PCSK9 Inhibitors and Cardiovascular Disease: Impact on Cardiovascular Outcomes

Author(s): Paraskevi Farmaki, Christos Damaskos, Nikolaos Garmpis, Anna Garmpi, Spyridon Savvanis, Evangelos Diamantis*

Journal Name: Current Drug Discovery Technologies

Volume 17 , Issue 2 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Cardiovascular Disease (CVD) remains the leading cause of morbidity and mortality in the western world. Hypolipidemic drugs have long been used for the primary and secondary prevention of heart disease. However, the high frequency of recurrent events in patients despite hypolipidemic therapy has increased the need for new more targeted therapeutic approaches. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are monoclonal antibodies to the PCSK9 gene and represent a new class of drugs that have been shown to further decrease LDL-C when administered as a monotherapy or in combination with statins. In addition to LDL reduction, PCSK9 inhibitors are shown to decrease apolipoprotein B and lipoprotein (a) levels without major adverse effects. Whether or not PCSK9 inhibitors can actually reduce the incidence of cardiovascular events and ameliorate CVD prognosis is yet to be clarified. This review summarizes recent literature on the safety and efficacy of PCSK9 inhibitors on CVD outcome and its potential role in the management of patients with high-risk cardiovascular disease.

Keywords: PCSK9, inhibitors, cardiovascular disease, hypolipidemic drugs, hypolipidemic therapy, PCSK9 inhibitors.

[1]
Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37(29): 2315-81.
[http://dx.doi.org/10.1093/eurheartj/ehw106] [PMID: 27222591]
[2]
Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet 2012; 5(2): 257-64.
[http://dx.doi.org/10.1161/CIRCGENETICS.111.961144] [PMID: 22331829]
[3]
Murphy SA, Cannon CP, Wiviott SD, McCabe CH, Braunwald E. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial. J Am Coll Cardiol 2009; 54(25): 2358-62.
[http://dx.doi.org/10.1016/j.jacc.2009.10.005] [PMID: 20082923]
[4]
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): 1670-81.
[http://dx.doi.org/10.1016/S0140-6736(10)61350-5] [PMID: 21067804]
[5]
Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366(9493): 1267-78.
[http://dx.doi.org/10.1016/S0140-6736(05)67394-1] [PMID: 16214597]
[6]
Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-Year Follow-Up of West of Scotland Coronary Prevention Study. Circulation 2016; 133(11): 1073-80.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.019014] [PMID: 26864092]
[7]
Ashen MD, Foody JM. Evidence-based guidelines for cardiovascular risk reduction: the safety and efficacy of high-dose statin therapy. J Cardiovasc Nurs 2009; 24(6): 429-38.
[http://dx.doi.org/10.1097/JCN.0b013e3181b4bab4] [PMID: 19786883]
[8]
Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol 2013; 20(4): 641-57.
[http://dx.doi.org/10.1177/2047487313480435] [PMID: 23447425]
[9]
Mills EJ, Wu P, Chong G. Ghement I, Singh S, Akl EA, et al.. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM 2011; 104(2): 109-24.
[10]
Tonelli M, Lloyd A, Clement F. Conly J, Husereau D, Hemmelgarn B, et al. Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ: Canadian Medical 2011; 183(16): E1189-202.
[http://dx.doi.org/10.1503/cmaj.101280]
[11]
Mills EJ, O’Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart J 2011; 32(11): 1409-15.
[http://dx.doi.org/10.1093/eurheartj/ehr035] [PMID: 21385791]
[12]
Chan DK, O’Rourke F, Shen Q, Mak JC, Hung WT. Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins. Acta Neurol Scand 2011; 124(3): 188-95.
[http://dx.doi.org/10.1111/j.1600-0404.2010.01450.x] [PMID: 20979581]
[13]
Vrecer M, Turk S, Drinovec J, Mrhar A. Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials. Int J Clin Pharmacol Ther 2003; 41(12): 567-77.
[http://dx.doi.org/10.5414/CPP41567] [PMID: 14692706]
[14]
Tavori H, Giunzioni I, Fazio S. PCSK9 inhibition to reduce cardiovascular disease risk: recent findings from the biology of PCSK9. Curr Opin Endocrinol Diabetes Obes 2015; 22(2): 126-32.
[http://dx.doi.org/10.1097/MED.0000000000000137] [PMID: 25692926]
[15]
Blom DJ, Dent R, Castro RC, Toth PP. PCSK9 inhibition in the management of hyperlipidemia: focus on evolocumab. Vasc Health Risk Manag 2016; 12: 185-97.
[http://dx.doi.org/10.2147/VHRM.S102564] [PMID: 27274264]
[16]
Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther 2005; 19(6): 403-14.
[http://dx.doi.org/10.1007/s10557-005-5686-z] [PMID: 16453090]
[17]
Corrao G, Conti V, Merlino L, Catapano AL, Mancia G. Results of a retrospective database analysis of adherence to statin therapy and risk of nonfatal ischemic heart disease in daily clinical practice in Italy. Clin Ther 2010; 32(2): 300-10.
[http://dx.doi.org/10.1016/j.clinthera.2010.02.004] [PMID: 20206788]
[18]
Norata GD, Tavori H, Pirillo A, Fazio S, Catapano AL. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc Res 2016; 112(1): 429-42.
[http://dx.doi.org/10.1093/cvr/cvw194] [PMID: 27496869]
[19]
Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 2003; 100(3): 928-33.
[http://dx.doi.org/10.1073/pnas.0335507100] [PMID: 12552133]
[20]
Kwakernaak AJ, Lambert G, Dullaart RP. Plasma proprotein convertase subtilisin-kexin type 9 is predominantly related to intermediate density lipoproteins. Clin Biochem 2014; 47(7-8): 679-82.
[http://dx.doi.org/10.1016/j.clinbiochem.2014.03.008] [PMID: 24680982]
[21]
Chan DC, Lambert G, Barrett PH, Rye KA, Ooi EM, Watts GF. Plasma proprotein convertase subtilisin/kexin type 9: a marker of LDL apolipoprotein B-100 catabolism? Clin Chem 2009; 55(11): 2049-52.
[http://dx.doi.org/10.1373/clinchem.2009.128645] [PMID: 19713274]
[22]
Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34(2): 154-6.
[http://dx.doi.org/10.1038/ng1161] [PMID: 12730697]
[23]
Browning JD, Horton JD. Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J Lipid Res 2010; 51(11): 3359-63.
[http://dx.doi.org/10.1194/jlr.P009860] [PMID: 20716520]
[24]
Persson L, Cao G, Ståhle L, et al. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler Thromb Vasc Biol 2010; 30(12): 2666-72.
[http://dx.doi.org/10.1161/ATVBAHA.110.214130] [PMID: 20884874]
[25]
Dunn KW, McGraw TE, Maxfield FR. Iterative fractionation of recycling receptors from lysosomally destined ligands in an early sorting endosome. J Cell Biol 1989; 109(6 Pt 2): 3303-14.
[http://dx.doi.org/10.1083/jcb.109.6.3303] [PMID: 2600137]
[26]
Kosenko T, Golder M, Leblond G, Weng W, Lagace TA. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J Biol Chem 2013; 288(12): 8279-88.
[http://dx.doi.org/10.1074/jbc.M112.421370] [PMID: 23400816]
[27]
Hori M, Ishihara M, Yuasa Y, et al. Removal of plasma mature and furin-cleaved proprotein convertase subtilisin/kexin 9 by low-density lipoprotein-apheresis in familial hypercholesterolemia: development and application of a new assay for PCSK9. J Clin Endocrinol Metab 2015; 100(1): E41-9.
[http://dx.doi.org/10.1210/jc.2014-3066] [PMID: 25313916]
[28]
Tavori H, Giunzioni I, Linton MF, Fazio S. Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis. Circ Res 2013; 113(12): 1290-5.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.302655] [PMID: 24122718]
[29]
Leren TP. Sorting an LDL receptor with bound PCSK9 to intracellular degradation. Atherosclerosis 2014; 237(1): 76-81.
[http://dx.doi.org/10.1016/j.atherosclerosis.2014.08.038] [PMID: 25222343]
[30]
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(2): 297-306.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.01.023] [PMID: 23422832]
[31]
Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354(12): 1264-72.
[http://dx.doi.org/10.1056/NEJMoa054013] [PMID: 16554528]
[32]
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37(2): 161-5.
[http://dx.doi.org/10.1038/ng1509] [PMID: 15654334]
[33]
Kathiresan S, Myocardial Infarction Genetics CAA. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med 2008; 358(21): 2299-300.
[http://dx.doi.org/10.1056/NEJMc0707445] [PMID: 18499582]
[34]
Kent ST, Rosenson RS, Avery CL, et al. PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. Circ Cardiovasc Genet 2017; 10(4)e001632
[http://dx.doi.org/10.1161/CIRCGENETICS.116.001632] [PMID: 28768753]
[35]
Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010; 55(25): 2833-42.
[http://dx.doi.org/10.1016/j.jacc.2010.02.044] [PMID: 20579540]
[36]
Hopkins PN, Defesche J, Fouchier SW, et al. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ Cardiovasc Genet 2015; 8(6): 823-31.
[http://dx.doi.org/10.1161/CIRCGENETICS.115.001129] [PMID: 26374825]
[37]
Qiu C, Zeng P, Li X, et al. What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis. Lipids Health Dis 2017; 16(1): 111.
[http://dx.doi.org/10.1186/s12944-017-0506-6] [PMID: 28606094]
[38]
Naoumova RP, Tosi I, Patel D, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 2005; 25(12): 2654-60.
[http://dx.doi.org/10.1161/01.ATV.0000190668.94752.ab] [PMID: 16224054]
[39]
Waters DD, Brotons C, Chiang CW, et al. Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation 2009; 120(1): 28-34.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.838466] [PMID: 19546386]
[40]
Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today 2006; 11(1-2): 81-8.
[http://dx.doi.org/10.1016/S1359-6446(05)03638-X] [PMID: 16478695]
[41]
Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med 2015; 163(1): 40-51.
[http://dx.doi.org/10.7326/M14-2957] [PMID: 25915661]
[42]
Li C, Lin L, Zhang W, et al. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: a meta-analysis of 20 randomized controlled trials. J Am Heart Assoc 2015; 4(6)e001937
[http://dx.doi.org/10.1161/JAHA.115.001937] [PMID: 26077586]
[43]
Qian LJ, Gao Y, Zhang YM, Chu M, Yao J, Xu D. Therapeutic efficacy and safety of PCSK9-monoclonal antibodies on familial hypercholesterolemia and statin-intolerant patients: A meta-analysis of 15 randomized controlled trials. Sci Rep 2017; 7(1): 238.
[http://dx.doi.org/10.1038/s41598-017-00316-3] [PMID: 28331223]
[44]
Nicholls SJ, Puri R, Anderson T, et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA 2016; 316(22): 2373-84.
[http://dx.doi.org/10.1001/jama.2016.16951] [PMID: 27846344]
[45]
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(16): 1500-9.
[http://dx.doi.org/10.1056/NEJMoa1500858] [PMID: 25773607]
[46]
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376(18): 1713-22.
[http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]
[47]
McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012; 59(25): 2344-53.
[http://dx.doi.org/10.1016/j.jacc.2012.03.007] [PMID: 22463922]
[48]
Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367(20): 1891-900.
[http://dx.doi.org/10.1056/NEJMoa1201832] [PMID: 23113833]
[49]
Yadav K, Sharma M, Ferdinand KC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Present perspectives and future horizons. Nutr Metab Cardiovasc Dis 2016; 26(10): 853-62.
[http://dx.doi.org/10.1016/j.numecd.2016.05.006] [PMID: 27352986]
[50]
Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med 2017; 376(16): 1527-39.
[http://dx.doi.org/10.1056/NEJMoa1701488] [PMID: 28304242]
[51]
Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med 2017; 376(16): 1517-26.
[http://dx.doi.org/10.1056/NEJMoa1614062] [PMID: 28304227]
[52]
Robinson JG, Colhoun HM, Bays HE, et al. Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies. Clin Cardiol 2014; 37(10): 597-604.
[http://dx.doi.org/10.1002/clc.22327] [PMID: 25269777]
[53]
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(18): 1870-82.
[http://dx.doi.org/10.1001/jama.2014.4030] [PMID: 24825642]
[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(19): 1809-19.
[http://dx.doi.org/10.1056/NEJMoa1316222] [PMID: 24678979]
[55]
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(23): 2497-506.
[http://dx.doi.org/10.1001/jama.2012.25790] [PMID: 23128163]
[56]
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(23): 2541-8.
[http://dx.doi.org/10.1016/j.jacc.2014.03.019] [PMID: 24694531]
[57]
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(20): 2408-17.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.144055] [PMID: 23129602]
[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(9965): 331-40.
[http://dx.doi.org/10.1016/S0140-6736(14)61399-4] [PMID: 25282519]
[59]
Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 2013; 128(19): 2113-20.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.004678] [PMID: 24014831]
[60]
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(9965): 341-50.
[http://dx.doi.org/10.1016/S0140-6736(14)61374-X] [PMID: 25282520]
[61]
Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy and safety of the proprotein convertase subtil-isin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. American heart journal 2015; 169(6): 906-15. e13
[62]
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. Eur Heart J 2015; 36(19): 1186-94.
[http://dx.doi.org/10.1093/eurheartj/ehv028] [PMID: 25687353]
[63]
Bays H, Gaudet D, Weiss R, et al. Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. J Clin Endocrinol Metab 2015; 100(8): 3140-8.
[http://dx.doi.org/10.1210/jc.2015-1520] [PMID: 26030325]
[64]
Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis 2016; 244: 138-46.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.11.010] [PMID: 26638010]
[65]
Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The odyssey alternative randomized trial. J Clin Lipidol 2015; 9(6): 758-69.
[http://dx.doi.org/10.1016/j.jacl.2015.08.006] [PMID: 26687696]
[66]
Roth EM, McKenney JM. ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol 2015; 11(1): 27-37.
[http://dx.doi.org/10.2217/fca.14.82] [PMID: 25606700]
[67]
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(16): 1489-99.
[http://dx.doi.org/10.1056/NEJMoa1501031] [PMID: 25773378]
[68]
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. Eur Heart J 2015; 36(43): 2996-3003.
[http://dx.doi.org/10.1093/eurheartj/ehv370] [PMID: 26330422]
[69]
Teramoto T, Kobayashi M, Tasaki H. Yagyu H, Higashikata T, Takagi Y,. Efficacy and safety of alirocumab in japanese patients with heterozygous familial hypercholesterolemia or at high car-diovascular risk With hypercholesterolemia not adequately controlled with statins- odyssey japan randomized controlled trial. Circulation Journal: Official Journal of the Japanese Circulation Society 2016; 80(9): 1980-7.
[70]
Kastelein JJ, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: Design and rationale of the odyssey FH studies. Cardiovasc Drugs Ther 2014; 28(3): 281-9.
[http://dx.doi.org/10.1007/s10557-014-6523-z] [PMID: 24842558]
[71]
Roth EM, Moriarty PM, Bergeron J, et al. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: Odyssey Choice I. Atherosclerosis 2016; 254: 254-62.
[http://dx.doi.org/10.1016/j.atherosclerosis.2016.08.043] [PMID: 27639753]
[72]
Stroes E, Guyton JR, Lepor N, et al. Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The Odyssey Choice II Study. J Am Heart Assoc 2016; 5(9)e003421
[http://dx.doi.org/10.1161/JAHA.116.003421] [PMID: 27625344]
[73]
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(1): 185-92.
[http://dx.doi.org/10.1007/s11095-016-2054-6] [PMID: 27822850]
[74]
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(17): 1360-9.
[http://dx.doi.org/10.1093/eurheartj/ehv707] [PMID: 26757788]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 2
Year: 2020
Page: [138 - 146]
Pages: 9
DOI: 10.2174/1570163816666181211112358
Price: $65

Article Metrics

PDF: 19
HTML: 2