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



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.


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.


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).


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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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.


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.


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.

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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.

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