Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials

BMC Medicine

Biao Xu²  Li-Na Kang²  Jun Xie²  Guan-Nan Li²  Qin-Hua Chen²  Jian-Zhou Chen²  Li Zhu¹  Qing-Qing Zhu³  Xin-Lin Zhang² 

[1] Department of Radiology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China;Department of Cardiology, Affiliated Drum Tower Hospital, Nanjing University School of Medicine, 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China;Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China

关键词: Randomized controlled trials;    Meta-analysis;    LDL-C;    Efficacy;    Safety;    Alirocumab;    Evolocumab;    Monoclonal antibody;    PCSK9;   

Others  :  1216034
DOI  :  10.1186/s12916-015-0358-8

 received in 2015-02-11, accepted in 2015-04-30,  发布年份 2015

【 授权许可】

   
2015 Zhang et al.; licensee BioMed Central.

【 参考文献 】

• [1]Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001; 285:2486-97.
• [2]Stone NJ, Robinson JG, Lichtenstein AH, Bairey MC, Blum CB, Eckel RH 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. J Am Coll Cardiol. 2014; 63:2889-934.
• [3]Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014; 11:563-75.
• [4]Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M et al.. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34:154-6.
• [5]Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD et al.. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007; 282:18602-12.
• [6]Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D et al.. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015; 115:1212-21.
• [7]Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D 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; 311:1870-82.
• [8]Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE et al.. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014; 383:60-8.
• [9]Kong WJ, Wei J, Zuo ZY, Wang YM, Song DQ, You XF et al.. Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism. 2008; 57:1029-37.
• [10]Schomig A, Mehilli J, de Waha A, Seyfarth M, Pache J, Kastrati A. A meta-analysis of 17 randomized trials of a percutaneous coronary intervention-based strategy in patients with stable coronary artery disease. J Am Coll Cardiol. 2008; 52:894-904.
• [11]Sterne JA, Bradburn MJ, Egger M. Meta-analysis in Stata. In: Systematic reviews in health care. Egger M, Smith GD, Altman D, editors. Blackwell BMJ Books, London; 2001: p.357.
• [12]Higgins JP, Deeks JJ. Selecting studies and collecting data. In: Cochrane handbook for systematic reviews of interventions. 0 Higgins JP, Green S, editors. The Cochrane Collaboration, Chichester; 2011: p.7:1.
• [13]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; 128:2113-20.
• [14]Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB et al.. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012; 366:1108-18.
• [15]Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman DS et al.. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012; 60:1888-98.
• [16]Robinson JG. Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: first results from the ODYSSEY LONG TERM study in 2,341 patients. Paper presented at 2014 Scientific Sessions of European Society of Cardiology, Barcelona; 2014.
• [17]Luscher TF. Efficacy and safety of alirocumab: results from the ODYSSEY COMBO II study and results of ODYSSEY FH I and FH II studies. Paper presented at 2014 Scientific Sessions of European Society of Cardiology, Barcelona; 2014.
• [18]Cannon CP. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study. Paper presented at 2014 Scientific Sessions of European Society of Cardiology, Barcelona; 2014.
• [19]Moriarty PM. 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. Paper presented at 2014 Scientific Sessions of American Heart Association, Chicago; 2014.
• [20]Kereiakes DJ. Efficacy and safety of alirocumab in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia on maximally tolerated doses of statins: the ODYSSEY COMBO I Study. Paper presented at 2014 Scientific Sessions of American Heart Association, Chicago; 2014.
• [21]Ginsberg HN. ODYSSEY HIGH FH: efficacy and safety of alirocumab in patients with severe heterozygous familial hypercholesterolemia. Paper presented at 2014 Scientific Sessions of American Heart Association, Chicago; 2014.
• [22]Bays H. Efficacy and safety of combining alirocumab with atorvastatin or rosuvastatin versus statin intensification or adding ezetimibe in high cardiovascular risk patients: ODYSSEY OPTIONS I and II. Paper presented at 2014 Scientific Sessions of American Heart Association, Chicago; 2014.
• [23]Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M et al.. Efficacy and safety of Alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1489-99.
• [24]Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R 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.
• [25]Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L et al.. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014; 370:1809-19.
• [26]Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF 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; 63:2541-8.
• [27]Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J et al.. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014; 63:2531-40.
• [28]Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V 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; 308:2497-506.
• [29]Hirayama A, Honarpour N, Yoshida M, Yamashita S, Huang F, Wasserman SM et al.. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk–primary results from the phase 2 YUKAWA study. Circ J. 2014; 78:1073-82.
• [30]Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G 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; 129:234-43.
• [31]Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L et al.. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012; 380:1995-2006.
• [32]Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F et al.. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012; 380:2007-17.
• [33]Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R et al.. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 385:341-50.
• [34]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; 126:2408-17.
• [35]Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L et al.. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 385:331-40.
• [36]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; 367:1891-900.
• [37]Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R et al.. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012; 380:29-36.
• [38]Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG 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.
• [39]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; 59:2344-53.
• [40]Awan Z, Seidah NG, MacFadyen JG, Benjannet S, Chasman DI, Ridker PM et al.. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem. 2011; 58:183-9.
• [41]Berge KE. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol. 2006; 26:1094-100.
• [42]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; 376:1670-81.
• [43]Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH 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; 380:581-90.
• [44]Cannon CP. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Paper presented at 2014 Scientific Sessions of American Heart Association, Chicago; 2014.
• [45]Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J et al.. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1500-9.
• [46]Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR et al.. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol. 2014; 64:485-94.
• [47]Boekholdt SM, Arsenault BJ, Hovingh GK, Mora S, Pedersen TR, Larosa JC et al.. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation. 2013; 128:1504-12.
• [48]Cohen JC, Boerwinkle E, Mosley TJ, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006; 354:1264-72.
• [49]Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjærg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Am Coll Cardiol. 2010; 55:2833-42.