Potential beneficial effect of treatment with PCSK9 inhibitors on vascular endothelial dysfunction: a systematic review and meta-analysis

INTRODUCTION: PCSK9 inhibitors (PCSK9i) are at the center of research for their pleiotropic effects. The aim of this study is to systematically review the literature for their effect on vascular endothelial dysfunction. METHODS: We systematically researched Embase, Ovid MEDLINE and CENTRAL for this purpose. Eligible studies were those assessing endothelial function by available noninvasive vascular methods. Meta-analysis was performed to compare differences on endothelial dysfunction between PCSK9i and placebo. Qualitative analysis was used for observational studies evaluating the outcome before and after PCSK9i. RESULTS: We found 8 articles eligible, with the main outcome, among others, to be changes on flow-mediated dilation (FMD). Observational studies report an increase on FMD after PCSK9i treatment. Only 5 studies (415 participants) were eligible for the meta-analysis. Compared to placebo, PCSK9i increased FMD but not statistically significant (MD:0.84, 95%CI:-0.07,1.74). Alirocumab was associated with no difference in two studies (MD:-0.20, 95%CI:-0.73,0.34), whereas evolocumab with a statistically significant increase in FMD in four studies (MD:1.31, 95%CI:0.22,2.4). CONCLUSION: This is the first effort to summarize evidence on the effect of PCSK9i on endothelial function. PCSK9i may improve FMD, suggesting additional therapeutic roles beyond the traditional ones. Further, high quality, large population studies are needed to confirm these findings. PROTOCOL REGISTRATION: The protocol utilized for this research is available in the Open Science Framework (OSF) database (https://osf.io/hz4d2/).