Impact of conventional lipid‐lowering therapy on circulating levels of p roprotein convertase subtilisin/kexin type 9: A systematic review and meta‐analysis of randomised controlled trials

Abstract Conventional lipid‐lowering agents, such as statins, ezetimibe, fibrates, bile acid sequestrants, nicotinic acid, bempedoic acid, and omega‐3, play a pivotal role in managing dyslipidemia. Despite their benefits, these agents are associated with increased levels of plasma proprotein convertase subtilisin kexin 9 (PCSK9), a serine protease linked to elevated cardiovascular risk. The literature lacks comprehensive data on how these commonly used drugs collectively impact circulating PCSK9 levels alongside their lipid‐modifying effects. This review addresses this gap by systematically analysing the effects of these agents on PCSK9 and lipid profiles. Following the preferred reporting items for systematic review and meta‐analysis protocols guidelines, this study conducts a systematic search across multiple databases including MEDLINE, Cochrane Central, EMBASE, Web of Science, SCOPUS, and ScienceDirect. We include published, peer‐reviewed randomised controlled trials (RCTs) that involve adult patients undergoing monotherapy or combination therapy with the mentioned lipid‐lowering drugs for at least 2 weeks, with recorded PCSK9 levels at baseline and post‐treatment. Our analysis encompasses data extraction and bias assessment independently performed by two researchers, utilising standardised mean difference for continuous data and risk ratios for dichotomous data. We also conduct subgroup and sensitivity analyses to assess treatment intensity, drug types, comorbidities, and geographical variations in study outcomes. Publication bias is evaluated through funnel plot and Egger's test. The meta‐analysis includes 14 RCTs with 21 treatment arms, involving 1313 participants. Results indicate a significant increase in plasma PCSK9 levels following treatment with conventional lipid‐lowering drugs (weighted mean difference: 23.25 ng/mL; 95% confidence interval: 17.00, 29.50; p < 0.01; I 2 = 56%). Notably, subgroup analyses reveal significant differences based on treatment intensity, type of lipid‐lowering agent, underlying diseases, and trial location. This systematic review confirms that conventional lipid‐lowering drugs significantly elevate plasma PCSK9 levels. These findings highlight the necessity for clinicians to monitor PCSK9 concentrations in patients undergoing lipid‐lowering treatment to optimise therapeutic strategies and mitigate associated cardiovascular risks. Our study contributes to a nuanced understanding of the biochemical effects of lipid‐lowering therapies, potentially guiding future clinical practices and research in cardiovascular risk management.