Background/Introduction: Blood proprotein convertase subtilisin/kexin type 9 (PCSK9) levels modestly predict future CV events and its inhibition reduces atherogenic lipoproteins and could lead to reduction of cardiovascular (CV) events.
Purpose: We performed a meta-analysis and meta-regression analysis of all longitudinal studies to determine the factors that influence the predictive role of PCSK9.
Methods: A comprehensive search of electronic databases was conducted up to April 2016. Longitudinal studies that reported events or relative risk (RR) estimates with 95% confidence intervals were included. Sensitivity analyses and meta-regression analysis with a random-efffects model were applied.
Results: All 9 studies included (12,081 participants, mean follow-up 6.62 years) reported results on total CV events. The pooled RR of total CV events for an increase in baseline PCSK9 by 1 standard deviation (SD) was 1.098 (95% CI, 1.02–1.18), corresponding to a risk increase of 10% (Z=2.43, P=0.015). (Figure) When pooled estimates were derived independently for low- and high-CV risk populations, baseline PCSK9 levels predicted total CV events only in apparently healthy subjects (RR=1.13, 95% CI: 1.050–1.222, Z=3.21, P=0.001) and not in populations with established CV or renal disease (RR=1.09, 95% CI: 0.961–1.23, Z=1.33, P=0.182). When pooled risk estimates were calculated independently for studies that measured PSCK9 with Assay A (i.e. all other ELISA assays apart from the most commonly used) and Assay B (i.e. the most commonly used ELISA assay in the included studies), baseline PCSK9 levels predicted total CV events only when measured with Assay A [(RR=1.15, 95% CI: 1.064–1.234, Z=3.61, P<0.001 versus (RR= 1.073, 95% CI: 0.948–1.214, Z=1.11, P=0.268) for Assay B]. A relevant test for interaction was marginally non-significant (P for interaction=0.073). C-reactive protein (CRP) at enrolment was the only baseline variable that showed a trend to be a predictor of the magnitude of the RR for total CV events (p=0.07) showing an inverse association with the predictive value of high PCSK9 levels.
Conclusions: PCSK9 levels are modestly but significantly associated with increased risk of total CV events and this predictive role is higher in low-inflammatory states and with specific measurement assays.