What is the significance of Lipoprotein(a) (LPA)?

From the Guidelines

Liprotein(a) (Lp(a)) is a significant risk factor for cardiovascular disease (CVD) and calcific aortic valve disease (CAVD), and its levels should be measured in patients at high risk of CVD, with a target level below 50 mg/dL. The significance of Lp(a) lies in its widespread implications for CVD risk, with elevated levels affecting 20-30% of the global population 1. Lp(a) is a highly prevalent, genetic risk factor for CVD and CAVD, and its levels are primarily determined by the LPA gene locus encoding apo(a) 1.

Key Points

• Lp(a) levels in the atherothrombotic range are generally accepted as >30–50 mg/dL or >75–125 nmol/L 1
• Convincing evidence has emerged from pathophysiological, epidemiologic, and genetic studies on the causality of Lp(a) in contributing to CVD (myocardial infarction, stroke, peripheral arterial disease, heart failure) and CAVD 1
• The European Society of Cardiology (ESC) guidelines recommend measuring Lp(a) in patients at high risk of cardiovascular disease (CVD) and to target levels below 50 mg/dL 1
• Several observational studies, including meta-analyses, as well as genomic studies suggest a causal association between Lp(a) levels and CVD events, also including emergent outcomes in the elderly, such as heart failure and calcific aortic valve stenosis 1

Clinical Implications

• Measuring Lp(a) levels is crucial in patients at high risk of CVD, as it can help identify those who may benefit from targeted therapies to lower Lp(a) levels 1
• Targeting Lp(a) levels below 50 mg/dL may help reduce the risk of CVD and CAVD in patients with elevated Lp(a) levels 1
• Further research is needed to fully understand the role of Lp(a) in CVD risk and to develop effective therapies to lower Lp(a) levels 1

From the Research

Significance of LPA

• Lipoprotein(a) (Lp(a)) is a complex circulating lipoprotein that has been demonstrated to be a risk factor for atherosclerotic cardiovascular disease (ASCVD) and a possible therapeutic target 2.
• High levels of Lp(a) are an independent and causal risk factor for atherosclerotic cardiovascular diseases through mechanisms associated with increased atherogenesis, inflammation, and thrombosis 3.
• Lp(a) remains a risk factor for cardiovascular disease development even in the setting of effective reduction of plasma low-density lipoprotein cholesterol and apoB100 3.
• Elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction 4.
• The optimal Lp(a) threshold for risk assessment may differ based on baseline ASCVD status, with individuals in the 91st to 100th Lp(a) percentile group having the highest relative risk of major adverse cardiovascular events (MACE) 5.

Measurement and Interpretation of LPA

• Lp(a) level measurement poses some challenges due to the absence of a definitive reference method and the reporting of Lp(a) values as molar or mass concentrations by different assays 2.
• Lp(a) measurement is recommended to refine cardiovascular risk in specific clinical settings, such as in individuals with a family history of premature ASCVD or in patients with ASCVD not explained by standard risk factors 2.
• Guidelines have begun to advocate measurement of Lp(a) to identify patients with very high levels that have a family history of premature CVD or elevated Lp(a) 6.

Therapeutic Targeting of LPA

• Available lipid-lowering agents have at best moderate impact on Lp(a) levels, with proprotein convertase subtilisin/kexin type 9 inhibitors being the most effective in reducing Lp(a) 2.
• Emerging nucleic acid-based therapies, such as antisense oligonucleotides, have potent Lp(a)-lowering effects and appear safe, with phase 3 trials to establish whether they improve cardiovascular outcomes 4, 6.
• Lipoprotein apheresis (LA) efficiently lowers Lp(a) and was recently associated with a reduction of incident CV events 6.