Lp(a): Looking Beyond LDL to Assess ASCVD Risk

Lp(a) Looking Beyond LDL to Assess ASCVD Risk

A risk calculator is an excellent tool in assessing potential risk for atherosclerotic cardiovascular disease (ASCVD), with a focus on age, sex, race, blood pressure, diabetes, tobacco use, and cholesterol—but clinicians should consider looking beyond LDL to assess ASCVD risk. One example is Lipoprotein(a), also known as Lp(a), which is an independent risk factor for heart attack, stroke, aortic stenosis, and more.

What is Lp(a)?

Lp(a) is an LDL-like particle that is synthesized in the liver. It is composed of apoprotein B100 (ApoB) bound to apolipoprotein(a) (ApoA) by a disulfide bridge.[i] Lipoproteins—including LDL, HDL, and Lp(a) – carry cholesterol around in the blood.

A person’s level of Lp(a) is almost entirely genetically determined and can be established by age 5. While it doesn’t change much throughout the lifespan, post-menopausal women may exhibit an increased Lp(a) level.  

Why Worry About Lp(a)?

As clinicians strive to look beyond LDL to assess ASCVD risk, Lp(a) is one of the key indicators to investigate. Elevated Lp(a) is the most common genetic lipidemia, affecting more than 1.4 billion individuals globally and 1 in 5 individuals in the US (those with an Lp(a) level of > 50 mg/dL or > 125 nmol/L).[ii]

It is important to recognize that a person may have normal lipid levels and yet have elevated Lp(a).

While Lp(a) was identified more than six decades ago, it only recently has been recognized as a prevalent risk for cardiovascular disease. Evidence for Lp(a) having an independent association with cardiovascular risk has been found in epidemiologic, Mendelian randomization, and genome-wide studies.

Lp(a) levels of > 50 mg/dL or > 125 nmol/L are associated with an increased risk of cardiovascular disease.[iii] Lp(a) is ‘stickier’ than other types of LDL, and like LDL-C, Lp(a)-cholesterol can build up as plaques in the walls of blood vessels.[iv] Plaques can decrease blood flow and may grow over time or even rupture, leading to heart attacks or strokes.[v] Lp(a) induces atherosclerosis by attaching to oxidized phospholipids. It also attaches to macrophages and leads to the formation of foam cells, ultimately leading to plaque development.[vi]

High Lp(a) can also lead to aortic valve stenosis, which is the most prevalent form of valvular heart disease in developed countries.[vii] A 2021 study reported a ‘robust’ association of Lp(a) and aortic valve calcium,[viii] reinforcing the research on the causal role of Lp(a) in the pathogenesis of aortic valve stenosis.[ix],[x]

Applications to Clinical Practice

Identifying elevated Lp(a) in patients involves a concerted effort by clinicians and the patient’s health care team. Educating patients about Lp(a) and its association with cardiovascular disease is key.

  1. There is a need for increased awareness of Lp(a) by clinicians and patients, as well as research around Lp(a)
    • The American Heart Association launched The Lp(a) Discovery Project in March 2023 to better understand the genetic and biologic basis for Lp(a) variations, and their relationship to disease.[xi]
  2. Identify who/when to test.
    • Lp(a) is not part of routine cholesterol screening tests and needs to be ordered separately. It may not be covered by insurance.
    • As measurement has not been standardized and may be subject to bias, it is recommended to use assays that report results in nmol/L, and which are calibrated against the World Health Organization/International Federation of Clinical Chemistry and Laboratory Medicine secondary reference materials[xii]
    • Within the scope of shared decision-making, Lp(a) test is reasonable (Class IIa recommendation) for those with:
      • First-degree relatives with premature ASCVD (men ˂55 years; women ˂65 years)
      • LDL-C ≥190 mg/dL, or suspected FH
      • Premature ASCVD, especially in the absence of traditional risk factors.
      • Multiple major ASVD events; or one major ASCVD event and multiple high-risk conditions.
    • Lp(a) testing may be reasonable (Class IIb recommendation) for those with:5
      • Intermediate or borderline 10-year ASCVD risk, to aid in the decision-making regarding initiating statin therapy in ages 40-75
      • Less-than-anticipated reduction of LDL-C despite adherence to lipid therapy
      • Family history of elevated Lp(a)
      • Calcific aortic valve stenosis
      • Recurrent or progressive ASCVD despite adequate control of other risk factors
    • Since Lp(a) levels remain relatively constant over the lifespan, there is generally no need for serial testing.
    • Lp(a) may also be identified as part of genetic testing
  3. Consider more aggressive prevention treatment strategies in patients with:
    • Heterozygous familial hypercholesterolemia (HeFH)
    • Premature ASCVD—or family history
    • Progressive ASCVD in spite of optimal medical therapy
    • Recent acute coronary syndromes
    • Family history of elevated Lp(a)
  4. Plasma Lp(a) levels remain relatively constant over the lifespan (starting at age 5)
    • Increases may be seen in specific situations including, but not limited to:
      • When inflammation increases, such as with acute illnesses
      • In individuals with chronic kidney disease
      • During pregnancy and post-menopause
  5. Apply guideline-directed treatments
    • While as of August 2023, there are no specific Lp(a) medications, research is underway.
    • While lifestyle has little or no impact on levels of Lp(a), diet, exercise, and smoking cessation can reduce the risk of cardiovascular disease.
    • The use of statins does not reduce the risk of ASCVD or progression of aortic stenosis in patients with elevated Lp(a).
    • Lp(a) apheresis is an FDA-approved therapy for those with elevated Lp(a) and recurrent ASCVD events, for those with FH, LDL ≥ 100 mg/dL, and Lp(a) ≥ 60 mg/dL.3

Lp(a) Resources

[i] Farzam K, Senthilkumaran S. Lipoprotein A. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 https://www.ncbi.nlm.nih.gov/books/NBK570621/ Accessed Aug. 22, 2023.

[ii] Scheel P, Meyer J, Blumenthal RS, Martin SS. Lipoprotein(a) in Clinical Practice. July 2, 2019. American College of Cardiology. https://www.acc.org/Latest-in-Cardiology/Articles/2019/07/02/08/05/Lipoproteina-in-Clinical-Practice. Accessed Aug. 22, 2023.

[iii] Centers for Disease Control and Prevention. Lipoprotein(a). 2023. https://www.cdc.gov/genomics/disease/lipoprotein_a.htm.  Accessed Aug. 16, 2023.

[iv] U.S. National Library of Medicine. Lipoprotein (a) Blood Test. MedlinePlus. https://medlineplus.gov/lab-tests/lipoprotein-a-blood-test/ Accessed Aug. 12, 2023.

[v] Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2022; 42(1):e48-e60.

[vi] Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005 Jul 07;353(1):46-57. 

[vii] Lindman BR, Clavel M-A, Mathieu P, et al. Calcific aortic stenosis. Nat Rev Dis Primers 2016;2:16006.

[viii] Kaiser Y, Singh SS, Zheng KH, et al. Lipoprotein(a) is robustly associated with aortic valve calcium. Heart. 2021. 107:1422–1428. https://heart.bmj.com/content/heartjnl/107/17/1422.full.pdf

[ix] Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014;63:470–7.

[x] Arsenault BJ, Boekholdt SM, Dubé M-P, et al. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort. Circulation: Genomic and Precision Medicine. 2014; 7:304-310. https://doi.org/10.1161/CIRCGENETICS.113.000400

[xi] American Heart Association New research project aims to set standardized approach to lipoprotein(a) management. March 24, 2023. https://newsroom.heart.org/news/new-research-project-aims-to-set-standardized-approach-to-lipoprotein-a-management. Accessed Aug. 22, 2023.

[xii] Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association. Journal of Clinical Lipidology. 2022;16:e77-e-95. https://www.lipidjournal.com/action/showPdf?pii=S1933-2874%2822%2900244-6

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