Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events　― Systematic Review and Meta-Analysis of Prospective Studies ―

Abstract

Background: Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and the risk of cardiovascular events. The aim of this meta-analysis was to evaluate this association in prospective studies. Methods and Results:A systematic search of prospective studies published through October 2016 was carried out in order to identify studies that met pre-specified inclusion criteria. After independent data extraction, summary relative risks were calculated using random-effects models. On meta-analysis of 6 cohort and 1 nested case-control study, circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events (overall RR, 1.12; 95% CI: 0.98-1.29; P=0.09), with significant heterogeneity (I 2 =55.1%, Pheterogeneity=0.038). The highest but not middle categories of circulating PCSK9 was significantly associated with the risk of cardiovascular events. On subgroup analysis of study design, mean age at baseline, sample size, follow-up time, and pre-existing disease, there was no significant association between PCSK9 and cardiovascular events. Sensitivity analysis with various exclusion and inclusion criteria did not materially change the results. Conclusions:Circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of cardiovascular events. More well-designed studies are needed to clarify the role of PCSK9 in cardiovascular risk.

Methotrexate Decreases the Level of PCSK9—A Novel Indicator of the Risk of Proatherogenic Lipid Profile in Psoriasis. The Preliminary Data

“…For instance, a meta-analysis performed in 2016 reported that PCSK9 levels were remarkably associated with an increased risk of cardiovascular events [38]. Although, another meta-analysis published one year later, found no associations between the same parameters [39]. Fang et al demonstrated significantly elevated PCSK9 levels in systemic lupus erythematosus, especially with coexisting lupus nephritis (LN) and presumed its role in atherogenic inflammation in SLE.…”

Circadian regulation of proprotein convertase subtilisin kexin type 9(pcsk9) for possible chronotherapy with pcsk9 inhibiters

“…It is clear that PCSK9 level in the plasma is an independent risk factor beyond the traditional cardiovascular risk factors and indicates a potential role of PCSK9 in the risk assessment. 4,5 However, earlier studies by Ridker et al and others were not consistent with these findings, which may be due to circadian variations in the synthesis of PCSK9 in the liver, which may be under influence of circadian clock. [17][18][19] High levels of PCSK9 can predispose atherosclerosis as shown in Figure 1.…”

“…12,13,16 In two recent meta-analysis, including 11 cohort studies comprising of 13,761 subjects, the relative risk for CVD was 1.25 (95% CI: 1.14-1.38, P < .001, I = 25%) while compared highest to lowest level of PCSK9. 4,5 It is clear that high circulating levels of PCSK9 may be associated with significantly increased risk of CVDs. These findings confirm for the first time that there is a nonlinear dose-response association between circulating PCSK9 level and risk of CVDs.…”

“…[2][3][4] However, in a meta-analysis, circulating PCSK9 level as a continuous variable was not significantly associated with the risk of cardiovascular events indicating that larger, properly designed studies would be required to clarify the role of PCSK9 in cardiovascular risk. 5 Clinical trials with PCSK9 inhibitors, including a meta-analysis published in 2017, have been conducted in which efficacy and safety of these agents, in reducing LDL-C up to 60% has been established. [6][7][8][9] In preliminary trials, evolocumab and alirocumab, the leading PCSK9 inhibitors, have been demonstrated for their efficacy and safety in reducing cardiovascular events but alirocumab was associated with greater adverse effects than evolocumab.…”

“…[6][7][8][9] In preliminary trials, evolocumab and alirocumab, the leading PCSK9 inhibitors, have been demonstrated for their efficacy and safety in reducing cardiovascular events but alirocumab was associated with greater adverse effects than evolocumab. 4,5,9 Poor nutrition during fetal life may cause under nutrition in new born with low birth weight which may be associated with increased susceptibility of these subjects to develop CVDs in later adult life. 10 The increased susceptibility could be due to abnormal PCSK9 and lipoprotein metabolism which enhances the damage to concerned tissues that may increase CVD risk in later adult life.…”