Pemafibrate is associated with greater reductions in MDA-LDL and small dense LDL fractions with exploratory PBMC gene-expression changes: a prespecified subanalysis of the PARADISE in Kagoshima study

Background: gene-expression changes in humans remain limited. In addition, whether pemafibrate-associated changes in oxidized LDL-related biomarkers have clinical implications for atherosclerotic progression or cardiovascular risk remains uncertain. Methods: In this prespecified subanalysis of the randomized, open-label, parallel-group PARADISE in Kagoshima study, 51 participants assigned to pemafibrate and 46 assigned to eicosapentaenoic acid (EPA) were included in the clinical analysis. All participants had type 2 diabetes and hypertriglyceridemia and received treatment for 16 weeks. We evaluated changes in MDA-LDL, lipoprotein fractions including small dense LDL-related fractions, and exploratory peripheral blood mononuclear cell (PBMC) gene expression. PBMC gene expression was assessed in 11 participants in the Pemafibrate group and 7 in the EPA group, and was considered exploratory and hypothesis-generating. Results: Compared with EPA, pemafibrate produced a significantly greater reduction in triglycerides (least-squares mean difference, -79.2 mg/dL; 95% confidence interval [CI], -117 to -41.5; P < 0.001), and a greater increase in HDL-C (4.64 mg/dL; 95% CI, 2.43 to 6.84; P < 0.001). The mean change in MDA-LDL from baseline to week 16 was -30.3 ± 32.4 U/L in the Pemafibrate group and -9.2 ± 44.3 U/L in the EPA group, yielding a least-squares mean difference of -21.2 U/L (95% CI, -36.9 to -5.4; P = 0.009). In the exploratory PBMC analysis, ABCA1 and LCAT remained significant after false discovery rate adjustment, whereas other genes showed only nominal differences. Conclusion: Pemafibrate was associated with greater 16-week reductions in MDA-LDL and small dense LDL fractions than EPA in patients with type 2 diabetes and hypertriglyceridemia. These findings suggest modification of selected lipid-quality biomarkers. Their clinical relevance remains to be established.