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Original research
Safety of proprotein convertase subtilisin/kexin 9 inhibitors: a systematic review and meta-analysis
  1. Jing Li1,
  2. Heyue Du1,2,
  3. Yang Wang1,
  4. Bert Aertgeerts3,
  5. Gordon Guyatt4,
  6. Qiukui Hao4,5,
  7. Yanjiao Shen1,
  8. Ling Li1,
  9. Na Su6,
  10. Nicolas Delvaux3,
  11. Geertruida Bekkering3,
  12. Safi U Khan7,
  13. Irbaz B Riaz8,
  14. Per Olav Vandvik9,
  15. Baihai Su2,
  16. Haoming Tian1,
  17. Sheyu Li1
  1. 1 Department of Endocrinology and Metabolism, Chinese Evidence-Based Medicine Center, Cochrane China Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  2. 2 Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  3. 3 Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
  4. 4 Department of Clinical Epidemiology and Biostatistics, and Department of Medicine, and School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
  5. 5 Department of Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  6. 6 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  7. 7 Department of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Pennsylvania, USA
  8. 8 Mayo Clinic Arizona and Brigham and Women hospital, Harvard Medical School, Boston, New York, USA
  9. 9 Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway
  1. Correspondence to Dr Sheyu Li, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China; lisheyu{at}


Objective To determine the harms of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in people who need lipid-lowering therapy.

Methods This systematic review included randomised controlled trials that compared PCSK9 inhibitors with placebo, standard care or active lipid-lowering comparators in people who need lipid-lowering therapy with the follow-up duration of at least 24 weeks. We summarised the relative effects for potential harms from PCSK9 inhibitors using random-effect pairwise meta-analyses and assessed the certainty of evidence using GRADE (Grading of Recommendation Assessment, Development and Evaluation) for each outcome.

Results We included 32 trials with 65 861 participants (with the median follow-up duration of 40 weeks, ranging from 24 to 146 weeks). The meta-analysis showed an incidence of injection-site reaction leading to discontinuation (absolute incidence of 15 events (95% CI 11 to 20) per 1000 persons in a 5-year time frame, high certainty evidence). PCSK9 inhibitors do not increase the risk of new-onset diabetes mellitus, neurocognitive events, cataracts or gastrointestinal haemorrhage with high certainty evidence. PCSK9 inhibitors probably do not increase the risks of myalgia or muscular pain leading to discontinuation or any adverse events leading to discontinuation with moderate evidence certainty. Given very limited evidence, PCSK9 inhibitors might not increase influenza-like symptoms leading to discontinuation (risk ratio 1.5; 95% CI 0.06 to 36.58). We did not identify credible subgroup analyses results, including shorter versus longer follow-up duration of trials.

Conclusions PCSK9 inhibitors slightly increase the risk of severe injection-site reaction but not cataracts, gastrointestinal haemorrhage, neurocognitive events, new-onset diabetes or severe myalgia or muscular pain.

  • coronary artery disease
  • hyperlipidaemias
  • meta-analysis
  • systematic reviews as topic
  • pharmacology, clinical

Data availability statement

No data are available.

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  • JL and HD contributed equally.

  • Presented at This article is part of a cluster of linked articles forming a BMJ Rapid Recommendation. Find the other articles and more details at

  • Contributors BA, GG, QH, ND, GB, POV, HT and SL conceived the study. JL and YW designed and performed the search strategy. JL, HD and YW screened the titles and abstracts for eligibility. JL and YW extracted the data (quantitative data) and reviewed the risk of bias of each included study. JL and YW analysed the data. JL and HD wrote the first draft. All authors revised this draft for critical content. All authors approved the final manuscript. SL is the guarantor of the study. All persons listed as authors have contributed to preparing the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

  • Funding This guideline was funded by 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (Nos 19HXFH011, ZYGD18022 and 2020HXF011).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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