Lipoprotein(a) as a Cardiovascular Risk Factor: Clinical Significance and Therapeutic Perspectives

Lipoprotein(a): Cardiovascular Risk and Emerging Targeted Therapies.

Lipoprotein(a) in cardiovascular disease: pathophysiology, residual risk, and emerging therapeutic strategies

This narrative review summarizes the molecular biology, genetics, epidemiology, pathophysiological mechanisms, and clinical relevance of Lp(a), and critically examines current and emerging therapeutic strategies aimed at reducing Lp(a)-mediated cardiovascular risk.

Lipoprotein(a) in Coronary Artery Disease and Aortic Stenosis: Pathophysiology, Clinical Impact, Interventional Implications and Emerging Targeted Therapies

Lipoprotein(a) (Lp(a)) is increasingly recognized as a genetically determined and clinically relevant contributor to residual cardiovascular risk. Through pro-atherogenic, pro-inflammatory, pro-thrombotic, and pro-calcific mechanisms, Lp(a) appears to play a significant role in both coronary artery disease and aortic valve disease. In patients undergoing percutaneous coronary intervention, elevated Lp(a) has been associated with worse long-term outcomes, including recurrent ischemic events, repeat revascularization, and in-stent restenosis, even in the setting of controlled low-density lipoprotein cholesterol. In parallel, experimental, genetic, and clinical data support a role for Lp(a) in the initiation and progression of calcific aortic stenosis, while its prognostic significance after transcatheter aortic valve interventions remains less clearly defined. Current guidelines now recognize Lp(a) as a relevant risk-enhancing factor, and emerging targeted therapies are achieving substantial reductions in circulating levels. Overall, Lp(a) should be regarded as both a meaningful biomarker and a promising therapeutic target, although ongoing outcome trials are needed to determine whether selective Lp(a) lowering translates into clinical benefit across interventional cardiovascular settings. The aim of this narrative review is to provide a single, comprehensive account of lipoprotein(a) [Lp(a)] in interventional cardiology, following this lipoprotein from its biology and pathophysiology through to its clinical impact and to the therapies that are now reaching the clinic, with a specific focus on the two most frequent catheter-based procedures in which it may carry prognostic weight: percutaneous coronary intervention (PCI) and transcatheter aortic valve implantation (TAVI). PCI and TAVI are deliberately addressed within the same review since they share a common upstream biology: Lp(a) contributes both to the atherosclerotic process that underlies coronary disease and to the calcific process that underlies aortic valve disease, and the corresponding patient populations overlap considerably in everyday interventional practice. Covering them together offers the interventional cardiologist a single, practical reference on how a patient with elevated Lp(a) may be approached in both scenarios.

Lipoprotein(a) as an independent cardiovascular risk factor

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.

Targeting Lipoprotein(a): A New Era in Cardiovascular Disease Prevention

Lipoprotein(a), or Lp(a), is a genetically determined low-density lipoprotein-like particle that is elevated in approximately one in five individuals worldwide and represents an independent causal risk factor for atherosclerotic cardiovascular disease and calcific aortic stenosis. Elevated Lp(a) levels contribute significantly to residual cardiovascular risk despite optimal management of traditional risk factors. The pathogenicity of Lp(a) derives from its unique structure and enrichment with oxidized phospholipids, conferring proinflammatory, prothrombotic, and proatherogenic properties. Current guidelines recommend at least one-time universal screening, with elevated levels informing personalized decisions regarding lipid-lowering therapy intensification. Novel unapproved therapies, including an antisense oligonucleotide (pelacarsen), small interfering RNAs (olpasiran, lepodisiran), and an oral small molecule (muvalaplin), have demonstrated Lp(a) reductions of up to 99% and are being tested in ongoing phase 3 cardiovascular outcomes trials to determine whether pharmacologic Lp(a) lowering translates into reduced cardiovascular events. We discuss current knowledge on genetics, biology, epidemiology, and measurement of Lp(a), examine its causal association with cardiovascular disease, and discuss emerging therapeutic strategies that may usher in a new era of cardiovascular disease prevention.

Novel Lipoprotein (a) Therapies: A Comprehensive Review

The Lp(a) treatment landscape has moved from basic science to an active late-stage clinical pipeline and positive outcomes from these CVOTs could lead to regulatory approvals and guideline updates affecting hundreds of millions of high-risk patients globally.