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
- 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 bmj.com/rapid-recommendations.
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.
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