Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients at High Cardiovascular Risk: An Updated Systematic Review and Meta-Analysis of 32 Randomized Controlled Trials

Abstract

Introduction

Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies are powerful lipid-lowering drugs which have been shown to improve clinical endpoints in patients with hypercholesterolemia. However, it is not clear how effective PCSK9 monoclonal antibodies are for patients at high cardiovascular risk. Also, whether the effectiveness of PCSK9 monoclonal antibodies varies between different drug types, dosages, race, and indications for PCSK9 monoclonal antibodies remains unclear. Therefore, we used recently published studies to systematically evaluate the efficacy and safety of PCSK9 monoclonal antibodies by analyzing the lipid profiles, adverse events, and clinical endpoints in patients at high cardiovascular risk.

Methods

Randomized controlled trials (RCTs) comparing PCSK9 monoclonal antibodies with placebos or active drugs in patients at high cardiovascular risk were retrieved from electronic databases from their inception until November 2019. Efficacy and safety outcomes included low-density lipoprotein cholesterol (LDL-C) and other lipid profiles, treatment-emergent adverse events (TEAEs) and adverse events of interests, and clinical endpoints. Subgroup analyses based on drug types, dosing, and race were conducted. Statistical analysis was performed using STATA 15.1 and RevMan 5.0.

Results

Thirty-two RCTs were included in the systematic review, and 25 of them (57,090 individuals) were included in the meta-analysis. PCSK9 monoclonal antibodies significantly improved LDL-C and other lipid profiles (P < 0.05), and no racial differences were found. A recommended dose of 140 mg of evolocumab every 2 weeks was likely to produce a relatively stronger effect than 150 mg of alirocumab every 2 weeks in terms of the absolute change (weighted mean differences (WMD) − 0.36; 95% confidence interval (CI) − 0.71 to − 0.01; P = 0.041) and percent change (WMD − 19.53; 95% CI − 32.02 to − 7.04; P = 0.002) in LDL-C levels. Overall, PCSK9 monoclonal antibodies were safe, except for the significantly increased risk of injection site reactions (relative risks (RR) 1.54; 95% CI 1.38–1.71; P < 0.001). Both alirocumab (RR 0.89; 95% CI 0.83–0.95; P < 0.001) and evolocumab (RR 0.86; 95% CI 0.80–0.92; P < 0.001) were associated with a lower risk of major cardiovascular events (MACEs), especially in secondary preventive patients (alirocumab group: RR 0.88; 95% CI 0.82–0.95; P < 0.001; evolocumab group: RR 0.86; 95% CI 0.80–0.92; P < 0.001). The reduction in MACEs was observed in White but not in Asian subjects. No significant reduction of all-cause mortality was found (RR 0.88; 95% CI 0.72–1.07; P = 0.182).

Conclusion

Both alirocumab and evolocumab are well tolerated and can greatly improve lipid profiles for patients at high cardiovascular risk. Both PCSK9 monoclonal antibodies significantly reduce the risk of nonfatal MACEs in patients with previous cardiovascular events, but the effect on all-cause mortality remains uncertain.

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References

  1. 1.

    Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–16.

  2. 2.

    Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73:e285–350.

  3. 3.

    Mach F, Baigent C, Catapano AL, et al. ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;2019:1–78.

    Google Scholar 

  4. 4.

    Kinoshita M, Yokote K, Arai H, et al. Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017. J Atheroscler Thromb. 2018;25:846–984.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    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.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Ference BA, Cannon CP, Landmesser U, Lüscher TF, Catapano AL, Ray KK. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018;39:2540–5.

    CAS  PubMed  Google Scholar 

  7. 7.

    Thompson GR. Atherosclerosis in cholesterol-fed rabbits and in homozygous and heterozygous LDL receptor-deficient humans. Atherosclerosis. 2018;276:148–54.

    CAS  PubMed  Google Scholar 

  8. 8.

    Ridker PM, Tardif J-C, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med. 2017;376:1517–26.

  9. 9.

    Zhang Y-S, Hao Y-H, Luo H-L, Xie B-C, Fu J-Y, Zhou Z-K. Comparisons of three different doses of alirocumab application in patients with hypercholesterolemia: a meta-analysis. Minerva Med. 2018;109:229–38.

    PubMed  Google Scholar 

  10. 10.

    Karatasakis A, Danek BA, Karacsonyi J, et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta‐analysis of 35 randomized controlled trials. J Am Heart Assoc. 2017;6. https://doi.org/10.1161/JAHA.117.006910 .

  11. 11.

    Toth PP, Worthy G, Gandra SR, et al. Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia. J Am Heart Assoc. 2017;6. https://doi.org/10.1161/JAHA.116.005367.

  12. 12.

    Eslami SM, Nikfar S, Ghasemi M, Abdollahi M. Does evolocumab, as a PCSK9 inhibitor, ameliorate the lipid profile in familial hypercholesterolemia patients? A meta-analysis of randomized controlled trials. J Pharm Pharm Sci. 2017;20:81–96.

    CAS  PubMed  Google Scholar 

  13. 13.

    Dicembrini I, Giannini S, Ragghianti B, Mannucci E, Monami M. Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. J Endocrinol Invest. 2019;42:1029–39.

    CAS  PubMed  Google Scholar 

  14. 14.

    Casula M, Olmastroni E, Boccalari MT, Tragni E, Pirillo A, Catapano AL. Cardiovascular events with PCSK9 inhibitors: an updated meta-analysis of randomised controlled trials. Pharmacol Res. 2019;143:143–50.

    CAS  PubMed  Google Scholar 

  15. 15.

    Guedeney P, Giustino G, Sorrentino S, et al. Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J. 2019. https://doi.org/10.1093/eurheartj/ehz430.

  16. 16.

    Turgeon RD, Tsuyuki RT, Gyenes GT, Pearson GJ. Cardiovascular efficacy and safety of PCSK9 inhibitors: systematic review and meta-analysis including the ODYSSEY OUTCOMES trial. Can J Cardiol. 2018;34:1600–5.

    PubMed  Google Scholar 

  17. 17.

    Du H, Li X, Su N, et al. Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis. Heart. 2019;105:1149–59.

  18. 18.

    Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–107.

    CAS  PubMed  Google Scholar 

  19. 19.

    NCT02715726. Evaluation of alirocumab versus ezetimibe on top of statin in Asia in high cardiovascular risk patients with hypercholesterolemia (ODYSSEY EAST). https://clinicaltrials.gov/ct2/show/NCT02715726?term=NCT02715726&draw=2&rank=1.

  20. 20.

    Rosenson RS, Daviglus ML, Handelsman Y, et al. Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study. Diabetologia. 2019;62:948–58.

  21. 21.

    Lorenzatti AJ, Eliaschewitz FG, Chen Y, et al. Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: primary results of the BERSON clinical trial. Diabetes Obes Metab. 2019;21:1455–63.

  22. 22.

    Müller-Wieland D, Rader DJ, Moriarty PM, et al. Efficacy and safety of alirocumab 300 mg every 4 weeks in individuals with type 2 diabetes on maximally tolerated statin. J Clin Endocrinol Metab. 2019;104:5253–62.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

  24. 24.

    Higgins JP, Green S, editors. Cochrane handbook for systematic reviews of interventions. Version 5. The Cochrane Collaboration. Hoboken, NJ: Wiley; 2011.

  25. 25.

    Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.

    CAS  PubMed  Google Scholar 

  26. 26.

    Stein EA, Turner T, Plunkett N, Zhou R, Fritz C. Friedewald formula significantly underestimates LDL cholesterol compared to preparative ultracentrifugation below 70 mg/dl leading to overestimation of the LDL cholesterol reduction for new drugs in development. J Am Coll Cardiol. 2014;63:A1457.

  27. 27.

    Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    CAS  PubMed  Google Scholar 

  29. 29.

    Ades AE, Lu G, Higgins JPT. The interpretation of random-effects meta-analysis in decision models. Med Decis Making. 2005;25:646–54.

    CAS  PubMed  Google Scholar 

  30. 30.

    Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50:683–91.

    CAS  PubMed  Google Scholar 

  32. 32.

    Catalá-López F, Tobías A. Síntesis de la evidencia clínica y metaanálisis en red con comparaciones indirectas. Med Clin (Barc). 2013;140:182–7.

    Google Scholar 

  33. 33.

    Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ. 2003;326:219.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    CAS  PubMed  Google Scholar 

  36. 36.

    Duval S, Tweedie R. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Stat Assoc. 2000;95:89–98.

    Google Scholar 

  37. 37.

    Pedroza-Tobías A. Assessing the influence of a single study in the meta-analysis estimate. Stata Technol Bull. 1999;8(47).

  38. 38.

    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;36:1186–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.

    CAS  PubMed  Google Scholar 

  40. 40.

    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;9:758–69.

    PubMed  Google Scholar 

  41. 41.

    Kereiakes DJ, Robinson JG, Cannon CP, 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.

    Google Scholar 

  42. 42.

    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;100:3140–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    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;385:341–50.

    CAS  PubMed  Google Scholar 

  44. 44.

    Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A. A phase 3 study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am J Cardiol. 2016;117:40–7.

    CAS  PubMed  Google Scholar 

  45. 45.

    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;80:1980–7.

    CAS  PubMed  Google Scholar 

  46. 46.

    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;316:2373–84.

    CAS  PubMed  Google Scholar 

  47. 47.

    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.

    CAS  PubMed  Google Scholar 

  48. 48.

    Ginsberg HN, Rader DJ, Raal FJ, 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;30:473–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J. 2016;37:3588–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Leiter LA, Cariou B, Müller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: the ODYSSEY DM-INSULIN randomized trial. Diabetes Obes Metab. 2017;19:1781–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–22.

    CAS  PubMed  Google Scholar 

  52. 52.

    Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527–39.

    CAS  PubMed  Google Scholar 

  53. 53.

    Koh KK, Nam CW, Chao T-H, et al. A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). J Clin Lipidol. 2018;12(162–172):e6.

    Google Scholar 

  54. 54.

    Ridker PM, Rose LM, Kastelein JJP, et al. Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: results from the SPIRE randomized trials of bococizumab. J Clin Lipidol. 2018;12:958–65.

    PubMed  Google Scholar 

  55. 55.

    Stein EA, Gipe D, Bergeron J, 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.

    CAS  PubMed  Google Scholar 

  56. 56.

    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. Circulation. 2012;126:2408–17.

    CAS  PubMed  Google Scholar 

  57. 57.

    Hirayama A, Honarpour N, Yoshida M, 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.

    CAS  PubMed  Google Scholar 

  58. 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;385:331–40.

    CAS  PubMed  Google Scholar 

  59. 59.

    Kastelein JJP, 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;36:2996–3003.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, 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.

  61. 61.

    Sirtori CR, Mombelli G, Triolo M, Laaksonen R. Clinical response to statins: mechanism(s) of variable activity and adverse effects. Ann Med. 2012;44:419–32.

    CAS  PubMed  Google Scholar 

  62. 62.

    Bates TR, Connaughton VM, Watts GF. Non-adherence to statin therapy: a major challenge for preventive cardiology. Expert Opin Pharmacother. 2009;10:2973–85.

    CAS  PubMed  Google Scholar 

  63. 63.

    Nanchen D, Gencer B, Muller O, et al. Prognosis of patients with familial hypercholesterolemia after acute coronary syndromes. Circulation. 2016;134:698–709.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Funding

This study was supported by grants from the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (nos. 2017ZX09304028-006, 2017ZX09101001, and 2018ZX09201014), National Key R&D Program of China (no. 2016YFC0904900), National Natural Science Foundation of China (nos. 81673509 and 81573504) and Natural Science Foundation of Beijing Municipality (no. 7171012). The journal’s Rapid Service Fee was funded by the authors.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

Conceptualization: GM, QX, YH, and YC; Methodology: GM, QX, ZW, and HZ; Formal analysis and investigation: GM, QX, SZ, and ZL; Writing—original draft preparation: GM; Writing—review and editing: LQ, JJ, YG, YH, and Y-MC. All authors approved the final manuscript.

Disclosures

Guangyan Mu, Qian Xiang, Shuang Zhou, Zhiyan Liu, Litong Qi, Jie Jiang, Yanjun Gong, Qiufen Xie, Zining Wang, Hanxu Zhang, Yong Huo and Yimin Cui have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Data Availability

All data and materials used in this research are freely available. References have been provided.

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Correspondence to Yimin Cui.

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Mu, G., Xiang, Q., Zhou, S. et al. Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients at High Cardiovascular Risk: An Updated Systematic Review and Meta-Analysis of 32 Randomized Controlled Trials. Adv Ther 37, 1496–1521 (2020). https://doi.org/10.1007/s12325-020-01259-4

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Keywords

  • Adverse events
  • Cardiology
  • Cardiovascular risk
  • Efficacy
  • Major cardiovascular events
  • PCSK9 monoclonal antibody