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Emerging Therapeutic Options for Lowering of Lipoprotein(a): Implications for Prevention of Cardiovascular Disease

  • Clinical Trials and Their Interpretations (J. Kizer, Section Editor)
  • Published:
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Abstract

Purpose of Review

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an independent and causal risk factor for cardiovascular diseases including coronary artery disease, ischemic stroke, and calcific aortic valve stenosis. This review summarizes the rationale for Lp(a) lowering and surveys relevant clinical trial data using a variety of agents capable of lowering Lp(a).

Recent Findings

Contemporary guidelines and recommendations outline populations of patients who should be screened for elevated Lp(a) and who might benefit from Lp(a) lowering. Therapies including drugs and apheresis have been described that lower Lp(a) levels modestly (∼20 %) to dramatically (∼80 %). Existing therapies that lower Lp(a) also have beneficial effects on other aspects of the lipid profile, with the exception of Lp(a)-specific apheresis and an antisense oligonucleotide that targets the mRNA encoding apolipoprotein(a).

Summary

No clinical trials conducted to date have managed to answer the key question of whether Lp(a) lowering confers a benefit in terms of ameliorating cardiovascular risk, although additional outcome trials of therapies that lower Lp(a) are ongoing. It is more likely, however, that Lp(a)-specific agents will provide the most appropriate approach for addressing this question.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518–28.

    Article  CAS  PubMed  Google Scholar 

  2. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301(22):2331–9.

    Article  CAS  PubMed  Google Scholar 

  3. Helgadottir A, Gretarsdottir S, Thorleifsson G, Holm H, Patel RS, Gudnason T, et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol. 2012;60(8):722–9.

    Article  CAS  PubMed  Google Scholar 

  4. Emerging Risk Factors C, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412–23.

    Article  Google Scholar 

  5. • Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503–12. A landmark report identifying elevated Lp(a) as a causal risk factor for CAVD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987;330(6144):132–7.

    Article  CAS  PubMed  Google Scholar 

  7. Castellino FJ, McCance SG. The kringle domains of human plasminogen. Ciba Found Symp. 1997;212:46–60. discussion -5.

    CAS  PubMed  Google Scholar 

  8. van der Hoek YY, Wittekoek ME, Beisiegel U, Kastelein JJ, Koschinsky ML. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms. Hum Mol Genet. 1993;2(4):361–6.

    Article  PubMed  Google Scholar 

  9. Lackner C, Cohen JC, Hobbs HH. Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet. 1993;2(7):933–40.

    Article  CAS  PubMed  Google Scholar 

  10. Marcovina SM, Albers JJ, Wijsman E, Zhang Z, Chapman NH, Kennedy H. Differences in Lp[a] concentrations and apo[a] polymorphs between Black and White Americans. J Lipid Res. 1996;37(12):2569–85.

    CAS  PubMed  Google Scholar 

  11. Koschinsky ML, Cote GP, Gabel B, van der Hoek YY. Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100. J Biol Chem. 1993;268(26):19819–25.

    CAS  PubMed  Google Scholar 

  12. Hughes SD, Lou XJ, Ighani S, Verstuyft J, Grainger DJ, Lawn RM, et al. Lipoprotein(a) vascular accumulation in mice. In vivo analysis of the role of lysine binding sites using recombinant adenovirus. J Clin Invest. 1997;100(6):1493–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, et al. Determinants of binding of oxidized phospholipids on apolipoprotein(a) and lipoprotein(a). J Lipid Res. 2013;54(10):2815–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gabel BR, Koschinsky MI. Analysis of the proteolytic activity of a recombinant form of apolipoprotein(a). Biochemistry. 1995;34(48):15777–84.

    Article  CAS  PubMed  Google Scholar 

  15. Cho T, Jung Y, Koschinsky ML. Apolipoprotein(a), through its strong lysine-binding site in KIV(10′), mediates increased endothelial cell contraction and permeability via a Rho/Rho kinase/MYPT1-dependent pathway. J Biol Chem. 2008;283(45):30503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Allen S, Khan S, Tam S, Koschinsky M, Taylor P, Yacoub M. Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity. FASEB J. 1998;12(15):1765–76.

    CAS  PubMed  Google Scholar 

  17. Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice. Nature. 1994;370(6489):460–2.

    Article  CAS  PubMed  Google Scholar 

  18. O’Neil CH, Boffa MB, Hancock MA, Pickering JG, Koschinsky ML. Stimulation of vascular smooth muscle cell proliferation and migration by apolipoprotein(a) is dependent on inhibition of transforming growth factor-beta activation and on the presence of kringle IV type 9. J Biol Chem. 2004;279(53):55187–95.

    Article  PubMed  Google Scholar 

  19. van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation. 2016.

  20. Seimon TA, Nadolski MJ, Liao X, Magallon J, Nguyen M, Feric NT, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010;12(5):467–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Scipione CA, Sayegh SE, Romagnuolo R, Tsimikas S, Marcovina SM, Boffa MB, et al. Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a). J Lipid Res. 2015;56(12):2273–85.

    Article  CAS  PubMed  Google Scholar 

  22. Boffa MB, Marcovina SM, Koschinsky ML. Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models. Clin Biochem. 2004;37(5):333–43.

    Article  CAS  PubMed  Google Scholar 

  23. Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest. 1992;90(1):52–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273(1):6–30.

    Article  CAS  PubMed  Google Scholar 

  25. White AL, Guerra B, Lanford RE. Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulum. J Biol Chem. 1997;272(8):5048–55.

    Article  CAS  PubMed  Google Scholar 

  26. Frischmann ME, Ikewaki K, Trenkwalder E, Lamina C, Dieplinger B, Soufi M, et al. In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a). Atherosclerosis. 2012;225(2):322–7.

    Article  CAS  PubMed  Google Scholar 

  27. Rader DJ, Cain W, Ikewaki K, Talley G, Zech LA, Usher D, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate. J Clin Invest. 1994;93(6):2758–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cain WJ, Millar JS, Himebauch AS, Tietge UJ, Maugeais C, Usher D, et al. Lipoprotein[a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein[a]. J Lipid Res. 2005;46(12):2681–91.

    Article  CAS  PubMed  Google Scholar 

  29. Hoover-Plow J, Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism. 2013;62(4):479–91.

    Article  CAS  PubMed  Google Scholar 

  30. Tam SP, Zhang X, Koschinsky ML. Interaction of a recombinant form of apolipoprotein[a] with human fibroblasts and with the human hepatoma cell line HepG2. J Lipid Res. 1996;37(3):518–33.

    CAS  PubMed  Google Scholar 

  31. Argraves KM, Kozarsky KF, Fallon JT, Harpel PC, Strickland DK. The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. J Clin Invest. 1997;100(9):2170–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marz W, Beckmann A, Scharnagl H, Siekmeier R, Mondorf U, Held I, et al. Heterogeneous lipoprotein (a) size isoforms differ by their interaction with the low density lipoprotein receptor and the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. FEBS Lett. 1993;325(3):271–5.

    Article  CAS  PubMed  Google Scholar 

  33. Niemeier A, Willnow T, Dieplinger H, Jacobsen C, Meyer N, Hilpert J, et al. Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro. Arterioscler Thromb Vasc Biol. 1999;19(3):552–61.

    Article  CAS  PubMed  Google Scholar 

  34. Yang XP, Amar MJ, Vaisman B, Bocharov AV, Vishnyakova TG, Freeman LA, et al. Scavenger receptor-BI is a receptor for lipoprotein(a). J Lipid Res. 2013;54(9):2450–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Marcovina SM, Albers JJ, Jacobs Jr DR, Perkins LL, Lewis CE, Howard BV, et al. Lipoprotein[a] concentrations and apolipoprotein[a] phenotypes in Caucasians and African Americans. The CARDIA study. Arterioscler Thromb. 1993;13(7):1037–45.

    Article  CAS  PubMed  Google Scholar 

  36. Lanktree MB, Anand SS, Yusuf S, Hegele RA, Investigators S. Comprehensive analysis of genomic variation in the LPA locus and its relationship to plasma lipoprotein(a) in South Asians, Chinese, and European Caucasians. Circ Cardiovasc Genet. 2010;3(1):39–46.

    Article  CAS  PubMed  Google Scholar 

  37. Brown WV, Ballantyne CM, Jones PH, Marcovina S. Management of Lp(a). J Clin Lipidol. 2010;4(4):240–7.

    Article  PubMed  Google Scholar 

  38. Khalifa M, Noureen A, Ertelthalner K, Bandegi AR, Delport R, Firdaus WJ, et al. Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians. Atherosclerosis. 2015;242(2):521–8.

    Article  CAS  PubMed  Google Scholar 

  39. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem. 2003;49(11):1785–96.

    Article  CAS  PubMed  Google Scholar 

  40. • Marcovina SM, Albers JJ. Lipoprotein(a) measurements for clinical application. J Lipid Res. 2016;57(4):526–37. Recent and incisive review concerning issues in Lp(a) measurement.

    Article  CAS  PubMed  Google Scholar 

  41. Beheshtian A, Shitole SG, Segal AZ, Leifer D, Tracy RP, Rader DJ, et al. Lipoprotein(a) level, apolipoprotein(a) size, and risk of unexplained ischemic stroke in young and middle-aged adults. Atherosclerosis. 2016;253:47–53.

    Article  CAS  PubMed  Google Scholar 

  42. Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation. 2008;117(2):176–84.

    Article  CAS  PubMed  Google Scholar 

  43. O’Donoghue ML, Morrow DA, Tsimikas S, Sloan S, Ren AF, Hoffman EB, et al. Lipoprotein(a) for risk assessment in patients with established coronary artery disease. J Am Coll Cardiol. 2014;63(6):520–7.

    Article  PubMed  Google Scholar 

  44. •• van Capelleveen JC, van der Valk FM, Stroes ES. Current therapies for lowering lipoprotein(a). J Lipid Res. 2015. Recent and comprehensive review of Lp(a)-lowering therapies.

  45. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129(6):635–42.

    Article  CAS  PubMed  Google Scholar 

  46. Dube JB, Boffa MB, Hegele RA, Koschinsky ML. Lipoprotein(a): more interesting than ever after 50 years. Curr Opin Lipidol. 2012;23(2):133–40.

    Article  CAS  PubMed  Google Scholar 

  47. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol. 2014;63(5):470–7.

    Article  CAS  PubMed  Google Scholar 

  48. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1–45.

    Article  PubMed  Google Scholar 

  49. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Davidson MH, Ballantyne CM, Jacobson TA, Bittner VA, Braun LT, Brown AS, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5(5):338–67.

    Article  PubMed  Google Scholar 

  51. Goldhaber SZ. European Atherosclerosis Society screening recommendations for lipoprotein(a) and high-sensitivity C-reactive protein: double standard or failure of evidence-based medicine? Clin Chem. 2010;56(10):1544–6.

    Article  CAS  PubMed  Google Scholar 

  52. Investigators A-H, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.

    Article  Google Scholar 

  53. Group HTC, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–12.

    Article  Google Scholar 

  54. • Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr M, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol. 2014;64(9):851–60. Directly demonstrates the clinical utility of considering Lp(a).

    Article  PubMed  Google Scholar 

  55. • Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. 2013;61(11):1146–56. Directly demonstrates the clinical utility of considering Lp(a).

    Article  CAS  PubMed  Google Scholar 

  56. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–81.

    Article  PubMed  Google Scholar 

  57. •• Hung MY, Tsimikas S. What is the ultimate test that lowering lipoprotein(a) is beneficial for cardiovascular disease and aortic stenosis? Curr Opin Lipidol. 2014;25(6):423–30. Excellent review that is particularly insightful regarding challenges in clinical trial design and interpretation.

    Article  CAS  PubMed  Google Scholar 

  58. de Bruin TW, van Barlingen H, van Linde-Sibenius TM, van Vuurst de Vries AR, Akveld MJ, Erkelens DW. Lipoprotein(a) and apolipoprotein B plasma concentrations in hypothyroid, euthyroid, and hyperthyroid subjects. J Clin Endocrinol Metab. 1993;76(1):121–6.

    PubMed  Google Scholar 

  59. Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–16.

    Article  CAS  PubMed  Google Scholar 

  60. Sjouke B, Langslet G, Ceska R, Nicholls SJ, Nissen SE, Ohlander M, et al. Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study. Lancet Diabetes Endocrinol. 2014;2(6):455–63.

    Article  CAS  PubMed  Google Scholar 

  61. Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu Rev Nutr. 2000;20:663–97.

    Article  CAS  PubMed  Google Scholar 

  62. Schonfeld G. Familial hypobetalipoproteinemia: a review. J Lipid Res. 2003;44(5):878–83.

    Article  CAS  PubMed  Google Scholar 

  63. Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013;62(23):2178–84.

    Article  CAS  PubMed  Google Scholar 

  64. Samaha FF, McKenney J, Bloedon LT, Sasiela WJ, Rader DJ. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2008;5(8):497–505.

    Article  CAS  PubMed  Google Scholar 

  65. Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol. 2015;35(3):689–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Visser ME, Witztum JL, Stroes ES, Kastelein JJ. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J. 2012;33(12):1451–8.

    Article  CAS  PubMed  Google Scholar 

  67. Stein EA, Raal F. Future directions to establish lipoprotein(a) as a treatment for atherosclerotic cardiovascular disease. Cardiovasc Drugs Ther. 2016;30(1):101–8.

    Article  CAS  PubMed  Google Scholar 

  68. Gurakar A, Hoeg JM, Kostner G, Papadopoulos NM, Brewer Jr HB. Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis. 1985;57(2-3):293–301.

    Article  CAS  PubMed  Google Scholar 

  69. Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH, et al. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Arch Intern Med. 1994;154(14):1586–95.

    Article  CAS  PubMed  Google Scholar 

  70. Stein EA, Davidson MH, Dujovne CA, Hunninghake DB, Goldberg RB, Illingworth DR, et al. Efficacy and tolerability of low-dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial. J Cardiovasc Pharmacol Ther. 1996;1(2):107–16.

    CAS  PubMed  Google Scholar 

  71. Capuzzi DM, Guyton JR, Morgan JM, Goldberg AC, Kreisberg RA, Brusco OA, et al. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol. 1998;82(12A):74U–81U. discussion 5U-6U.

    Article  CAS  PubMed  Google Scholar 

  72. Chennamsetty I, Kostner KM, Claudel T, Vinod M, Frank S, Weiss TS, et al. Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice. J Lipid Res. 2012;53(11):2405–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. • Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich Jr PO, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1575–9. The only analysis of an outcome trial specifically addressing the role of Lp(a) lowering.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406–15.

    Article  CAS  PubMed  Google Scholar 

  75. Kastelein JJ, Besseling J, Shah S, Bergeron J, Langslet G, Hovingh GK, et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2015;385(9983):2153–61.

    Article  CAS  PubMed  Google Scholar 

  76. Hovingh GK, Kastelein JJ, van Deventer SJ, Round P, Ford J, Saleheen D, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2015;386(9992):452–60.

    Article  CAS  PubMed  Google Scholar 

  77. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53(12):2515–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114(6):1022–36.

    Article  CAS  PubMed  Google Scholar 

  79. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59(25):2344–53.

    Article  CAS  PubMed  Google Scholar 

  80. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367(20):1891–900.

    Article  CAS  PubMed  Google Scholar 

  81. Desai NR, Kohli P, Giugliano RP, O’Donoghue ML, Somaratne R, Zhou J, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation. 2013;128(9):962–9.

    Article  CAS  PubMed  Google Scholar 

  82. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63(13):1278–88.

    Article  CAS  PubMed  Google Scholar 

  83. Stein EA, Giugliano RP, Koren MJ, Raal FJ, Roth EM, Weiss R, et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J. 2014;35(33):2249–59.

    Article  CAS  PubMed  Google Scholar 

  84. Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014;114(5):711–5.

    Article  CAS  PubMed  Google Scholar 

  85. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Blom D, Seidah NG, et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res. 2016;57(6):1086–96.

    Article  CAS  PubMed  Google Scholar 

  86. Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, et al. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest. 1995;95(3):1403–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Romagnuolo R, Scipione CA, Boffa MB, Marcovina SM, Seidah NG, Koschinsky ML. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem. 2015;290(18):11649–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mayne J, Dewpura T, Raymond A, Cousins M, Chaplin A, Lahey KA, et al. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis. 2008;7:22.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Villard EF, Poirier B, Guillot E, Le Bail JC, Blankenstein J, Lambert G, et al. PCSK9 increases Lp(a) secretion in primary human hepatocytes without modifying Lp(a) uptake. Poster presentation, 17th International Symposium On Atherosclerosis, Amsterdam. 2015.

  90. Croyal M, Ouguerram K, Passard M, Ferchaud-Roucher V, Chetiveaux M, Billon-Crossouard S, et al. Effects of extended-release nicotinic acid on apolipoprotein (a) kinetics in hypertriglyceridemic patients. Arterioscler Thromb Vasc Biol. 2015.

  91. Ooi EM, Watts GF, Chan DC, Pang J, Tenneti VS, Hamilton SJ, et al. Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2015;35(12):2686–93.

    Article  CAS  PubMed  Google Scholar 

  92. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128(19):2113–20.

    Article  CAS  PubMed  Google Scholar 

  93. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341–50.

    Article  CAS  PubMed  Google Scholar 

  94. • Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99. Largest single trial showing extent of Lp(a) lowering by alirocumab.

    Article  CAS  PubMed  Google Scholar 

  95. • Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9. Largest single trial showing extent of Lp(a) lowering by evolocumab.

    Article  CAS  PubMed  Google Scholar 

  96. • Waldmann E, Parhofer KG. Lipoprotein apheresis to treat elevated lipoprotein(a). J Lipid Res. 2016. Detailed review of use of apheresis methods to lower Lp(a).

  97. Safarova MS, Ezhov MV, Afanasieva OI, Matchin YG, Atanesyan RV, Adamova IY, et al. Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography. Atheroscler Suppl. 2013;14(1):93–9.

    Article  CAS  PubMed  Google Scholar 

  98. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med. 2009;6(3):229–39.

    Article  CAS  PubMed  Google Scholar 

  99. Rosada A, Kassner U, Vogt A, Willhauck M, Parhofer K, Steinhagen-Thiessen E. Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) levels reduce the incidence of cardiovascular events? Artif Organs. 2014;38(2):135–41.

    Article  CAS  PubMed  Google Scholar 

  100. • Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breitenberger P, et al. Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apo(a) characterization. Arterioscler Thromb Vasc Biol. 2016. Most recent and largest analysis of effect of apheresis on Lp(a) levels and CVD events.

  101. Thompson GR, Maher VM, Matthews S, Kitano Y, Neuwirth C, Shortt MB, et al. Familial Hypercholesterolaemia Regression Study: a randomised trial of low-density-lipoprotein apheresis. Lancet. 1995;345(8953):811–6.

    Article  CAS  PubMed  Google Scholar 

  102. Graham MJ, Viney N, Crooke RM, Tsimikas S. Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans. J Lipid Res. 2016;57(3):340–51.

    Article  CAS  PubMed  Google Scholar 

  103. •• Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker BF, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;386(10002):1472–83. First clinical trial of a therapy specifically aimed at Lp(a) lowering.

    Article  CAS  PubMed  Google Scholar 

  104. Tsimikas S. Lipoprotein(a): novel target and emergence of novel therapies to lower cardiovascular disease risk. Curr Opin Endocrinol Diabetes Obes. 2016;23(2):157–64.

    Article  CAS  PubMed  Google Scholar 

  105. Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 2014;42(13):8796–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Biochemistry, Room 4245A Robarts Research Institute, University of Western Ontario, 1151 Richmond Street North, London, ON, Canada, N6A 5B7

    Michael B. Boffa

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Boffa, M.B. Emerging Therapeutic Options for Lowering of Lipoprotein(a): Implications for Prevention of Cardiovascular Disease. Curr Atheroscler Rep 18, 69 (2016). https://doi.org/10.1007/s11883-016-0622-1

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