-IR by -1.60 across 2381 patients, indicating a robust effect on a critical marker of metabolic health.