From the Guidelines
Individuals with normal LDL levels can have high Lipoprotein(a) levels because Lp(a) is genetically determined and largely independent of traditional lipid measurements. Lp(a) consists of an LDL-like particle bound to apolipoprotein(a), and its levels are primarily controlled by the LPA gene, with approximately 80-90% of the variation in Lp(a) levels attributable to genetics 1. Unlike standard LDL, Lp(a) concentrations are minimally affected by diet, exercise, or most lipid-lowering medications that target LDL. This explains why someone can maintain excellent LDL control through lifestyle modifications or medications like statins while still having elevated Lp(a) levels.
Some key points to consider:
- Lp(a) is a highly prevalent, genetic risk factor for cardiovascular disease (CVD) and calcific aortic valve disease (CAVD) 1
- Lp(a) levels in the atherothrombotic range are generally accepted as >30–50 mg/dL or >75–125 nmol/L 1
- The presence of high Lp(a) represents an independent cardiovascular risk factor that requires specific attention
- Currently, treatment options specifically targeting Lp(a) are limited, with niacin and PCSK9 inhibitors showing modest reductions, while specialized therapies like antisense oligonucleotides are being developed 1
- Screening for Lp(a) is particularly important in individuals with premature cardiovascular disease, family history of early heart disease, or those with recurrent cardiovascular events despite well-controlled LDL levels
The effect of therapeutic agents on circulating levels of Lp(a) are not well understood, with some studies showing that statins and low-saturated fat diets actually raise Lp(a) levels, while others like niacin, mipomersen, PCSK9 inhibitors, and CETP inhibitors decrease Lp(a) levels modestly 1. The FOURIER trial has shown a 27% reduction in Lp(a) levels with PCSK9 inhibition, which is half of that seen for LDL-C reduction, suggesting that LDLR up-regulation caused by PCSK9 inhibition also affects clearance of Lp(a) 1.
In terms of management, it is essential to screen for Lp(a) in individuals with premature cardiovascular disease, family history of early heart disease, or those with recurrent cardiovascular events despite well-controlled LDL levels, and consider treatment options that target Lp(a) specifically, such as niacin and PCSK9 inhibitors, while awaiting the development of more effective therapies 1.
From the Research
Background on Lipoprotein(a) and LDL
- Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a) 2
- Elevated Lp(a) is a causal genetic risk factor for cardiovascular disease, with a continuous association between Lp(a) concentrations and cardiovascular risk 3
Relationship between Lp(a) and LDL
- Lp(a) is an independent and causal risk factor for atherosclerosis and major cardiovascular events, even in individuals with normal LDL levels 4
- High Lp(a) levels can persist in the presence of target LDL-C levels and adherence to lifestyle modifications, contributing to residual cardiovascular risk 5
- Statins have neutral or detrimental effects on Lp(a), while PCSK9 inhibitors can reduce Lp(a) levels by up to 30% 4, 6
Prevalence and Screening of High Lp(a) Levels
- Elevated Lp(a) (≥50 mg/dL) is a prevalent condition affecting >20% of the population, but is still underdiagnosed 4
- Guidelines recommend Lp(a) measurement in specific clinical conditions, such as a family history of premature cardiovascular disease or elevated Lp(a) 4, 5
- Candidates for Lp(a) screening include patients with a personal or family history of premature cardiovascular disease, familial hypercholesterolemia, or recurrent cardiovascular events 3
Management of High Lp(a) Levels
- Reducing LDL-C to the lowest attainable value with a high-potency statin should be the primary focus of lipid-modifying therapies 3
- Emerging nucleic acid-based therapies, such as antisense oligonucleotides, have potent Lp(a)-lowering effects and appear safe, with phase 3 trials underway to establish their cardiovascular benefits 4, 2