Sex differences in coronary plaque stabilization with evolocumab: a post hoc analysis of the YELLOW III trial

Whether coronary plaque response to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition differs by sex remains uncertain. We assessed sex-related differences in serial intravascular imaging and transcriptomic responses to evolocumab. This post hoc analysis of the YELLOW III trial included 110 patients with chronic coronary disease (CCD) receiving maximally tolerated statin therapy who had lipid-rich, non-obstructive coronary lesions on optical coherence tomography (OCT). All received evolocumab 140 mg every 2 weeks for 26 weeks. Serial OCT, near-infrared spectroscopy, and intravascular ultrasound were performed at baseline and follow-up. Peripheral blood mononuclear cells underwent RNA sequencing. Among 110 patients, 29 were women and 81 were men. Absolute low-density lipoprotein cholesterol reduction did not differ significantly between women and men (-56.6 ± 35.9 vs. -58.1 ± 26.4 mg/dL; p = 0.830). Plaque response did not differ significantly by sex for minimum fibrous cap thickness (+ 27.9 ± 26.5 vs. + 26.4 ± 20.7 μm; p = 0.755), maximum lipid core burden index within a 4-mm segment (-86.8 ± 158.6 vs. -96.2 ± 134.4; p = 0.756), and percent atheroma volume (-1.2 ± 1.1 vs. -1.5 ± 1.6%; p = 0.353). At baseline, 2,650 genes were differentially expressed, with neutrophil degranulation and nuclear factor-κB-related inflammatory pathways upregulated in men. At follow-up, 301 genes were differentially expressed, and the baseline inflammatory pathway differences were attenuated. Evolocumab was associated with similar short-term plaque stabilization in women and men with CCD, despite baseline sex-related differences in inflammatory pathways. These findings warrant confirmation in larger prospective studies.