PCSK9 inhibitors in the management of patients with high cardiovascular risk – effective treatment to reach
Authors‘ workplace: Metabol KLINIK s. r. o., Ambulancia pre diabetológiu, poruchy látkovej premeny a výživy ; Špecializovaná lipidologická ambulancia, MED PED centrum, Bratislava
Published in: AtheroRev 2016; 1(1): 42-48
First-line therapy in secondary prevention and also in primary prevention (in keeping with lifestyle management) are statins with wide range of evidence. The current standards for the prevention of cardio-cerebrovascular diseases emphasize the importance of achieving target levels for LDL-cholesterol. Despite everything statins in clinical practice can’t meet all the goals. It is therefore no wonder that in the lipid-lowering agents still evolve new medication. The latest promise for high-risk patients (with high or very high cardiovascular risk, with homozygous or heterozygous familial hypercholesterolaemia, intolerant of statins or higher doses of statins) are human monoclonal antibodies against PCSK 9 (proprotein convertase subtilisin/kexin type 9). The results of clinical trials from large-scale programs are groundbreaking. Their importance is comparable to the results of 4S study with simvastatin, which was the first in 1994 demonstrated the benefit of statins in secondary prevention. In the near future we will have in clinical practice available alirocumab (Praluent) and evolocumab (Repatha). Despite all this enthusiasm, however, we have to wait for the results of long term studies with morbidity-mortality endpoints (ODYSSEY- OUTCOMES and FOURIER).
alirocumab – evolocumab – ODYSSEY – PCSK9-i – PROFICIO
1. Catapano AL, Reiner Z, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011; 217(1): 3–46.
2. Expert Dyslipidemia Panel, Grundy SM. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia. J Clin Lipidol 2013; 7(6): 561–565.
3. 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(9753): 1670–1681.
4. Mihaylova B, Emberson J, Blackwell L et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380(9841): 581–90.
5. EUROASPIRE IV reveals success and challenges in secondary prevention of CVD across Europe. ESC: 2013. Dostupné z WWW: http://www.escardio.org/about/press/press-releases/esc13-amsterdam/Pages/euroaspire-iv-success-challenges-secondary-prevention-CVD-europe.aspx.
6. Cannon CP, Blazing MA, Giuglino RP et al. Ezetimibe added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372(25): 2387–2397.
7. Dukát A. Reziduálne kardiovaskulárne riziko – závažný problém, ktorý si bude vyžadovať nové liečebné prístupy. Cardiol 2008; 17(6): 229–233.
8. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26. Dostupné z DOI: <http://dx.doi.org/10.1186/1475–2840–13–26>.
9. Ridker PM. Lipids and cardiovascular disease 1: LDL cholesterol: controversies and future therapeutic directions. Lancet 2014; 384(9943): 607–617.
10. Fábryová Ľ. Monoklonálne protilátky proti PCSK9 – nová nádejj pre pacientov s vysokým kardiovaskulárnym rizikom. Interná Med 2014; 14(10): 408–416.
11. Abifadel M, Varret M, Rabès JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34(2): 154–156.
12. Cohen JC, Boerwinkle E, Mosley TH et al. Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease. N Engl J Med 2006; 354(12): 1264–1272.
13. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009; 50(Suppl): S172-S177.
14. Mousavi SA, Berge KE, Leren TP. The unique role of proprotein convertase subtilisin⁄kexin 9 in cholesterol homeostasis. J Intern Med 2009; 266(6): 507–519.
15. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014; 11(10): 563–575.
16. Reichert JM. Which are the antibodies to wath in 2013? Mabs 2013; 5(1): 1–4.
17. Kastelein JJP, Ginsberg H, Langslet G et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolaemia not adequately controlled with current lipid lowering therapy: results of ODYSSEY FH I and FH II studies. Presented on August 31, 2014 at the 2014 European Society of Cardiology (ESC) Congress, Barcelona, Spain, August 30-September 3, 2014. Dostupné z WWW: http://www.escardio.org/Congresses-&-Events/Congress-resources/ESC-Congress-365/ESC-Congress/Session-Reports/Efficacy-and-safety-of-alirocumab-Results-from-the-ODYSSEY-COMBO-II-study-and-r#presenter2.
18. Ginsberg HN, Rader DJ, Raal FJ. ODYSSEY HIGH FH: efficacy and safety of alirocumab in patients with severe heterozygous familial hypercholesterolemia. Circulation 2014; 130(Suppl 2 – Abstracts from the American Heart Association's 2014 Scientific Sessions and Resuscitation Science Symposium): 2119.
19. Kereiakes DJ, Robinson JG, Cannon CP et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9, inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J 2015; 169(6): 906–915.
20. Cannon CP, Cariou B, Blom D et al. Efficay and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J 2015; 36(19): 1186–1194.
21. Roth EM, Taskinen MR, Ginsberg et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol 2014; 176(1): 55–61.
22. Moriarty PM, Thompson PD, Canon CP et al. ODYSSEY ALTERNATIVE: efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody, alirocumab, versus ezetimibe, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm. Circulation 2014; 130(Suppl 2 – Abstracts from the American Heart Association's 2014 Scientific Sessions and Resuscitation Science Symposium): 2108–2109.
23. Bays H, Farnier M, Weiss R et al. Alirocumab as add-on to atorvastatin versus other lipid trreatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab 2015; 100(8): 3140–3148.
24. Bays H, Farnier M, Gaudet D et al. Efficacy and safety of combining alirocumab with atorvastatin rosuvastatin versus statin intensificaion or adding ezetimibe in high cardiovascular risk patients: ODYSSEY OPTION I and II. Circulation 2014; 130(Suppl 2 – Abstracts from the American Heart Association's 2014 Scientific Sessions and Resuscitation Science Symposium): 2118–2119.
25. Robinson JG, Farnier M, Krempf M. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med. 2015; 372(16): 1489–1499.
26. Regeneron Pharmaceuticals Inc, Sanofi-Aventis. PRALUENT (alirocumab): US precribing Information 2015. Dostupné z WWW: http://www.regeneron.com/Praluent/Praluent-fpi.
27. Robinson JG, Rogers W, Nedergaard BS et al. Rationale and Design of LAPLACE-2: A Phase 3, Randomized, Double-Blind, Placebo- and Ezetimibe-Controlled Trial Evaluating the Efficacy and Safety of Evolocumab in Subjects With Hypercholesterolemia on Background Statin Therapy. Clin Cardiol 2014; 37(4): 195–203.
28. Stroes E, Colquhoun D, Sullivan D et al. GAUSS-2 Investigators. Anti-PCSK9 antibody effectively lowers cholesterol in patiensts with statin intolerance. The GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014; 63(23): 2541–2548.
29. Koren MJ, Lundquist P, Bolognese M et al. MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolaemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014; 63(23): 2531–2540.
30. 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(9965): 341–350.
31. 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: 341–350.
32. Blom DJ, Hala T, Bolognese M et al (for the DESCARTES Investigators). A 52-week placebo-controlled trial of evolocumab in hyperlipidaemia. N Engl J Med 2014; 370(19): 1809–1819.
33. Koren MJ, Giugliano RP, Raal FJ et al. Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolaemia: 52 –Week Results from the Open-Label Study of Ong-Term Evaluation Against LDL-C (OSLER) Randomized Trial. Circulation 2014; 129(2): 234–243.
34. Stroes E, Robinson J, Raal F et al. Clinical equivalence of evolocumab among patient subgroups in PROFICIO: A pooled analysis of 3146 patients from phase 3 Studies. European Society of Cardiology 19.8. – 2.9.2015. London. Abstract P1756. Poster Presentation.
35. Koren M, Rosenson R, Khan B et al. LDL cholesterol reduction in elderly patients with the PCSK9 monoclonal antibody evolocumab (AMG145): a pooled analysis of 1779 patients in phase 2,3 and open label extension studies. ACC 2015 Scientific Sessions, San Diego 14–16 March 2015.Abstract 1107–101.
36. Sabatine MS, Giugliano RP, Wioviott SD et al. Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015; 372(16): 1500–1509.
LabelsAngiology Diabetology Internal medicine Cardiology General practitioner for adults
Article was published in
2016 Issue 1
Most read in this issue
- Familial hypercholesterolemia: clinical reports, molecular genetics and differential diagnosis
- PCSK9 inhibitors in the management of patients with high cardiovascular risk – effective treatment to reach
- Turn in hypercholesterolemia treatment – PCSK9 inhibitors. What we know about the alirocumab (product Praluent®) yet?
- Statin-associated myopathy: clinical guideline of Slovak Atherosclerosis Association and Czech Society for Atherosclerosis