Circulating Levels of Proprotein Convertase Subtilisin Kexin Type 9 are Elevated by Fibrate Therapy A Systematic Review and Meta-Analysis of Clinical Trials

Proprotein convertase subtilisin kexin type 9 (PCSK9) affects lipid metabolism through modulation of low-density lipoprotein (LDL) receptor degradation. Circulating PCSK9 status is an important determinant of LDL-cholesterol levels and is thus implicated in atherogenesis. The present study aimed to resolve inconsistencies in clinical findings on the impact of fibrate therapy on circulating PCSK9 concentrations using a meta-analysis of all published studies. A comprehensive literature search in Medline and Scopus was carried out to identify clinical reports on the impact of treatment with fibrates on circulating concentrations of PCSK9. A meta-analysis of eligible studies was performed using a random-effects model. A weighed mean difference (WMD) with 95% confidence interval (CI) was used to assess the magnitude of fibrates' effect on PCSK9 concentrations. Six studies comprising 218 subjects fulfilled the eligibility criteria and were included for systematic review and quantitative data synthesis. A meta-analysis indicated a significant elevation of circulating PCSK9 concentrations following fibrate therapy (WMD: +60.37; 95% CI: 11.04-109.71; P = 0.02). The PCSK9-elevating effect of fibrates remained significant after comparison with a control group receiving either placebo or a statin (WMD: +23.97; 95% CI: 5.68-42.26; P = 0.01). Meta-regression analysis indicated that the effect size of fibrates in modulating circulating PCSK9 levels is not dependent on the duration of treatment (point estimate for slope = 0.59, SE = 4.56; 95% CI = -8.34 to 9.53; z = 0.130, P = 0.897). Fibrate therapy is associated with a significant increase in circulating PCSK9 concentrations. Such a PCSK9 elevation may partly explain the modest efficacy of fibrates on LDL-C.