Elsevier

Atherosclerosis Supplements

Volume 18, May 2015, Pages 263-267
Atherosclerosis Supplements

Lipoprotein(a) – An independent causal risk factor for cardiovascular disease and current therapeutic options

https://doi.org/10.1016/j.atherosclerosissup.2015.02.039Get rights and content

Abstract

It is widely accepted that elevated levels of lipoprotein(a) (Lp(a)) are associated with an increased risk for cardiovascular diseases. Several studies have identified Lp(a) as independent cardiovascular risk factor. Consequently, therapeutic concepts are targeting at lowering Lp(a) serum levels. To date, in Europe no pharmaceutical treatment to lower levels of Lp(a) is available. Current developments of pharmaceutical agents like the apolipoprotein-(B-100)-antisense mipomersen, inhibitors of PCSK9 and apolipoprotein-(a)-antisense have shown promising results in lowering Lp(a). Presently, the only available therapy to effectively reduce levels of Lp(a) is regular extracorporeal lipoprotein apheresis. Different apheresis methods show a similar lowering effect of about 60–70 % by a single session. Apart from one small-scale study there has been no randomized, controlled study which could prove that lowering Lp(a) will result in a risk reduction for cardiovascular disease. This review looks into the current scientific evidence of

  • i) Lp(a) as an independent cardiovascular risk factor;

  • ii) risk stratification for Lp(a), especially which patients should be screened;

  • iii) lipoprotein apheresis effectiveness in lowering Lp(a) levels as well as cardiovascular outcome parameters;

  • iv) new pharmaceutical agents targeting at lowering Lp(a) serum levels.

Introduction

Lipoprotein-(a) (Lp(a)) is a complex of a low-density lipoprotein (LDL)-like particle and apolipoprotein-(B-100) covalently bound to apolipoprotein-a [1]. It has been first described by Berg about 50 years ago who found high serum levels of Lp(a) to be inherited and associated with an increased risk for premature cardiovascular disease (CVD) [2], [3]. The physiological function of Lp(a) and its effects on the vasculature remain indefinite to date. It was found that Lp(a) is able to enter the intima of blood vessels in humans and animals [4]. There it may contribute to inflammation of the intima, thrombosis and foam cell formation – processes that are known to be involved in the development of arteriosclerosis [5], [6]. Serum levels of Lp(a) show a widespread variation between individuals and race (<0.1 mg/dL to >250 mg/dL), whereas they are more or less stable within an individual over time [7]. Diet, physical exercise and other environmental influences seem not to alter serum levels of Lp(a) significantly [8]. In fact, they are predominantly determined by the size of the apolipoprotein-a isoforms which are encoded by different variations of the LPA-gene [9]. Utermann ascertained an inverse relationship between the size of apo-a isoform and the corresponding Lp(a) concentration [10]. Furthermore, Erqou found high Lp(a) concentrations and low molecular weight of apolipoprotein-a isoforms associated with a high risk for CVD [11]. More recently, an analysis of a subsample of white participants of the JUPITER study revealed that concomitant elevated Lp(a) levels represent a significant determinant of residual risk for CVD in participants whose LDL levels were very low under potent statin therapy [12].

Section snippets

Lipoprotein(a) as independent, causal risk factor for cardiovascular disease

The Copenhagen Heart Study could show that individuals with Lp(a) levels > 50 mg/dl have an 2- to 3-fold increased risk to suffer from myocardial infarction [13]. Later, the Emerging Risk Factors Collaboration performed a meta-analysis to further investigate the dosing effect of Lp(a) concentration. They investigated patient data of 36 studies to determine the association between Lp(a) concentration with the risk for coronary heart disease (CHD) and stroke [5]. They found that each 3.5-fold

Which patient groups should be screened for Lp(a)?

The European Atherosclerosis Society Consensus Panel recommended that Lp(a) should be measured in patients with intermediate or high risk for CVD or CHD. In particular, they suggest to screen those patients presenting with i) premature CVD, (ii) familial hypercholesterolemia, (iii) a family history of premature CVD and/or elevated Lp(a), (iv) recurrent CVD despite statin treatment, (v) ≥3% 10-year risk of fatal CVD according to the European guidelines [17] and (vi) ≥10% 10-year risk of fatal

Therapeutic options to lower Lp(a)

Since elevated serum levels of Lp(a) are associated with an increased risk for CVD, therapeutic options targeting at lowering Lp(a) are under development. The European Atherosclerosis Society Consensus Panel considers Lp(a) concentrations below the 80th percentile (<50 mg/dl) as desirable [19]. Consequently, Lp(a) reduction would then result in lower risk for CVD expressed by the reduction of cardiovascular events or a deceleration of CVD progression in patients. Since lifestyle in general

Conclusions

Recent clinical as well as Mendelian randomization studies provide evidence for lipoprotein(a) to be an independent, causal risk factor for cardiovascular disease. The European Atherosclerosis Society Consensus Panel defined criteria to identify patients at high risk, who should be screened for elevated Lp(a). Since diet, exercise and lifestyle in general have no effect on Lp(a) regular lipoprotein apheresis is currently the only therapy to reduce Lp(a). Current studies suggest that lowering of

Conflict of interest

TS received honoraria for lectures by Fresenius Medical Care Germany. AR received speakers' honoraria for presentations and advisory board activities by Fresenius Medical Care Germany and Braun. UK received speakers' honoraria for presentations and advisory board activities by Fresenius Medical Care Germany, Amgen and Sanofi. ESTH received speakers' honoraria for presentations and advisory board activities by Fresenius Medical Care Germany, Amgen and Sanofi.

References (37)

  • M. von Dryander et al.

    Differences in the atherogenic risk of patients treated by lipoprotein apheresis according to their lipid pattern

    Atheroscler Suppl

    (2013)
  • G.R. Thompson et al.

    Lipoprotein(a): the underestimated cardiovascular risk factor

    Heart

    (2014)
  • K. Berg

    A new serum type system in man–the Lp system

    Acta Pathol Microbiol Scand

    (1963)
  • L.B. Nielsen et al.

    In vivo transfer of lipoprotein(a) into human atherosclerotic carotid arterial intima

    Arterioscler Thromb Vasc Biol

    (1997)
  • S. Erqou et al.

    Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality

    JAMA

    (2009)
  • F. Kronenberg et al.

    Lipoprotein(a): resurrected by genetics

    J Intern Med

    (2013)
  • A.M. Scanu et al.

    Lipoprotein (a). Heterogeneity and biological relevance

    J Clin Invest

    (1990)
  • G. Utermann et al.

    Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma

    J Clin Invest

    (1987)
  • Cited by (47)

    • Application of low molecular weight and high molecular weight biosurfactant in medicine/biomedical/pharmaceutical industries

      2022, Green Sustainable Process for Chemical and Environmental Engineering and Science: Biomedical Application of Biosurfactant in Medical Sector
    • Specific Lp(a) apheresis: A tool to prove lipoprotein(a) atherogenicity

      2017, Atherosclerosis Supplements
      Citation Excerpt :

      Hitherto therapeutic approaches targeting Lp(a) have been limited to niacin (unavailable in the EU due to concerns about side effects and lack of efficacy) and lipoprotein apheresis [1,3]. Several novel drugs decreasing low-density lipoprotein (LDL) levels such as antisense oligonucleotide (ASO) and PCSK9 inhibitors, are also possess a moderate Lp(a)-lowering potential [4]. A specific apolipoprotein(a) ASO reduces apo(a)-mRNA and Lp(a) by up to 86% [5], however, no randomized trials so far demonstrated improvemed ASCVD outcomes due to Lp(a) reduction.

    View all citing articles on Scopus
    1

    Ursula Kassner and Thomas Schlabs contributed equally to this manuscript.

    View full text