Remnant cholesterol, C-reactive protein, cholesterol-lowering medication, and cardiovascular outcome: novel findings from UK Biobank

Abstract

Despite substantial reductions in cardiovascular events with intensive LDL-C lowering, significant residual risk persists. Remnant cholesterol (RC) and C-reactive protein (CRP) reflect lipid dysregulation and inflammation, respectively, and may synergistically promote atherosclerosis. However, large-scale cohort evidence on their combined impact, particularly the quantitative interaction between the two and the modifying role of cholesterol-lowering therapy, remains limited. This study included 376,817 participants with a median follow-up of 13.4 years. Cox proportional hazards regression models were used to evaluate the individual and joint associations of RC and CRP with major adverse cardiovascular events (MACE) risk. Stratified analyses by cholesterol-lowering therapy were further conducted to explore its modifying effect on the combined risk. Both RC (≥0.8 mmol/L) and CRP (≥2 mg/L) were independently associated with MACE risk, with adjusted hazard ratios (HR) of 1.074 [95% confidence interval (CI): 1.024–1.126] and 1.168 (95% CI: 1.129–1.207), respectively. Concurrent elevation of both biomarkers conferred the highest risk (HR = 1.239, 95% CI: 1.167–1.316), and a significant positive multiplicative interaction was observed between RC and CRP. Stratified analyses suggested effect modification by cholesterol-lowering medication: the association between isolated RC elevation and MACE was attenuated in medication users, whereas risks remained significant for isolated CRP elevation and combined elevation of both markers. Concurrent elevation of RC and CRP yields the highest MACE risk with a positive additive interaction. Cholesterol-lowering therapy reduces RC-related risk but not inflammation-driven risk in isolated CRP elevation. These findings support combined assessment of both biomarkers for personalized cardiovascular risk stratification.