Sex Differences in Coronary Atheroma Regression After Intensive Lipid-Lowering Therapy: A Pooled Analysis

Intensive lipid-lowering therapy with high-intensity statins, with or without proprotein convertase subtilisin/kexin type 9 inhibitors, reduces coronary plaque burden. However, whether men and women experience similar atheroma regression and plaque compositional changes remains uncertain.

The objective of the study was to quantify sex-specific changes in percent atheroma volume (PAV), total atheroma volume (TAV), and plaque composition after intensive lipid-lowering, using pooled individual-participant data from four serial intravascular ultrasound trials.

Data from REVERSAL, ASTEROID, SATURN, and GLAGOV trials (N = 2,737; 1,987 men, 750 women) were analyzed centrally. Over a median follow-up of 20.7 months, annualized changes in PAV, TAV, and virtual histology components were compared using linear mixed-effects models adjusted for baseline plaque burden and trial.

Women were older with higher rates of hypertension and diabetes but presented with lower baseline PAV (mean: 34.5% vs 38.5%) and less extensive plaque composition abnormalities, even when normalized for plaque burden. Virtual histology analysis revealed women had lower baseline fibro-fatty volume (median: 13.7 vs 34.3 mm³), necrotic core volume (median: 7.7 vs 13.1 mm³), and higher fibrous content (mean: 41.5% vs 36.7%). Following treatment achieving similar low-density lipoprotein-cholesterol (LDL-C) (∼70 mg/dL), women showed greater regression in PAV (least-squares-mean: -0.25% vs -0.05%) and TAV, with similar plaque stabilization. Female sex independently predicted PAV regression, which was most pronounced in women achieving LDL-C <55 mg/dL.

Women undergoing clinically indicated procedures present with paradoxically less extensive atheroma and more favorable plaque composition despite higher cardiovascular risk burden. They experience greater coronary plaque regression than men after intensive lipid-lowering, especially when LDL-C is below 55 mg/dL, with similar plaque stabilization.