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Dtsch Med Wochenschr 2016; 141(12): 863-869
DOI: 10.1055/s-0042-102801
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Fettstoffwechselstörungen
© Georg Thieme Verlag KG Stuttgart · New York

PCSK9-Inhibitoren – Durchbruch bei der LDL-Cholesterin-Senkung?

PCSK9 Inhibitors – the magic bullet for LDL cholesterol reduction?
Kurt Richter
1   Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden
,
Andreas Barthel
2   Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden
3   Endokrinologikum Ruhr, Bochum
,
Stefan R. Bornstein
2   Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden
4   Paul-Langerhans-Institut für Diabetesforschung des Helmholtz Zentrums München am Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden
5   DFG Center for Regenerative Therapies, Technische Universität Dresden, Dresden
6   Department of Diabetes and Endocrinology, Divison of Diabetes and Nutritional Sciences, King’s College, London, UK
,
Ali El-Armouche
1   Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden
,
Michael Wagner
1   Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden
› Author Affiliations
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Publication History

Publication Date:
15 June 2016 (online)

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Zusammenfassung

Die Proproteinkonvertase-Subtilisin / Kexin-Typ-9 (PCSK9) spielt eine wichtige Rolle im LDL-Cholesterin(LDL-C)-Stoffwechsel. So weisen Menschen mit Mutationen im PCSK9-Gen, die zu einer Funktionseinschränkung des Enzyms führen, deutlich erniedrigte LDL-C-Plasmaspiegel auf. PCSK9 wird in der Leber sezerniert, bindet an den LDL-Rezeptor und bewirkt, dass er mit dem gebundenen LDL-C lysosomal abgebaut wird. Bei den derzeitigen PCSK9 Inhibitoren handelt es sich um monoklonale Antikörper, die PCSK9 spezifisch binden und funktionell neutralisieren. Somit kann der Rezeptor vom LDL-C dissoziieren und wird nicht abgebaut, sondern recycelt, was die LDL Rezeptordichte der Hepatozyten erhöht und die LDL-C Clearance steigert. Die subkutan applizierten PCSK9 Inhibitoren Alirocumab und Evolocumab bewirkten in klinischen Studien Senkungen des LDL-C von maximal ca. 70 % bei mit Statin behandelten und unbehandelten Patienten. Das Nebenwirkungspotenzial erscheint bisher vertretbar. Weil diese Wirkstoffe einen hohen klinischen Nutzen erwarten lassen, wurden sie von der EMA im Sommer 2015 bereits vor Abschluss der Studien zu patientenrelevanten Endpunkten (kardiovaskuläre Morbidität und Mortalität) zugelassen. Eine bessere Beurteilung des tatsächlichen Nutzens sowie der Langzeitsicherheit der PCSK9-Inhibitoren wird erst nach Publikation der Ergebnisse der Outcome-Studien ab 2017 möglich sein.

Abstract

The proprotein convertase subtilisin / kexin type 9 (PCSK9) plays an important role in LDL cholesterol (LDL-C) metabolism. Subjects harboring loss-of-function mutations in the gene encoding for PCSK9 display markedly reduced LDL-C plasma levels. PCSK9 is secreted by the liver, binds to the LDL receptor and, following endocytosis, induces lysosomal degradation of the receptor together with the bound LDL-C. Current PCSK9 inhibitors are monoclonal antibodies that specifically absorb PCSK9. Subsequently, instead of being degraded the receptor can dissociate from LDL-C and recycle, consecutively resulting in an increased hepatocyte LDL receptor density and higher LDL-C clearance. In clinical trials, the PCSK9 inhibitors alirocumab and evolocumab induced reductions in LDL-C of up to 70 % in statin-treated as well as statin-naïve patients. So far, serious side effects (requiring cessation of drug treatment) occurred only in rare cases. Since this new class of lipid lowering drugs promises a high potential benefit, they have been approved by the EMA even before completion of the studies addressing clinically relevant endpoints like cardiovascular events and mortality. Therefore, the expected publication of these study results in 2017 may allow a better assessment of the efficacy and safety of PCSK9 inhibitors.

Schlüsselwörter

PCSK9-Inhibitoren - Evolocumab - Alirocumab - LDL-Cholesterin - kardiovaskuläre Erkrankungen

Keywords

PCSK9 inhibitors - evolocumab - alirocumab - LDL cholesterol - cardiovascular disease
 

  • Literatur

  • 1 Mullard A. PCSK9 inhibitors are go. Nat Rev Drug Discov 2015; 14: 593
    PubMedGoogle Scholar
  • 2 European Medicines Agency. Praluent: EPAR – Product Information, Anhang I, Zusammenfassung der Merkmale des Arzneimittels. http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/003882/WC500194521.pdf (letzter Zugriff 15.4.2016)
    PubMedGoogle Scholar
  • 3 European Medicines Agency. Repatha: EPAR – Product Information, Anhang I, Zusammenfassung der Merkmale des Arzneimittels. http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/003766/WC500191398.pdf (letzter Zugriff 15.4.2016)
    PubMedGoogle Scholar
  • 4 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: 3-46
    CrossrefPubMedGoogle Scholar
  • 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: 1670-1681
    CrossrefPubMedGoogle Scholar
  • 6 Stone NJ, Robinson JG, Lichtenstein AH 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: S1-45
    CrossrefPubMedGoogle Scholar
  • 7 Arzneimittelkommission der deutschen Ärzteschaft. Handlungsleitlinie Fettstoffwechselstörungen aus Empfehlungen zur Therapie von Fettstoffwechselstörungen. http://www.akdae.de/Arzneimitteltherapie/TE/A-Z/PDF/Fettstoffwechselstoerungen.pdf#page = 1&view=fitB (letzter Zugriff 15.4.2016)
    PubMedGoogle Scholar
  • 8 Karlson BW, Nicholls SJ, Lundman P et al. Achievement of 2011 European low-density lipoprotein cholesterol (LDL-C) goals of either < 70 mg / dl or >/= 50 % reduction in high-risk patients: results from VOYAGER. Atherosclerosis 2013; 228: 265-269
    CrossrefPubMedGoogle Scholar
  • 9 Seidah NG, Mayer G, Zaid A et al. The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol 2008; 40: 1111-1125
    CrossrefPubMedGoogle Scholar
  • 10 Abifadel M, Varret M, Rabès JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154-156
    CrossrefPubMedGoogle Scholar
  • 11 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: 161-165
    CrossrefPubMedGoogle Scholar
  • 12 Rudenko G, Henry L, Henderson K et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science (New York, NY) 2002; 298: 2353-2358
    CrossrefPubMedGoogle Scholar
  • 13 Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science (New York, NY) 1986; 232: 34-47
    CrossrefPubMedGoogle Scholar
  • 14 Yamamoto T, Lu C, Ryan RO. A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor. J Biol Chem 2011; 286: 5464-5470
    CrossrefPubMedGoogle Scholar
  • 15 Sharotri V, Collier DM, Olson DR et al. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin / kexin type 9 (PCSK9). J Biol Chem 2012; 287: 19266-19274
    CrossrefPubMedGoogle Scholar
  • 16 Rousselet E, Marcinkiewicz J, Kriz J et al. PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke. J Lipid Res 2011; 52: 1383-1391
    CrossrefPubMedGoogle Scholar
  • 17 Langhi C, Le May C, Gmyr V et al. PCSK9 is expressed in pancreatic delta-cells and does not alter insulin secretion. Biochem Biophysical Res Commun 2009; 390: 1288-1293
    CrossrefPubMedGoogle Scholar
  • 18 Roubtsova A, Munkonda MN, Awan Z et al. Circulating proprotein convertase subtilisin / kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler Thromb Vasc Biol 2011; 31: 785-791
    CrossrefPubMedGoogle Scholar
  • 19 Ferri N, Tibolla G, Pirillo A et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2012; 220: 381-386
    CrossrefPubMedGoogle Scholar
  • 20 Levy E, Ben Djoudi Ouadda A, Spahis S et al. PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells. Atherosclerosis 2013; 227: 297-306
    CrossrefPubMedGoogle Scholar
  • 21 Sun X, Essalmani R, Day R et al. Proprotein convertase subtilisin / kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia (New York, NY) 2012; 14: 1122-1131
    CrossrefPubMedGoogle Scholar
  • 22 Giugliano RP, Sabatine MS. Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field?. J Amer Coll Cardiol 2015; 65: 2638-2651
    CrossrefPubMedGoogle Scholar
  • 23 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 Amer Coll Cardiol 2014; 63: 2531-2540
    CrossrefPubMedGoogle Scholar
  • 24 Roth EM, Taskinen MR, Ginsberg HN 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: 55-61
    CrossrefPubMedGoogle Scholar
  • 25 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. Amer Heart J 2015; 169: 906-915.e913
    CrossrefPubMedGoogle Scholar
  • 26 Cannon CP, Cariou B, Blom D et al. Efficacy 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. Europ Heart J 2015; 36: 1186-1194
    CrossrefPubMedGoogle Scholar
  • 27 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: 1870-1882
    CrossrefPubMedGoogle Scholar
  • 28 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 Amer Coll Cardiol 2014; 63: 2541-2548
    CrossrefPubMedGoogle Scholar
  • 29 Kastelein JJ, Ginsberg HN, Langslet G et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Europ Heart J 2015; 36: 2996-3003
    PubMedGoogle Scholar
  • 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: 331-340
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 32 Koren MJ, Giugliano RP, Raal FJ et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014; 129: 234-243
    CrossrefPubMedGoogle Scholar
  • 33 Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; 372: 1489-1499
    CrossrefPubMedGoogle Scholar
  • 34 Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe added to statin therapy after acute coronary syndromes. New Engl J Med 2015; 372: 2387-2397
    CrossrefPubMedGoogle Scholar
  • 35 Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New Engl J Med 2006; 354: 1264-1272
    CrossrefPubMedGoogle Scholar
  • 36 Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; 372: 1500-1509
    CrossrefPubMedGoogle Scholar
  • 37 FDA Clinical Briefing Document BLA 125 522 Repatha® (evolocumab) subcutaneous injection. http://www.fda.gov / downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM450072.pdf (letzter Zugriff 15.4.2016)
    PubMedGoogle Scholar
  • 38 FDA Clinical Briefing Document BLA 125 559 Praluent® (alirocumab) injection. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM449865.pdf (letzter Zugriff 15.4.2016)
    PubMed
  • 39 Nissen SE, Stroes E, Dent-Acosta RE et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance. The GAUSS-3 randomized clinical trial. JAMA 2016; 315: 1580-1590
    CrossrefPubMedGoogle Scholar