In short Read article

PCSK9 inhibitors for familial hypercholesterolaemia


An elevated LDL-cholesterol concentration is one of the risk factors for atherosclerotic vascular disease that can be modified by lifestyle interventions or medication. Due to their greatly elevated LDL-cholesterol level, patients with familial hypercholesterolaemia (FH) have a high risk of developing this form of vascular disease at a young age. Lowering the LDL-cholesterol concentration nearly always requires pharmacotherapy. So far, however, no randomised studies among patients with FH have been conducted to investigate the effect of lowering LDL-cholesterol levels on cardiovascular endpoints. Findings of observational studies suggest that lowering the cholesterol, the dominant risk factor in FH, reduces the risk of atherosclerotic vascular disease, while randomised studies have shown the effect of lowering LDL-cholesterol levels in patients without FH. In addition, randomised research has shown that PCSK9 (proprotein-convertase subtilisin-kexin type 9) inhibitors, combined with a statin, further lower LDL cholesterol in patients without FH, and could thus also be useful. In view of their relatively high price, the use of PCSK9 inhibitors is limited to patients with a high cardiovascular risk and an excessive LDL-cholesterol concentration according to the guidelines, despite treatment with regular cholesterol-lowering agents, such as a potent statin and ezetimibe, at the maximum tolerable dosage.

What is Ge-Bu’s opinion?
  • There have been no randomised studies investigating the effect of lowering LDL-cholesterol concentrations on the risk of atherosclerotic vascular disease in patients with familial hypercholesterolaemia. Such studies are ethically unacceptable will therefore not be conducted.
  • The results of observational studies show that for patients with familial hypercholesterolaemia, there is a causal relationship between the LDL-cholesterol concentration and the development of atherosclerotic vascular disease.
  • Randomised, placebo-controlled studies have found that the use of PCSK9 inhibitors causes a further lowering of LDL-cholesterol concentrations by 50% in patients with heterozygous familial hypercholesterolaemia who are already being treated with a statin and/or ezetimibe.
  • Based on national and international guidelines, the effect of PCSK9 inhibitors for the treatment of heterozygous familial hypercholesterolaemia is assumed to have been sufficiently proven to improve the prognosis regarding atherosclerotic vascular disease.

  1. NVVC, NIV, NVIVG, NHG, NVK, Hartstichting. Reactie op Radar m.b.t. LDL-cholesterol en hart- en vaatziekten. 26 oktober 2020. Available from: https://www.nvvc.nl/Vereniging%20-%20bestuur/Nieuws/201026-reactie-op-radar-m-b-t-ldl-cholesterol-en-hart-en-vaatziekten. Accessed 8 July 2021.
  2. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-2472. doi: 10.1093/eurheartj/ehx144.
  3. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, 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 Nov 13;376(9753):1670-81. doi: 10.1016/S0140-6736(10)61350-5.
  4. Dekkers OM. Bewijskracht: gerandomiseerd of observationeel onderzoek? Gebu. 2020;54(1):1-8.
  5. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012 Aug;223(2):262-8. doi: 10.1016/j.atherosclerosis.2012.02.019.
  6. Mundal L, Igland J, Ose L, Holven KB, Veierød MB, Leren TP, et al. Cardiovascular disease mortality in patients with genetically verified familial hypercholesterolemia in Norway during 1992-2013. Eur J Prev Cardiol. 2017 Jan;24(2):137-144. doi: 10.1177/2047487316676135.
  7. Scientific Steering Committee on behalf of the Simon Broome Register Group. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Atherosclerosis. 1999 Jan;142(1):105-12.
  8. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008 Nov 11;337:a2423. doi: 10.1136/bmj.a2423.
  9. Khera AV, Won HH, Peloso GM, Lawson KS, Bartz TM, Deng X, et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J Am Coll Cardiol. 2016 Jun 7;67(22):2578-89. doi: 10.1016/j.jacc.2016.03.520.
  10. Bélanger AM, Akioyamen L, Alothman L, Genest J. Evidence for improved survival with treatment of homozygous familial hypercholesterolemia. Curr Opin Lipidol. 2020 Aug;31(4):176-181. doi: 10.1097/MOL.0000000000000686.
  11. Thompson GR, Blom DJ, Marais AD, Seed M, Pilcher GJ, Raal FJ. Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol. Eur Heart J. 2018 Apr 7;39(14):1162-1168. doi: 10.1093/eurheartj/ehx317.
  12. Humphries SE, Cooper JA, Seed M, Capps N, Durrington PN, Jones B, et al. Simon Broome Familial Hyperlipidaemia Register Group. Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register. Atherosclerosis. 2018 Jul;274:41-46. doi: 10.1016/j.atherosclerosis.2018.04.040.
  13. Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E, et al. 20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia. N Engl J Med. 2019 Oct 17;381(16):1547-1556. doi: 10.1056/NEJMoa1816454.
  14. Harada-Shiba M, Sugisawa T, Makino H, Abe M, Tsushima M, Yoshimasa Y, et al. Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia. J Atheroscler Thromb. 2010 Jul 30;17(7):667-74. doi: 10.5551/jat.4143.
  15. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012 Dec;53(12):2515-24. doi: 10.1194/jlr.R026658.
  16. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, et al. ODYSSEY 95% and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov 14;36(43):2996-3003. doi: 10.1093/eurheartj/ehv370.
  17. Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, et al. Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher. Cardiovasc Drugs Ther. 2016 Oct;30(5):473-483. doi: 10.1007/s10557-016-6685-y.
  18. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, et al. RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):331-40. doi: 10.1016/S0140-6736(14)61399-4.
  19. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, 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 Nov 13;126(20):2408-17. doi: 
  20. Hovingh GK, Raal FJ, Dent R, Stefanutti C, Descamps O, Masana L, et al. Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017 Nov-Dec;11(6):1448-1457. doi: 10.1016/j.jacl.2017.09.003.
  21. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. 
  22. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664.
  23. Correspondence. Evolocumab in Patients with Cardiovascular Disease. N Engl J Med. 2017 Aug 24;377(8):785-8. doi: 
  24. Correspondence. Alirocumab after Acute Coronary Syndrome. N Engl J Med. 2019 May 23;380(21):2074-7. doi: 10.1056/NEJMc1902955. 
  25. Debacker AJ, Voutila J, Catley M, Blakey D, Habib N. Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug. Mol Ther. 2020 Aug 5;28(8):1759-1771. doi: 10.1016/j.ymthe.2020.06.015.
  26. Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 2018 Oct;277:483-492. doi: 10.1016/j.atherosclerosis.2018.06.859
  27. France M. Homozygous familial hypercholesterolaemia: update on management. Paediatr Int Child Health. 2016 Nov;36(4):243-247. doi: 10.1080/20469047.2016.1246640. 
  28. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014 Aug 21;35(32):2146-57. doi: 10.1093/eurheartj/ehu274.
  29. Walma EP, Wiersma Tj. NHG-Standpunt Diagnostiek en behandeling van familiaire hypercholesterolemie. Huisarts Wet. 2006;49(4):202-4. Via: https://richtlijnen.nhg.org/files/2020-05/standpunt_diagnostiek_en_behandeling_van_familiaire_hypercholesterolemie.pdf.
  30. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991 Oct 12;303(6807):893-6. doi: 10.1136/bmj.303.6807.893.
  31. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013 Dec;34(45):3478-90a. doi: 10.1093/eurheartj/eht273. Erratum in: Eur Heart J. 2020 Dec 14;41(47):4517. 
  32. EMA. Productinformatie Praluent. Available from: https://www.ema.europa.eu/en/documents/product-information/praluent-epar-product-information_nl.pdf. Accessed 20 September 2021.
  33. G-standaard Z-Index. september 2021. Available from: kennisbank.knmp.nl. Accessed 20 September 2021.
  34. EMA. Productinformatie Repatha. Available from: https://www.ema.europa.eu/en/documents/product-information/repatha-epar-product-information_nl.pdf. Accessed 20 September 2021.

The literature refers to the Dutch text

Authors

  • Melvin Lafeber
  • Gerard A. Rongen, Prof dr, vascular internist and clinical pharmacologist Department of Internal Medicine
    Radboudumc, Nijmegen
    the Netherlands