Lipoprotein(a): Why is it important?

ABSTRACT: Elevated lipoprotein(a) is an independent risk factor for cardiovascular disease, particularly in individuals with elevated low-density-lipoprotein cholesterol. Candidates for lipoprotein(a) screening include patients with familial hypercholesterolemia, those with personal or family history of premature cardiovascular disease, or those with recurrent cardiovascular events despite treatment with statins. While niacin is the most effective pharmalogical agent for lowering Lp(a) levels, the initial step should be to decrease risk due to Lp(a) by lowering LDL-C below 2.0 mmol/L with a statin.

Selected patients may need to use niacin alone or in combination with a statin to lower elevated Lp(a) levels and reduce cardiovascular disease risk.

Although lipoprotein(a) or Lp(a) was discovered 50 years ago, its role in cardiovascular disease (CVD) still challenges both basic scientists and clinicians. Elevated Lp(a) is an independent risk factor for atherosclerotic coronary artery disease (CAD) and stroke, particularly in those with high low-density-lipoprotein cholesterol (LDL-C) or non-high-density-lipoprotein cholesterol (non-HDL-C) levels.[1,2] The association of elevated Lp(a) with an increased risk of cardiovascular mortality and morbidity suggests that lowering Lp(a) using the therapeutic options available may be beneficial.

Lp(a) and cardiovascular disease
Lp(a) consists of an LDL particle attached to apolipoprotein(a) or apo(a)—a distinct protein responsible for the functional properties of Lp(a).[1,2] The presence of apo(a) increases the density of Lp(a) compared with LDL-C, and reduces its affinity for the LDL receptor. Lp(a) also promotes thrombosis by interfering with the fibrinolytic pathway.[3,4] There is considerable heterogeneity in the size and molecular weight of apo(a), both of which are determined by the LPA gene.[1-4]

Several studies have found an independent and continuous association between Lp(a) and CVD,[1,2] while others indicate that the risk is markedly greater at the extreme levels of Lp(a).[5,6] The size of Lp(a) modulates CAD risk, with the smaller apo(a) isoforms associated more strongly with risk of CAD.[1-4] Polymorphism in the LPA gene also influences Lp(a) levels and increases the risk of myocardial infarction, with some common variants of the LPA gene being associated with a more than 50% risk of heart disease.[7] Lp(a) is found in a wide range of plasma concentrations (from 20 mg/L to more than 2000 mg/L), with almost 20% of individuals at the extreme levels.[1-4]

Even though elevated Lp(a) is a known CAD risk factor, the clinical utility of using elevated Lp(a) as a prognostic factor in secondary prevention is not fully established. This may be because clinical studies undertaken to date lack consistency in patient selection, doses and duration of treatment, and methods used for measuring Lp(a).[8]

Testing and treatment options
Nordestgaard and colleagues[2] recommend that Lp(a) should be measured in patients with:
•    Familial hypercholesterolemia.
•    Strong family history of CVD.
•    Personal history of premature CVD.
•    Recurrent CVD despite statin treatment.
•    Inadequate response to statins.

Repeat measurement is indicated only in individuals treated for high Lp(a).

Unlike elevated LDL-C, elevated Lp(a) is resistant to both lifestyle modification and statin treatment. Statins decrease Lp(a) only modestly.[9] In patients with familial hypercholesterolemia, statins have been shown to reduce Lp(a) by 17% to 22%.[10] The only treatment that effectively lowers Lp(a) in a dose-response manner is niacin alone or in combination with a statin.[1,2] Lowering appears to be greater at extreme Lp(a) levels, with several studies showing that niacin reduces Lp(a) by up to 40%.[1,2] Niacin also has other beneficial effects, such as reducing LDL-C and triglycerides, and raising HDL-C.[1,2]

Other agents that have a minor effect on Lp(a) (lowering levels by less than 10%) are aspirin, estrogen, thyroxine replacement, fish oil, and calcium antagonists.[2]

Lipoprotein apheresis is the most effective way to lower Lp(a).[1-4,9] Mipomersen, an antisense oligonucleotide,[1,2] is a new agent that lowers both Lp(a) and LDL by inhibiting synthesis of apolipoprotein B. The protein convertase subtilisin/kexin-type 9 (PCSK9) inhibitor and cholesterol ester transfer protein (CETP) inhibitor are two other compounds that reduce Lp(a) by 40% and 17%, respectively, but they are currently undergoing phase 3 clinical trials.[1]

Even though niacin reduces Lp(a) by 40%, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III says it is unclear if this niacin-induced reduction in Lp(a) decreases risk of CAD.[11] In patients with elevated Lp(a) in the presence of elevated LDL-C, the first LDL-C step should be to lower the level.[11] Several studies have shown that Lp(a)-associated cardiovascular risk is markedly decreased in patients with LDL-C levels below 2.0 mmol/L.[12,13] Consequently, the following treatment approaches are indicated:
•    If the Lp(a) level is greater than 300 mg/L (above the 75th percentile in most populations) the patient should be treated with a maximally tolerated dose of statin and/or other LDL-lowering medications to achieve a reduction in LDL-C below 2.0 mmol/L.
•    If LDL remains between 2.0 and 2.6 mmol/L, the addition of niacin should be considered, up to 2 g daily.
•    If LDL remains equal to or greater than 4.1 mmol/L, or if the patient has progressive CAD, LDL-C apher-esis should be considered.

Recently, Bruckert and colleagues[14] published a meta-analysis on the use of niacin in patients with elevated Lp(a) that supported the following recommendations:
•    After elevated LDL-C levels have been reduced, elevated Lp(a) levels should be reduced.
•    Elevated Lp(a) levels should be reduced in patients at intermediate or high risk of CVD, even if they do not have diabetes or established CVD.
•    Combination therapy with a statin and niacin should be used in patients with Lp(a) greater than 500 mg/L, and in those with familial hypercholesterolemia, those with a family history of premature CVD and high Lp(a), those with premature CVD, and those with recurrent CVD and resistance to statins.

Epidemiological and genetic studies have identified elevated lipoprotein(a) as an independent risk factor for cardiovascular disease. Elevated Lp(a) levels promote atherosclerosis and thrombosis. Selected patients should be screened and treated. While niacin is the most effective pharmacological agent, the first step for lowering Lp(a) should be to lower LDL-C below 2.0 mmol/L with a statin.

Competing interests
None declared.

This article has been peer reviewed.


1.    Jacobson TA. Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin Proc 2013;88:1294-1311.
2.    Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: Current status. Eur Heart J 2010;31:2844-2853.
3.    Lippi G, Guidi G. Lipoprotein(a): An emerging cardiovascular risk factor. Crit Rev Clin Lab Sci 2003;40:1-42.
4.    Dubé JB, Boffa MB, Hegele RA, et al. Lipoprotein(a): More interesting than ever after 50 years. Curr Opin Lipidol 2012;23:133-140.
5.    Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol 2013;61:1146-1156.
6.    Kamstrup PR, Benn M, Tybjærg-Hansen A, et al. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: The Copenhagen City Heart Study. Circulation 2008;117:176-184.
7.    Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009;361:2518-2528.
8.    Scanu AM, Bamba R. Niacin and lipoprotein(a): Facts, uncertainties, and clinical considerations. Am J Cardiol 2008;101:44B-47B.
9.    Lippi G, Targher G. Optimal therapy for reduction of lipoprotein(a). J Clin Pharm Ther 2012;37:1-3.
10.    van Wissen S, Smilde TJ, Trip MD, et al. Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia. Heart 2003;89:893-896.
11.    Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421.
12.    Nicholls SJ, Tang WH, Scoffone H, et al. Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy. J Lipid Res 2010;51:3055-3061.
13.    Maher VM, Brown BG, Marcovina SM, et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 1995;274:1771-1774.
14.    Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210:353-361.

Dr Saeedi is a medical biochemistry resident in the Department of Pathology and Laboratory Medicine at the University of British Columbia. Dr Li is a research associate in the Healthy Heart Program at St. Paul’s Hospital. Dr Frohlich is clinical trials director of the Healthy Heart Program, and a professor in the Department of Pathology and Laboratory Medicine at UBC.

Ramesh Saeedi, MD, PhD,, Min Li, MD, PhD,, Jiri Frohlich, MD, FRCPC. Lipoprotein(a): Why is it important?. BCMJ, Vol. 56, No. 4, March, 2014, Page(s) 180-182 - Clinical Articles.

Above is the information needed to cite this article in your paper or presentation. The International Committee of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.

About the ICMJE and citation styles

The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.

An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.

BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:

  • Only the first three authors are listed, followed by "et al."
  • There is no period after the journal name.
  • Page numbers are not abbreviated.

For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit

BCMJ Guidelines for Authors

Leave a Reply