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Vaccines Targeting PCSK9: A Promising Alternative to Passive Immunization with Monoclonal Antibodies in the Management of Hyperlipidaemia?

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Abstract

Hypercholesterolaemia is frequently observed in patients with cardiovascular diseases (CVD) and is associated with increased mortality. Statin treatment has been the standard of care for reducing low-density lipoprotein cholesterol (LDL-C) to improve cardiovascular outcomes. However, statins have limited effects in some patients and may be discontinued due to adverse effects resulting in LDL-C above target levels. The proprotein convertase subtilisin kexin type 9 (PCSK9) is a pivotal regulator in the LDL-C metabolism by degrading the LDL-C receptor on hepatocytes. Inhibition of PCSK9 by monoclonal antibodies (mAb) significantly lowers LDL-C levels and is considered to reduce the likelihood of adverse cardiac events. However, such treatment regimens are not cost-effective, and require frequent administrations at high doses that may be associated with side effects and poor drug adherence. Furthermore, it has been shown that these PCSK9 medicines may trigger the formation of antidrug antibodies followed by a significant attenuation of the LDL-C-lowering effect. Active vaccination inducing high-affinity antibodies against PCSK9 with less frequent administration intervals may be a novel promising therapeutic approach to overcome the drawback of passive immunization with PCSK9 mAb. However there is a paucity of available clinical safety and efficacy data. This article discusses challenges in the development of PCSK9 vaccines and their potential therapeutic benefits by reviewing clinical studies that evaluated the safety and efficacy of PCSK9 mAb.

Notes

Compliance with ethical standards

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Stefan Weisshaar and Markus Zeitlinger declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

References

  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:e38–360.CrossRefPubMedGoogle Scholar
  2. 2.
    Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–9.Google Scholar
  3. 3.
    Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.CrossRefGoogle Scholar
  4. 4.
    Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18:220–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Jacobson TA, Maki KC, Orringer CE, et al. National lipid association recommendations for patient—centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(S1–122):e121.Google Scholar
  7. 7.
    Lin L, Teng M, Zhao YJ, et al. Long-term cost-effectiveness of statin treatment for primary prevention of cardiovascular disease in the elderly. Cardiovasc Drugs Ther. 2015;29:187–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Braamskamp M, Langslet G, McCrindle BW, et al. Efficacy and safety of rosuvastatin therapy in children and adolescents with familial hypercholesterolemia: Results from the CHARON study. J Clin Lipidol. 2015;9:741–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Raal FJ, Pappu AS, Illingworth DR, et al. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia. Atherosclerosis. 2000;150:421–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Langslet G, Breazna A, Drogari E. A 3-year study of atorvastatin in children and adolescents with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2016;10(1153–1162):e1153.CrossRefGoogle Scholar
  11. 11.
    Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403–14.CrossRefPubMedGoogle Scholar
  12. 12.
    Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther. 2007;29:253–60.CrossRefPubMedGoogle Scholar
  13. 13.
    Cohen JD, Brinton EA, Ito MK, et al. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012;6:208–15.CrossRefPubMedGoogle Scholar
  14. 14.
    Cheetham TC, Niu F, Green K, et al. Primary nonadherence to statin medications in a managed care organization. J Manag Care Pharm. 2013;19:367–73.PubMedGoogle Scholar
  15. 15.
    Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA. 2002;288:462–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Bellosta S, Corsini A. Statin drug interactions and related adverse reactions: an update. Expert Opin Drug Saf. 2018;17:25–37.CrossRefPubMedGoogle Scholar
  17. 17.
    Karr S. Epidemiology and management of hyperlipidemia. Am J Manag Care. 2017;23:S139–48.PubMedGoogle Scholar
  18. 18.
    Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50(Suppl):S172–7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Peterson AS, Fong LG, Young SG. PCSK9 function and physiology. J Lipid Res. 2008;49:1595–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rashid S, Curtis DE, Garuti R, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA. 2005;102:5374–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005;102:2069–74.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Luo Y, Warren L, Xia D, et al. Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice. J Lipid Res. 2009;50:1581–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zaid A, Roubtsova A, Essalmani R, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology. 2008;48:646–54.CrossRefPubMedGoogle Scholar
  24. 24.
    Grefhorst A, McNutt MC, Lagace TA, et al. Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J Lipid Res. 2008;49:1303–11.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.CrossRefPubMedGoogle Scholar
  26. 26.
    Kotowski IK, Pertsemlidis A, Luke A, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006;78:410–22.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Cunningham D, Danley DE, Geoghegan KF, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol. 2007;14:413–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Food and Drug Administration. Praluent Alirocumab. 2015.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125559Orig1s000TOC.cfm. Accessed 18 Jan 2018.
  31. 31.
  32. 32.
    Food and Drug Administration. Repatha Evolocumab. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125522s000lbl.pdf. Accessed 18 Jan 2018.
  33. 33.
  34. 34.
    Pfizer. Pfizer discontinues global development of bococizumab, its investigational PCSK9 inhibitor. 2016. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_inhibitor. Accessed 14 Dec 2017.
  35. 35.
    Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med. 2017;376:1517–26.CrossRefPubMedGoogle Scholar
  36. 36.
    Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527–39.CrossRefPubMedGoogle Scholar
  37. 37.
    Ridker PM, Amarenco P, Brunell R, et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials. Am Heart J. 2016;178:135–44.CrossRefPubMedGoogle Scholar
  38. 38.
    Manniello M, Pisano M. Alirocumab (Praluent): first in the new class of PCSK9 inhibitors. P T. 2016;41:28–53.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.CrossRefPubMedGoogle Scholar
  40. 40.
    Zhang XL, Zhu QQ, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med. 2015;13:123.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Zhu Y, Shen X, Jiang Q, et al. Effects of monoclonal antibodies against PCSK9 on clinical cardiovascular events: a meta-analysis of randomized controlled trials. Herz. 2017.  https://doi.org/10.1007/s00059-017-4640-8.Google Scholar
  42. 42.
    Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 odyssey trials comparing alirocumab with control. Circulation. 2016;134:1931–43.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014;168:682–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Sanofi. Praluent® (alirocumab) significantly reduced risk of cardiovascular events in high-risk patients, and was associated with lower death rate 2018. http://mediaroom.sanofi.com/praluent-alirocumab-significantly-reduced-risk-of-cardiovascular-events-in-high-risk-patients-and-was-associated-with-lower-death-rate/. Accessed 29 Mar 2018.
  45. 45.
    European Medicines Agency. Product information—Repatha. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003766/WC500191398.pdf. Accessed 18 Jan 2018.
  46. 46.
    Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341–50.CrossRefPubMedGoogle Scholar
  47. 47.
    Stein EA, Honarpour N, Wasserman SM, et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation. 2013;128:2113–20.CrossRefPubMedGoogle Scholar
  48. 48.
    Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007–17.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995–2006.CrossRefPubMedGoogle Scholar
  51. 51.
    Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408–17.CrossRefPubMedGoogle Scholar
  52. 52.
    Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497–506.CrossRefPubMedGoogle Scholar
  53. 53.
    Hirayama A, Honarpour N, Yoshida M, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk–primary results from the phase 2 YUKAWA study. Circ J. 2014;78:1073–82.CrossRefPubMedGoogle Scholar
  54. 54.
    Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–19.CrossRefPubMedGoogle Scholar
  55. 55.
    Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311:1870–82.CrossRefPubMedGoogle Scholar
  56. 56.
    Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531–40.CrossRefPubMedGoogle Scholar
  57. 57.
    Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2541–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331–40.CrossRefPubMedGoogle Scholar
  59. 59.
    Dent R, Joshi R, Stephen Djedjos C, et al. Evolocumab lowers LDL-C safely and effectively when self-administered in the at-home setting. Springerplus. 2016;5:300.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia: Results Up to 4 Years From the Open-Label OSLER-1 Extension Study. JAMA Cardiol. 2017;2:598–607.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Toth PP, Worthy G, Gandra SR, et al. Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia. J Am Heart Assoc 2017;6(10).  https://doi.org/10.1161/JAHA.116.005367.
  62. 62.
    Schmidt AF, Pearce LS, Wilkins JT, et al. Cochrane corner: PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Heart. 2018.  https://doi.org/10.1136/heartjnl-2017-312858.PubMedGoogle Scholar
  63. 63.
    Sabatine MS, Giugliano RP, Pedersen TR. Evolocumab in patients with cardiovascular disease. N Engl J Med. 2017;377:787–8.PubMedGoogle Scholar
  64. 64.
    Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390:1962–71.CrossRefPubMedGoogle Scholar
  65. 65.
    Gumbiner B, Joh T, Liang H, et al. The effects of single- and multiple-dose administration of bococizumab (RN316/PF-04950615), a humanized IgG2Deltaa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies. Cardiovasc Ther. 2018.  https://doi.org/10.1111/1755-5922.12309.Google Scholar
  66. 66.
    Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015;115:1212–21.CrossRefPubMedGoogle Scholar
  67. 67.
    Schroeder KM, Beyer TP, Hansen RJ, et al. Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody. J Lipid Res. 2015;56:2124–32.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Hansen RJ, Berna MJ, Sperry AE, et al. Quantitative characterization of the mechanism of action and impact of a ‘proteolysis-permitting’ anti-PCSK9 antibody. MAbs. 2017;9:285–96.CrossRefPubMedGoogle Scholar
  69. 69.
    Shen T, James DE, Krueger KA. Population Pharmacokinetics (PK) and Pharmacodynamics (PD) Analysis of LY3015014, a Monoclonal Antibody to Protein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Healthy Subjects and Hypercholesterolemia Patients. Pharm Res. 2017;34:185–92.CrossRefPubMedGoogle Scholar
  70. 70.
    Kastelein JJ, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study. Eur Heart J. 2016;37:1360–9.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Hlatky MA, Kazi DS. PCSK9 inhibitors: economics and policy. J Am Coll Cardiol. 2017;70:2677–87.CrossRefPubMedGoogle Scholar
  72. 72.
    Anderson JL, Heidenreich PA, Barnett PG, et al. ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2304–22.CrossRefPubMedGoogle Scholar
  73. 73.
    Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305:1460–8.CrossRefPubMedGoogle Scholar
  74. 74.
    Galabova G, Brunner S, Winsauer G, et al. Peptide-based anti-PCSK9 vaccines—an approach for long-term LDLc management. PLoS One. 2014;9:e114469.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Schneeberger A, Mandler M, Otawa O, et al. Development of AFFITOPE vaccines for Alzheimer’s disease (AD)—from concept to clinical testing. J Nutr Health Aging. 2009;13:264–7.CrossRefPubMedGoogle Scholar
  76. 76.
    Ferrer I, Boada Rovira M, Sanchez Guerra ML, et al. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol. 2004;14:11–20.CrossRefPubMedGoogle Scholar
  77. 77.
    Chackerian B, Durfee MR, Schiller JT. Virus-like display of a neo-self antigen reverses B cell anergy in a B cell receptor transgenic mouse model. J Immunol. 2008;180:5816–25.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Crossey E, Amar MJ, Sampson M, et al. A cholesterol-lowering VLP vaccine that targets PCSK9. Vaccine. 2015;33:5747–55.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Landlinger C, Pouwer MG, Juno C, et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. Eur Heart J. 2017;38:2499–507.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Pan Y, Zhou Y, Wu H, et al. A therapeutic peptide vaccine against PCSK9. Sci Rep. 2017;7:12534.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Kawakami R, Nozato Y, Nakagami H, et al. Development of vaccine for dyslipidemia targeted to a proprotein convertase subtilisin/kexin type 9 (PCSK9) epitope in mice. PLoS One. 2018;13:e0191895.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Krähenbühl S, Pavik-Mezzour I, von Eckardstein A. Unmet needs in LDL-C lowering: when statins won’t do! Drugs. 2016;76:1175–90.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyMedical University of ViennaViennaAustria

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