Measuring Lipoprotein(a) in Clinical Practice to Reduce the Burden of Cardiovascular Disease? Still Work in Progress.

A recent review suggested that the use of lipoprotein (Lp) (a) measurement in clinical practice may have clinical and economic benefits for patients, healthcare systems, and society as a whole. However, widespread adoption of Lp(a) measurement in the general population has been hindered by limited treatment options targeting Lp(a) reduction.

Cardiovascular disease (CVD) remains the leading cause of death in the U.S. and worldwide despite significant progress in risk reduction interventions. Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD), the most prevalent form of CVD. Studies have shown that high levels of Lp(a) are an inherited, independent risk factor for ASCVD. At any level of LDL-C, ASCVD event rates are higher when the Lp(a) level is elevated. An estimated 20-30% of the global population has high Lp(a), defined as above the 80^th percentile (corresponds to an Lp(a) concentration of > 50 mg/dl, or > 100 nmol/L).

See our recent information page on Lp(a) and its role in heart disease.

What does the evidence say about the causal link between high Lp(a) and CVD?

Genome-wide association studies (GWAS), observational cohort studies, and meta-analyses of prospective, population-based studies provide evidence supporting a causal relationship between high Lp(a) and ASCVD, aortic stenosis, and stroke. Unlike LDL cholesterol, Lp(a) levels are predominantly genetically predetermined and are not significantly impacted by diet and exercise. Mendelian Randomization (MR) studies which are less subject to confounding and reverse causation, have assessed genetic variants affecting Lp(a) levels and provided evidence for direct causal relationships between high Lp(a) and CVD.

Lp(a) measurement in clinical practice?

According to a scientific statement issued by the National Lipid Association, of all evidence from Mendelian randomization studies for any disease or biomarker, the evidence supporting a causal link between Lp(a) and ASCVD is the strongest. Despite the causal relationship between Lp(a) and ASCVD, the use of Lp(a) in clinical practice has faced challenges in both clinical validity and utility. Issues related to clinical validity include lack of standardization of assays used to measure Lp(a) levels and absence of universal guidelines for screening and subsequent risk assessment of high Lp(a) levels. Several European and Canadian societies recommend the measurement of Lp(a) at least once in a person’s lifetime.

Median levels of Lp(a) in the population vary by ancestry and sex, with higher median levels observed among people of African and South Asian descent, compared with those of non-Hispanic White and East Asian descent. One recommendation has been to establish ancestry-specific cut points to define a high Lp(a) level. However, some studies have proposed that the risk of CVD over a certain Lp(a) threshold is the same regardless of ancestry, while others have shown differences in risk by ancestry. Due to these issues, current guidelines and scientific statements focus on measuring Lp(a) levels in those with a personal or family history of premature ASCVD, those with familial hypercholesterolemia (FH), patients with ASCVD without traditional risk factors, or those with recurrent CVD events despite optimal management of conventional risk factors; none of these guidelines address population-wide screening.

Currently, lipoprotein apheresis, a specialized and potentially costly therapy, is the only treatment approved by the Food and Drug Administration (FDA) for specifically lowering Lp(a) levels. In the United States, lipoprotein apheresis is potentially covered and can be considered for Lp(a) reduction among people with LDL≥100 mg/dL, Lp(a)≥60 mg/dL, and coronary or peripheral artery disease. A single course of lipoprotein apheresis acutely lowers Lp(a) levels by approximately 60–75%.  Traditional LDL-C lowering agents have been shown to have minimal Lp(a)-lowering efficacy, with statins resulting in a slight increase in Lp(a) levels. A recent post-hoc analysis addressing the impact of PCKS9 inhibitor therapy related to Lp(a) demonstrated that in patients with acute coronary syndrome on maximal tolerated statin therapy, addition of PCSK9 inhibitors may provide clinical benefit only when Lp(a) concentration is elevated. New therapies that directly target Lp(a) are being investigated in phase III clinical trials. For example, an apo(a) antisense oligonucleotide has been shown to lower Lp(a) levels by 80%. These therapies, if approved, may serve as an impetus for population-wide screening of Lp(a) in an effort to identify high-risk individuals. Even when therapies are available, barriers such as lack of awareness, limited value perception, and healthcare system barriers will need to be addressed. Engaging policymakers and further prospective studies will be an important part of strategies to address these barriers.

Going Forward

While Lp(a) testing aids in the identification of individuals with potentially increased ASCVD risk, studies on clinical validity and utility are needed. Public health efforts can help raise awareness, improve clinician and public knowledge, as well as improve availability of evidence-based interventions. Results of ongoing clinical trials may provide guidance on the utility of universal screening of Lp(a) as a public health strategy to reduce the burden of heart disease.