Advertisement

Long-term efficacy and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibodies: A meta-analysis of 11 randomized controlled trials

Published:January 11, 2018DOI:https://doi.org/10.1016/j.jacl.2018.01.004

      Highlights

      • The data of 11 randomized controlled trials with follow-up duration at least 48 weeks were extracted.
      • PCSK9 antibodies could reduce LDL-C levels and improve cardiovascular outcomes significantly.
      • PCSK9 antibodies have a satisfactory safety profile over a long-term follow-up period.

      Background

      Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels.

      Objective

      The purpose of this study was to assess the long-term efficacy and safety of PCSK9 antibodies.

      Methods

      PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched for relevant studies.

      Results

      A total of 11 studies including 38,235 participants who were treated for at least 48 weeks were included in this meta-analysis. The results suggested that PCSK9 antibody treatment significantly decreased LDL-C levels (mean difference, −50.23% [95% confidence interval {CI}, −56.65% to −43.82%]) compared with no PCSK9 antibody treatment and also decreased other atherogenic lipid fractions. PCSK9 antibody treatment also elicited a significant reduction in cardiovascular event rates compared with no antibody treatment (relative risk [RR], 0.86 [95% CI, 0.81–0.92]). This reduction consisted of separate significant reductions in the rates of myocardial infarction (RR, 0.73 [95% CI, 0.65–0.82]), coronary revascularization (RR, 0.79 [95% CI, 0.73–0.87]), and stroke (RR, 0.81 [95% CI, 0.68–0.96]). There were no clear differences in the incidences of treatment-emergent adverse events (TEAEs), serious TEAEs, or TEAEs of interest between the 2 groups; moreover, no differences between the 2 groups were found for other laboratory parameters.

      Conclusion

      PCSK9 antibodies have significant effects on reducing LDL-C levels and improve cardiovascular outcomes. These antibodies have a satisfactory safety profile, which suggests that they are suitable for use as a long-term treatment.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
        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) final report.
        Circulation. 2002; 106: 3143-3421
        • Stone N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • et al.
        • American College of Cardiology/American Heart Association Task Force on Practice Guidelines
        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: 2889-2934
        • Catapano A.L.
        • Graham I.
        • De Backer G.
        • et al.
        2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: the task force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR).
        Atherosclerosis. 2016; 253: 281-344
        • Waters D.D.
        • Brotons C.
        • Chiang C.W.
        • et al.
        • Lipid Treatment Assessment Project 2 Investigators
        Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals.
        Circulation. 2009; 120: 28-34
        • Lee P.
        • Hegele R.A.
        Current phase II proprotein convertase subtilisin/kexin 9 inhibitor therapies for dyslipidemia.
        Expert Opin Investig Drugs. 2013; 22: 1411-1423
        • US Food and Drug Administration
        FDA approves Praluent to treat certain patients with high cholesterol: first in a new class of injectable cholesterol-lowering drugs. Press Announcements.
        (Available at:)
        • US Food and Drug Administration
        FDA approves Repatha to treat certain patients with high cholesterol. Press Announcements.
        (Available at:)
        • Robinson J.G.
        • Nedergaard B.S.
        • Rogers W.J.
        • et al.
        • LAPLACE-2 Investigators
        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
        • Stroes E.
        • Colquhoun D.
        • Sullivan D.
        • et al.
        • GAUSS-2 Investigators
        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: 2541-2548
        • Moriarty P.M.
        • Thompson P.D.
        • Cannon C.P.
        • et al.
        • ODYSSEY ALTERNATIVE Investigators
        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: 758-769
        • Zhang X.L.
        • Zhu Q.Q.
        • Zhu L.
        • et al.
        Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials.
        BMC Med. 2015; 13: 123
        • 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: e001937
        • The Cochrane Collaboration
        Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0.
        (Available at:)
        http://training.cochrane.org/handbook
        Date: 2011
        Date accessed: April 18, 2017
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • et al.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        J Clin Epidemiol. 2009; 62: 1006-1012
        • Kastelein J.J.
        • Ginsberg H.N.
        • 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: 2996-3003
        • Kereiakes D.J.
        • Robinson J.G.
        • Cannon C.P.
        • 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: 906-915.e13
        • Cannon C.P.
        • Cariou B.
        • Blom D.
        • et al.
        • ODYSSEY COMBO II Investigators
        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: 1186-1194
        • Robinson J.G.
        • Farnier M.
        • Krempf M.
        • et al.
        • ODYSSEY LONG TERM Investigators
        Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
        N Engl J Med. 2015; 372: 1489-1499
        • Roth E.M.
        • Moriarty P.M.
        • Bergeron J.
        • et al.
        • ODYSSEY CHOICE I investigators
        A phase III randomized trial evaluating alirocumab 300mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I.
        Atherosclerosis. 2016; 254: 254-262
        • Teramoto T.
        • Kobayashi M.
        • Tasaki H.
        • et al.
        Efficacy and safety of alirocumab in Japanese patients with heterozygous familial hypercholesterolemia or at high cardiovascular risk with hypercholesterolemia not adequately controlled with statins - ODYSSEY JAPAN randomized controlled trial.
        Circ J. 2016; 80: 1980-1987
        • Ginsberg H.N.
        • Rader D.J.
        • Raal F.J.
        • et al.
        Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dL or higher.
        Cardiovasc Drugs Ther. 2016; 30: 473-483
        • Sabatine M.S.
        • Giugliano R.P.
        • Wiviott S.D.
        • et al.
        • Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators
        Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.
        N Engl J Med. 2015; 372: 1500-1509
        • Nicholls S.J.
        • 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: 2373-2384
        • Sabatine M.S.
        • Giugliano R.P.
        • Keech A.C.
        • et al.
        • FOURIER Steering Committee and Investigators
        Evolocumab and clinical outcomes in patients with cardiovascular sisease.
        N Engl J Med. 2017; 376: 1713-1722
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.
        • et al.
        • JUPITER Study Group
        Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N Engl J Med. 2008; 359: 2195-2207
        • Nicholls S.J.
        • Ballantyne C.M.
        • Barter P.J.
        • et al.
        Effect of two intensive statin regimens on progression of coronary disease.
        N Engl J Med. 2011; 365: 2078-2087
        • National Institute for Health and Care Excellence
        Cardiovascular disease: risk assessment and reduction, including lipid modification. Clinical guidelines [CG181].
        (Available at:)
        http://www.nice.org.uk/guidance/cg181
        Date: 2016
        Date accessed: May 31, 2017
        • Stroes E.S.
        • Thompson P.D.
        • Corsini A.
        • et al.
        • EuropeanAtherosclerosisSocietyConsensusPanel
        Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.
        Eur Heart J. 2015; 36: 1012-1022
        • Chodick G.
        • Shalev V.
        • Gerber Y.
        • et al.
        Long-term persistence with statin treatment in a not-for-profit health maintenance organization: a population-based retrospective cohort study in Israel.
        Clin Ther. 2008; 30: 2167-2179
        • Béliard S.
        • Carreau V.
        • Carrié A.
        • et al.
        Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects.
        Atherosclerosis. 2014; 234: 136-141
        • Chapman M.J.
        • Stock J.K.
        • Ginsberg H.N.
        PCSK9 Forum. PCSK9 inhibitors and cardiovascular disease: heralding a new therapeutic era.
        Curr Opin Lipidol. 2015; 26: 511-520
        • Cohen J.C.
        • Boerwinkle E.
        • Mosley Jr., T.H.
        • et al.
        Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
        N Engl J Med. 2006; 354: 1264-1272
        • Kathiresan S.
        • Myocardial Infarction Genetics Consortium
        A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction.
        N Engl J Med. 2008; 358: 2299-2300
        • Ray K.K.
        • Ginsberg H.N.
        • Davidson M.H.
        • et al.
        Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control.
        Circulation. 2016; 134: 1931-1943
        • Orringer C.E.
        • Jacobson T.A.
        • Saseen J.J.
        • et al.
        Update on the use of PCSK9 inhibitors in adults: recommendations from an Expert Panel of the National Lipid Association.
        J Clin Lipidol. 2017; 11: 880-890
        • Cannon C.P.
        • Blazing M.A.
        • Giugliano R.P.
        • et al.
        • IMPROVE-IT Investigators
        Ezetimibe added to statin therapy after acute coronary syndromes.
        N Engl J Med. 2015; 372: 2387-2397
        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • et al.
        • CholesterolTreatmentTrialists’ (CTT) Collaboration
        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
        • Kostapanos M.S.
        • Elisaf M.S.
        Statins and mortality: the untold story.
        Br J Clin Pharmacol. 2016; 83: 938-941
        • Warren J.B.
        • Dimmitt S.
        • Stampfer H.
        Cholesterol trials and mortality.
        Br J Clin Pharmacol. 2016; 82: 168-177
        • Reiner Z.
        • Catapano A.L.
        • De Backer G.
        • et al.
        • European Association for Cardiovascular Prevention & Rehabilitation
        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. 2011; 32: 1769-1818
        • Bohula E.A.
        • Giugliano R.P.
        • Cannon C.P.
        • et al.
        Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.
        Circulation. 2015; 132: 1224-1233
        • Sattar N.
        • Preiss D.
        • Robinson J.G.
        • et al.
        Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data.
        Lancet Diabetes Endocrinol. 2016; 4: 403-410
        • Colhoun H.M.
        • Ginsberg H.N.
        • Robinson J.G.
        • et al.
        No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies.
        Eur Heart J. 2016; 37: 2981-2989
        • Ridker P.M.
        • Tardif J.C.
        • Amarenco P.
        • et al.
        • SPIRE Investigators
        Lipid-reduction variability and antidrug-antibody formation with bococizumab.
        N Engl J Med. 2017; 376: 1517-1526
        • Ridker P.M.
        • Revkin J.
        • Amarenco P.
        • et al.
        • SPIRE Cardiovascular Outcome Investigators
        Cardiovascular efficacy and safety of bococizumab in high-risk patients.
        N Engl J Med. 2017; 376: 1527-1539
        • Glerup S.
        • Schulz R.
        • Laufs U.
        • et al.
        Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease.
        Basic Res Cardiol. 2017; 112: 32