Residual risk in atherosclerotic cardiovascular disease after statin therapy: Clinical mechanisms and management strategies

Table 1 Summary of major biomarkers of residual risk and their clinical relevance

Major biomarkers	Clinical relevance
Non-HDL-C/apoB	Superior to LDL-C in predicting residual ASCVD risk; elevated levels increase all-cause mortality and MI risk (Copenhagen, Danish registry, meta-analysis); stable non-fasting lipid target for better risk stratification
Lp(a)	Independent predictor of residual CVD risk in statin-treated patients; elevated ≥ 50 mg/dL increases events by 31%-43%; genetically determined via LPA variants; recommended once-in-lifetime testing (ESC/EAS, NLA)
TRLs/RC	Elevated TRLs, TG, and RC increase residual CVD risk independent of LDL-C; TRLs promote foam-cell formation, inflammation, and atherogenesis; RC > 29 mg/dL raises CVD risk by 20%-43% (PESA, MESA, KP-REACH)
HDL dysfunction/HDL-C-related ratio	HDL dysfunction impairs cholesterol efflux, NO production, and anti-inflammatory effects. Ratios such as apoA1/apoB, TG/HDL-C, and non-HDL-C/HDL-C predict ACS, CAD progression, and mortality, offering superior prognostic value over HDL-C alone
hsCRP/IL-6/NLRP3 inflammasome	Elevated hsCRP (> 2 mg/L) predicts higher CVD risk and mortality. The NLRP3-IL-1β-IL-6 axis drives vascular inflammation; IL-6 serves as a biomarker of residual inflammatory risk and therapeutic target for anti-inflammatory intervention

HDL-C: High-density lipoprotein cholesterol; apoB: Apolipoprotein B; LDL-C: Low-density lipoprotein cholesterol; ASCVD: Atherosclerotic cardiovascular disease; MI: Myocardial infarction; Lp(a): Lipoprotein(a); CVD: Cardiovascular disease; LPA: Lipoprotein(a) gene; ESC: European Society of Cardiology; EAS: European Atherosclerosis Society; NLA:National Lipid Association; TRLs: Triglyceride-rich lipoproteins; RC: Remnant cholesterol; PESA: Progression of early subclinical atherosclerosis; MESA: Multi-ethnic study of atherosclerosis; KP-REACH: Kaiser permanente regional examination of atherosclerosis, cardiometabolic health, and heart disease; HDL: High-density lipoprotein; NO: Nitric oxide; apoA1: Apolipoprotein A1; TG: Triglycerides; ACS: Acute coronary syndrome; CAD: Coronary artery disease; hsCRP: High-sensitivity C-reactive protein; NLRP3: NOD-like receptor pyrin domain-containing protein 3; IL: Interleukin.