Advertisement

The efficacy advantage of evolocumab (AMG 145) dosed at 140mg every 2weeks versus 420mg every 4weeks in patients with hypercholesterolemia: Evidence from a meta-analysis

  • Author Footnotes
    1 These authors contributed equally to this work.
    Xiao-Xiao He
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Key Laboratory of Geriatrics of Health Ministry, Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Rong Zhang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Key Laboratory of Geriatrics of Health Ministry, Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Pei-Yuan Zuo
    Affiliations
    Key Laboratory of Geriatrics of Health Ministry, Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Yu-Wei Liu
    Affiliations
    Key Laboratory of Geriatrics of Health Ministry, Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Xiang-Nan Zha
    Affiliations
    Key Laboratory of Geriatrics of Health Ministry, Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Sheng-Shuai Shan
    Affiliations
    Key Laboratory of Geriatrics of Health Ministry, Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Cheng-Yun Liu
    Correspondence
    Corresponding author at: Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
    Affiliations
    Key Laboratory of Geriatrics of Health Ministry, Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
Published:October 27, 2016DOI:https://doi.org/10.1016/j.ejim.2016.10.009

      Highlights

      • The efficacy and safety of evolocumab at 140 mg Q2W and 420 mg Q4W were compared.
      • Evolocumab was more effective at 140 mg Q2W in statin-treated patients.
      • There was no difference in the rate of main treatment-related adverse events.

      Abstract

      Background

      Evolocumab (AMG 145), a PCSK9 inhibitor, has been shown to decrease low-density lipoprotein cholesterol (LDL-C) levels. Doses of 140 mg administered every 2 weeks (Q2W) and 420 mg administered every 4 weeks (Q4W) are widely used, and both dosing schedules were effective in clinical trials. However, some researchers have speculated that 140 mg Q2W administration has equal or even greater efficacy. This meta-analysis was performed to assess the differences in efficacy and safety between the two doses.

      Methods

      We searched the PubMed, EMBASE, and Web of Science databases to identify relevant clinical trials published before January 2016. A total of 2403 patients from 8 randomized controlled trials were identified and included in the analysis.

      Results

      Evolocumab administered at 140 mg Q2W resulted in a greater percent change from baseline in LDL-C concentration (−7.27; 95% confidence interval (CI), −10.36 to −4.18) and had greater efficacy in achieving the treatment goal of LDL-C ≤1.8 mmol/L with an relative risk (RR) of 1.09 (95% CI, 1.00 to 1.18) compared with 420 mg Q4W in patients who were concomitantly treated with statins. These findings were not significantly different between the 140 mg Q2W and 420 mg Q4W groups when evolocumab was administered as monotherapy. There was no difference in the rate of occurrence of the main treatment-related adverse events between the two doses.

      Conclusions

      Evolocumab administered at 140 mg Q2W was more effective than the 420 mg Q4W dosage at lowering lipid concentrations, especially in patients who concomitantly received stable statin therapy.

      Abbreviations:

      ApoB/ApoA-I (Apolipoprotein B/Apolipoprotein A-I), ALT (Alanine aminotransferase), AST (Aspartate aminotransferase), CI (Confidence interval), CVD (Cardiovascular disease), CHD (Coronary heart disease), AMG 145 (Evolocumab), Q2W (Every 2weeks), Q4W (Every 4weeks), HoFH (Homozygous familial hypercholesterolemia), HDL-C (High density lipoprotein cholesterol), LDL-C (Low density lipoprotein cholesterol), LDLR (Low density lipoprotein receptor), MD (Mean difference), Non-HDL-C (Non-high-density lipoprotein cholesterol), PCSK9 (Proprotein convertase subtilisin/kexin type 9), RCTs (Randomized controlled trials), RR (Relative risk), SD (Standard deviation), TC (Total cholesterol), TG (Triglycerides), TEAE (Treatment emergent adverse events), VLDL-C (Very low density lipoprotein cholesterol)

      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 European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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
        • Reiner Ž.
        • De Bacquer D.
        • Kotseva K.
        • et al.
        Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey.
        Atherosclerosis. 2013; 231: 300-307
        • Artenstein A.W.
        • Opal S.M.
        Proprotein convertases in health and disease.
        N Engl J Med. 2011; 365: 2507-2518
        • Horton J.D.
        • Cohen J.C.
        • Hobbs H.H.
        PCSK9: a convertase that coordinates LDL catabolism.
        J Lipid Res. 2009; 50 ([Supplement]): S172-S177
        • Qian Y.W.
        • Schmidt R.J.
        • Zhang Y.
        • et al.
        Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis.
        J Lipid Res. 2007; 48: 1488-1498
        • Ahn C.H.
        • Choi S.H.
        New drugs for treating dyslipidemia: beyond statins.
        Diabetes Metab J. 2015; 39: 87-94
        • Chan J.C.Y.
        • Piper D.E.
        • Cao Q.
        • et al.
        A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
        Proc Natl Acad Sci U S A. 2009; 106: 9820-9825
        • Markham A.
        Evolocumab: first global approval.
        Drugs. 2015; 75: 1567-1573
        • Cicero A.F.G.
        • Tartagni E.
        • Ertek S.
        Efficacy and safety profile of evolocumab (AMG145), an injectable inhibitor of the proprotein convertase subtilisin/kexin type 9: the available clinical evidence.
        Expert Opin Biol Ther. 2014; 14: 863-868
        • 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
        • Jacobson T.A.
        • Ito M.K.
        NLA Recommendations for Patient-Centered Management of Dyslipidemia (Draft).
        2014
        • Loke Y.K.
        • PDHA
        Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0.
        2011
        • Higgins J.P.T.
        • Thompson S.G.
        • Deeks J.J.
        • et al.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 1088-1101
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339: b2535
        • Kiyosue A.
        • Honarpour N.
        • Kurtz C.
        • et al.
        A phase 3 study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk.
        Am J Cardiol. 2016; 117: 40-47
        • Raal F.J.
        • Stein E.A.
        • 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
        • Hirayama A.
        • Honarpour N.
        • 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: 1073-1082
        • Koren M.J.
        • Lundqvist P.
        • et al.
        The MENDEL-2 randomized, controlled phase III clinical trial of evolocumab.
        J Am Coll Cardiol. Jun 17 2014; 63: 2531-2540
        • Robinson J.G.
        • Nedergaard B.S.
        • Rogers W.J.
        • 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: 1870-1883
        • 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: 2541-2548
        • Koren M.J.
        • Scott R.
        • Kim J.B.
        • 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
        • Giugliano R.P.
        • Desai N.R.
        • 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. Dec 8 2012; 380: 2007-2017
        • Chiang C.E.
        • Ferrières J.
        • Gotcheva N.N.
        • et al.
        Suboptimal control of lipid levels: results from 29 countries participating in the centralized pan-regional surveys on the undertreatment of hypercholesterolemia (CEPHEUS).
        Circulation. 2014; 130: A12344
        • Welder G.
        • Zineh I.
        • Pacanowski M.A.
        • et al.
        High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol.
        J Lipid Res. 2010; 51: 2714-2721
        • Trialists C.T.
        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
        • Jones P.H.
        • Nair R.
        • Thakker K.M.
        Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis.
        J Am Heart Assoc. 2012; 1e001800
        • Pekkanen J.
        • Nissinen A.
        • Vartiainen E.
        • et al.
        Changes in serum cholesterol level and mortality: a 30-year follow-up the Finnish cohorts of the seven countries study.
        Am J Epidemiol. 1994; 139: 155-165
        • Preiss D.
        • Seshasai S.R.K.
        • Welsh P.
        • et al.
        Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
        JAMA. 2011; 305: 2556-2564
        • Ravnskov U.
        • Rosch P.J.
        • Sutter M.C.
        • et al.
        Should we lower cholesterol as much as possible?.
        BMJ. 2006; 332: 1330-1332
        • Arsenault B.J.
        • Rana J.S.
        • Stroes E.S.G.
        • et al.
        Beyond low-density lipoprotein cholesterol: respective contributions of non–high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women.
        J Am Coll Cardiol. 2009; 55: 35-41
        • Boekholdt S.M.
        • Arsenault B.J.
        • Mora S.
        • et al.
        Association of LDL cholesterol, non–HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
        JAMA. 2012; 307: 1302-1309
        • Walldius G.
        • Jungner I.
        • Aastveit A.H.
        • et al.
        The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk.
        Clin Chem Lab Med. 2004; 42: 1355-1363
        • Sabatine M.S.
        • Giugliano R.P.
        • Wiviott S.D.
        • et al.
        Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.
        N Engl J Med. 2015; 372: 1500-1509