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Erschienen in: Herz 4/2016

20.05.2016 | Hypercholesterinämie | Schwerpunkt

PCSK9-Inhibitoren

Empfehlungen zur Patientenauswahl

verfasst von: Prof. Dr. U. Laufs, F. Custodis, C. Werner

Erschienen in: Herz | Ausgabe 4/2016

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Zusammenfassung

Die 2‑ oder 4‑wöchentliche subkutane Therapie mit den neu zugelassenen Antikörpern Alirocumab und Evolocumab zur Hemmung von PCSK9 (Proproteinkonvertase Subtilisin/Kexin Typ 9) senkt das LDL-C („Low-density-lipoprotein“-Cholesterin) zusätzlich zu Statinen und Ezetimib um 50–60 %. Die Therapie ist gut verträglich. Die Ergebnisse der großen randomisierten Studien zum Einfluss auf kardiovaskuläre Ereignisse und zur Beurteilung der Sicherheit liegen noch nicht vor, sie werden 2016 bis 2018 erwartet. Daher kommen aktuell (Frühjahr 2016) insbesondere Patienten mit hohem kardiovaskulären Risiko und hohem LDL-C trotz Einsatz einer maximal verträglichen oralen lipidsenkenden Therapie für eine PCSK9-Hemmung in Frage. Dies betrifft z. B. ausgewählte Patienten mit statinassoziierten Muskelbeschwerden (SAMS) und Patienten mit familiärer Hypercholesterinämie.
Literatur
1.
Zurück zum Zitat Custodis F, Laufs U (2015) LDL-Cholesterol – Is there an “LDL hypothesis”? Dtsch Med Wochenschr 140(10):761–764CrossRefPubMed Custodis F, Laufs U (2015) LDL-Cholesterol – Is there an “LDL hypothesis”? Dtsch Med Wochenschr 140(10):761–764CrossRefPubMed
2.
Zurück zum Zitat Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD (2015) Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial Mendelian randomization study. J Am Coll Cardiol 65(15):1552–1561CrossRefPubMed Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD (2015) Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial Mendelian randomization study. J Am Coll Cardiol 65(15):1552–1561CrossRefPubMed
3.
Zurück zum Zitat Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, Kahn J, Afonso L, Williams KA Sr, Flack JM (2012) Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 60(25):2631–2639CrossRefPubMed Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, Kahn J, Afonso L, Williams KA Sr, Flack JM (2012) Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 60(25):2631–2639CrossRefPubMed
4.
Zurück zum Zitat Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, Ferrari GM De, Ruzyllo W, Lucca P De, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM, Investigators I‑I (2015) Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 372(25):2387–2397CrossRefPubMed Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, Ferrari GM De, Ruzyllo W, Lucca P De, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM, Investigators I‑I (2015) Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 372(25):2387–2397CrossRefPubMed
5.
6.
Zurück zum Zitat Reiner Z, Catapano AL, Backer G De, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D (2011) 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). Eur Heart J 32(14):1769–1818 (European Association for Cardiovascular P, Rehabilitation)CrossRefPubMed Reiner Z, Catapano AL, Backer G De, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D (2011) 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). Eur Heart J 32(14):1769–1818 (European Association for Cardiovascular P, Rehabilitation)CrossRefPubMed
7.
Zurück zum Zitat Stone NJ, Robinson JG, Lichtenstein AH, Bairey MCN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr., Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Tomaselli GF (2014) 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 129(2):1–45 (American College of Cardiology/American Heart Association Task Force on Practice G) Stone NJ, Robinson JG, Lichtenstein AH, Bairey MCN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr., Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Tomaselli GF (2014) 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 129(2):1–45 (American College of Cardiology/American Heart Association Task Force on Practice G)
8.
Zurück zum Zitat Schulz R, Schluter KD, Laufs U (2015) Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9). Basic Res Cardiol 110(2:4CrossRef Schulz R, Schluter KD, Laufs U (2015) Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9). Basic Res Cardiol 110(2:4CrossRef
9.
Zurück zum Zitat Urban D, Poss J, Bohm M, Laufs U (2013) Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 62(16):1401–1408CrossRefPubMed Urban D, Poss J, Bohm M, Laufs U (2013) Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 62(16):1401–1408CrossRefPubMed
10.
Zurück zum Zitat Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003) The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 100(3):928–933CrossRefPubMedPubMedCentral Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, Basak A, Prat A, Chretien M (2003) The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A 100(3):928–933CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34(2):154–156CrossRefPubMed Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34(2):154–156CrossRefPubMed
12.
Zurück zum Zitat Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chretien M, Prat A, Seidah NG (2004) NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 279(47):48865–48875CrossRefPubMed Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chretien M, Prat A, Seidah NG (2004) NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem 279(47):48865–48875CrossRefPubMed
13.
Zurück zum Zitat Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 44(11):2109–2119CrossRefPubMed Maxwell KN, Soccio RE, Duncan EM, Sehayek E, Breslow JL (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 44(11):2109–2119CrossRefPubMed
14.
Zurück zum Zitat Park SW, Moon YA, Horton JD (2004) Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 279(48):50630–50638CrossRefPubMed Park SW, Moon YA, Horton JD (2004) Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 279(48):50630–50638CrossRefPubMed
15.
Zurück zum Zitat Dietschy JM, Turley SD, Spady DK (1993) Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 34(10):1637–1659PubMed Dietschy JM, Turley SD, Spady DK (1993) Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 34(10):1637–1659PubMed
16.
Zurück zum Zitat Goldstein JL, Brown MS, Anderson RG, Russell DW, Schneider WJ (1985) Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol 1:1–39CrossRefPubMed Goldstein JL, Brown MS, Anderson RG, Russell DW, Schneider WJ (1985) Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol 1:1–39CrossRefPubMed
17.
Zurück zum Zitat Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (2004) Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 24(8):1454–1459CrossRefPubMed Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A (2004) Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 24(8):1454–1459CrossRefPubMed
18.
Zurück zum Zitat Berge KE, Ose L, Leren TP (2006) Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol 26(5):1094–1100CrossRefPubMed Berge KE, Ose L, Leren TP (2006) Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol 26(5):1094–1100CrossRefPubMed
19.
Zurück zum Zitat Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37(2):161–165CrossRefPubMed Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37(2):161–165CrossRefPubMed
20.
Zurück zum Zitat Cohen JC, Boerwinkle E, Mosley TH (2006) Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354(12):1264–1272CrossRefPubMed Cohen JC, Boerwinkle E, Mosley TH (2006) Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354(12):1264–1272CrossRefPubMed
21.
Zurück zum Zitat Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79(3):514–523CrossRefPubMedPubMedCentral Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79(3):514–523CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR (2007) The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193(2):445–448CrossRefPubMed Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR (2007) The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193(2):445–448CrossRefPubMed
23.
Zurück zum Zitat Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, Lazure C, Seidah NG, Prat A (2012) Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 125(7):894–901CrossRefPubMed Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, Lazure C, Seidah NG, Prat A (2012) Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 125(7):894–901CrossRefPubMed
24.
Zurück zum Zitat Al-Mashhadi RH, Sorensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP, Thim T, Du Y, Li J, Liu Y, Moldt B, Schmidt M, Vajta G, Larsen T, Purup S, Bolund L, Nielsen LB, Callesen H, Falk E, Mikkelsen JG, Bentzon JF (2013) Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci Transl Med 5(166):166ra1CrossRefPubMed Al-Mashhadi RH, Sorensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP, Thim T, Du Y, Li J, Liu Y, Moldt B, Schmidt M, Vajta G, Larsen T, Purup S, Bolund L, Nielsen LB, Callesen H, Falk E, Mikkelsen JG, Bentzon JF (2013) Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci Transl Med 5(166):166ra1CrossRefPubMed
25.
Zurück zum Zitat Kuhnast S, Hoorn JW van der, Pieterman EJ, Hoek AM van den, Sasiela WJ, Gusarova V, Peyman A, Schafer HL, Schwahn U, Jukema JW, Princen HM (2014) Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res 55(10):2103–2112CrossRefPubMedPubMedCentral Kuhnast S, Hoorn JW van der, Pieterman EJ, Hoek AM van den, Sasiela WJ, Gusarova V, Peyman A, Schafer HL, Schwahn U, Jukema JW, Princen HM (2014) Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res 55(10):2103–2112CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Galabova G, Brunner S, Winsauer G, Juno C, Wanko B, Mairhofer A, Luhrs P, Schneeberger A, Bonin A von, Mattner F, Schmidt W, Staffler G (2014) Peptide-based anti-PCSK9 vaccines – an approach for long-term LDLc management. PLoS ONE 9(12):e114469CrossRefPubMedPubMedCentral Galabova G, Brunner S, Winsauer G, Juno C, Wanko B, Mairhofer A, Luhrs P, Schneeberger A, Bonin A von, Mattner F, Schmidt W, Staffler G (2014) Peptide-based anti-PCSK9 vaccines – an approach for long-term LDLc management. PLoS ONE 9(12):e114469CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA (2014) 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 114(5):711–715CrossRefPubMed Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA (2014) 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 114(5):711–715CrossRefPubMed
28.
Zurück zum Zitat Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA (2014) 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 63(13):1278–1288CrossRefPubMed Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, Wasserman SM, Huang F, Xue A, Albizem M, Scott R, Stein EA (2014) 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 63(13):1278–1288CrossRefPubMed
29.
Zurück zum Zitat Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ (2013) Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 128(19):2113–2120CrossRefPubMed Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ (2013) Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 128(19):2113–2120CrossRefPubMed
30.
Zurück zum Zitat May C Le, Kourimate S, Langhi C, Chetiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P (2009) Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol 29(5):684–690CrossRefPubMed May C Le, Kourimate S, Langhi C, Chetiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P (2009) Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol 29(5):684–690CrossRefPubMed
31.
Zurück zum Zitat Levy E, Ben Djoudi Ouadda A, Spahis S, Sane AT, Garofalo C, Grenier E, Emonnot L, Yara S, Couture P, Beaulieu JF, Menard D, Seidah NG, Elchebly M (2013) PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells. Atherosclerosis 227(2):297–306CrossRefPubMed Levy E, Ben Djoudi Ouadda A, Spahis S, Sane AT, Garofalo C, Grenier E, Emonnot L, Yara S, Couture P, Beaulieu JF, Menard D, Seidah NG, Elchebly M (2013) PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells. Atherosclerosis 227(2):297–306CrossRefPubMed
32.
Zurück zum Zitat Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S (2014) Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms. Circulation 130(5):431–441CrossRefPubMedPubMedCentral Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S (2014) Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms. Circulation 130(5):431–441CrossRefPubMedPubMedCentral
33.
Zurück zum Zitat Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, Shahawy M El, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, Investigators (2015) Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 372(16):1489–1499CrossRefPubMed Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, Shahawy M El, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, Investigators (2015) Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 372(16):1489–1499CrossRefPubMed
34.
Zurück zum Zitat Laufs U, Parhofer KG (2015) Simplified algorithm to facilitate communication of familial hypercholesterolaemia. Eur Heart J 36(43):3004–3006PubMed Laufs U, Parhofer KG (2015) Simplified algorithm to facilitate communication of familial hypercholesterolaemia. Eur Heart J 36(43):3004–3006PubMed
35.
Zurück zum Zitat Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA (2015) Open-Label Study of Long-Term Evaluation against LDLCI. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 372(16):1500–1509CrossRefPubMed Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA (2015) Open-Label Study of Long-Term Evaluation against LDLCI. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 372(16):1500–1509CrossRefPubMed
36.
Zurück zum Zitat Klose G, Laufs U, Marz W, Windler E (2014) Familial hypercholesterolemia: developments in diagnosis and treatment. Dtsch Arztebl Int 111(31/32):523–529PubMedPubMedCentral Klose G, Laufs U, Marz W, Windler E (2014) Familial hypercholesterolemia: developments in diagnosis and treatment. Dtsch Arztebl Int 111(31/32):523–529PubMedPubMedCentral
37.
Zurück zum Zitat Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A, European Atherosclerosis Society Consensus (2013) 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 34(45):3478–3490 (a)CrossRefPubMedPubMedCentral Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A, European Atherosclerosis Society Consensus (2013) 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 34(45):3478–3490 (a)CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ, Sijbrands EJ (2008) Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337:a2423CrossRefPubMedPubMedCentral Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JJ, Sijbrands EJ (2008) Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337:a2423CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Marks D, Thorogood M, Neil HA, Humphries SE (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168(1):1–14CrossRefPubMed Marks D, Thorogood M, Neil HA, Humphries SE (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168(1):1–14CrossRefPubMed
40.
Zurück zum Zitat Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, Forge R La, Daniels SR, Wilson DP, Morris PB, Wild RA, Grundy SM, Daviglus M, Ferdinand KC, Vijayaraghavan K, Deedwania PC, Aberg JA, Liao KP, McKenney JM, Ross JL, Braun LT, Ito MK, Bays HE, Brown WV, Panel NLAE (2015) National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol 9(6 Suppl):S1–S122CrossRefPubMed Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, Forge R La, Daniels SR, Wilson DP, Morris PB, Wild RA, Grundy SM, Daviglus M, Ferdinand KC, Vijayaraghavan K, Deedwania PC, Aberg JA, Liao KP, McKenney JM, Ross JL, Braun LT, Ito MK, Bays HE, Brown WV, Panel NLAE (2015) National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol 9(6 Suppl):S1–S122CrossRefPubMed
41.
Zurück zum Zitat Laufs U, Scharnagl H, Halle M, Windler E, Endres M, Marz W (2015) Treatment Options for Statin-Associated Muscle Symptoms. Dtsch Arztebl Int 112(44):748–755PubMedPubMedCentral Laufs U, Scharnagl H, Halle M, Windler E, Endres M, Marz W (2015) Treatment Options for Statin-Associated Muscle Symptoms. Dtsch Arztebl Int 112(44):748–755PubMedPubMedCentral
42.
Zurück zum Zitat Cho L, Rocco M, Colquhoun D et al (2014) Design and rationale of the GAUSS-2 study trial: a double-blind, ezetimibe-controlled phase 3 study of the efficacy and tolerability of evolocumab (AMG 145) in subjects with hypercholesterolemia who are intolerant of statin therapy. Clin Cardiol 37(3):131–139CrossRefPubMed Cho L, Rocco M, Colquhoun D et al (2014) Design and rationale of the GAUSS-2 study trial: a double-blind, ezetimibe-controlled phase 3 study of the efficacy and tolerability of evolocumab (AMG 145) in subjects with hypercholesterolemia who are intolerant of statin therapy. Clin Cardiol 37(3):131–139CrossRefPubMed
43.
Zurück zum Zitat Moriarty PM, Jacobson TA, Bruckert E et al (2014) Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 8(6):554–561CrossRefPubMed Moriarty PM, Jacobson TA, Bruckert E et al (2014) Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 8(6):554–561CrossRefPubMed
Metadaten
Titel
PCSK9-Inhibitoren
Empfehlungen zur Patientenauswahl
verfasst von
Prof. Dr. U. Laufs
F. Custodis
C. Werner
Publikationsdatum
20.05.2016
Verlag
Springer Medizin
Erschienen in
Herz / Ausgabe 4/2016
Print ISSN: 0340-9937
Elektronische ISSN: 1615-6692
DOI
https://doi.org/10.1007/s00059-016-4429-1

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