Association Between Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Concentrations and Cardiovascular Events in Cardiovascular Disease: A Systemic Review and Meta-Analysis

Abstract

Background: A large amount of evidence suggests that proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors have clinical benefits in patients with cardiovascular disease (CVD). However, whether PCSK9 concentrations predict future cardiovascular (CV) events remains unclear.Methods: We conducted a meta-analysis to investigate the ability of PCSK9 concentrations to predict future CV events in patients with established CVD. A comprehensive search of electronic databases was conducted in June 2021. We included relative risk (RR) estimates with 95% CI or events of interest.Results: Eleven cohort studies including 8,471 patients with CVD were enrolled. The pooled RR of CV events for the increase in the circulating baseline PCSK9 concentrations by 1 SD showed a positive association in a random-effect model (RR 1.226, 95% CI: 1.055–1.423, P = 0.008). Similarly, the risk of the total CV events increased by 52% in the patients in the highest tertile compared with those in the lowest tertile of circulating PCSK9 concentrations (RR 1.523, 95% CI: 1.098–2.112, P = 0.012). The association between PCSK9 and CV events was stronger in stable patients with CVD, patients treated with statins, and Asian patients.Conclusions: High PCSK9 concentrations are significantly related to the increased risk of future CV events. These results enrich the knowledge of PCSK9 function and suggest the further possible clinical role of PCSK9 inhibitors.

PCSK9 inhibitors for acute coronary syndrome: the era of early implementation

“…PCSK9, as a trigger for the expression of pro-inflammatory cytokines, is significantly elevated during ACS ( 23 , 39 ). Several studies found that it was positively associated with the risk of cardiovascular events, which may be related to multiple mechanisms, such as inflammatory cascade activation and additional platelet release and aggregation ( 40 – 42 ). Early PCSK9 inhibitor treatment can potentially inhibit PCSK9-related inflammatory effects in patients with ACS.…”

“…release and aggregation (40)(41)(42). Early PCSK9 inhibitor treatment can potentially inhibit PCSK9-related inflammatory effects in patients with ACS.…”

Impact of conventional lipid-lowering therapy on circulating levels of PCSK9: protocol for a systematic review and meta-analysis of randomised controlled trials

“…13 Accumulating evidence has demonstrated that elevated circulating PCSK9 level has been associated with increased CVD risk. 14 Although multiple randomised controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of PCSK9 inhibitors in treating dyslipidaemia, several studies have reported that conventional lipid-lowering therapies could lead to increased circulating PCSK9 levels. [15][16][17][18][19][20] On the other hand, it has been reported that statin treatment raises PCSK9 in primarily the inactivated form.…”

“…PCSK9 is a serine protease that binds to the LDL receptors on the cellular membrane of hepatocytes, inhibiting LDL receptor recycling and promoting its lysosomal degradation, which results in elevated plasma LDL-C as well as promotes vascular remodelling and atheroma development 13. Accumulating evidence has demonstrated that elevated circulating PCSK9 level has been associated with increased CVD risk 14. Although multiple randomised controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of PCSK9 inhibitors in treating dyslipidaemia, several studies have reported that conventional lipid-lowering therapies could lead to increased circulating PCSK9 levels 15–20.…”