Lipoprotein(a) as an independent cardiovascular risk factor

Abstract

Lipoprotein(a) (Lp(a)) is an independent, genetically determined cardiovascular risk factor that remains underrecognized in clinical practice. Elevated Lp(a) exerts pro-atherogenic, pro-thrombotic, and pro-infl ammatory effects, contributing to coronary artery disease, ischemic stroke, and calcifi c aortic valve stenosis. About 20% of the global population has high Lp(a) (> 50 mg/dL or > 125 nmol/L), associated with a 2-4-fold increased risk of events, independent of low-density lipoprotein cholesterol (LDL-C). Unlike LDL-C, Lp(a) levels are ~90% genetically determined, minimally affected by lifestyle, and stable throughout life. Traditional lipid-lowering therapies (e.g., statins) have little effect on Lp(a). PCSK9 inhibitors provide modest reduction (~ 20-30%), while novel RNA-targeted agents (antisense oligonucleotides, siRNAs) and gene-editing approaches are under active investigation. Recent guidelines, including the 2025 ESC/EAS Focused Update, recognize Lp(a) > 50 mg/dL (~ 105 nmol/L) as a cardiovascular risk-enhancing factor (Class IIa, Level B). They recommend once-in-a-lifetime Lp(a) measurement, particularly in patients at high cardiovascular risk, and emphasize intensive LDL-C lowering in acute coronary syndrome. Bempedoic acid is endorsed for statin-intolerant patients (Class I, Level B), while evinacumab may be considered in homozygous familial hypercholesterolemia (Class IIa, Level B). Emerging evidence also links Lp(a) to atrial fi brillation, broadening its clinical relevance. Large outcome trials of Lp(a)-lowering agents are underway and will determine whether reduction translates into improved cardiovascular outcomes. As one in fi ve adults worldwide has elevated Lp(a), integrating Lp(a) testing into risk assessment and preparing for targeted therapies are critical steps in modern cardiovas-cular prevention.