Abstract
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a pivotal protein in low-density lipoprotein cholesterol metabolism, has been validated to be an established target for cardiovascular (CV) risk reduction. Nevertheless, prospective studies concerning the associations between circulating PCSK9 and the risk of CV events and mortality have yielded, so far, inconsistent results. Herein, we conducted a meta-analysis to evaluate the association systemically.Methods: Pertinent studies were identified from PubMed, EMBASE, and Cochrane Library database through July 2020. Longitudinal studies investigating the value of circulating PCSK9 for predicting major adverse cardiovascular events (MACEs) or stroke or all-cause mortally with risk estimates and 95% confidence intervals (CI) were included in the analyses. Dose-response meta-analysis was also applied to evaluate circulating PCSK9 and risk of MACEs in this study.Results: A total of 22 eligible cohorts comprising 28,319 participants from 20 eligible articles were finally included in the study. The pooled relative risk (RR) of MACEs for one standard deviation increase in baseline PCSK9 was 1.120 (95% CI, 1.056–1.189). When categorizing subjects into tertiles, the pooled RR for the highest tertile of baseline PCSK9 was 1.252 (95% CI, 1.104–1.420) compared with the lowest category. This positive association between PCSK9 level and risk of MACEs persisted in sensitivity and most of the subgroup analyses. Twelve studies were included in dose-response meta-analysis, and a linear association between PCSK9 concentration and risk of MACEs was observed (x2 test for non-linearity = 0.31, P non-linearity = 0.575). No significant correlation was found either on stroke or all-cause mortality.Conclusion: This meta-analysis added further evidence that high circulating PCSK9 concentration significantly associated with increased risk of MACEs, and a linear dose-response association was observed. However, available data did not suggest significant association either on stroke or all-cause mortality. Additional well-designed studies are warranted to further investigate the correlations between PCSK9 concentration and stroke and mortality.
Highlights
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a circulating serine protease, has a fundamental role in low-density lipoprotein cholesterol (LDL-C) metabolism by enhancing the endosomal and lysosomal degradation of hepatic LDL-Receptor, thereby resulting in increased LDL-C concentration.Over the past years, PCSK9 has been validated to be an established target for cholesterol-lowering therapies
Studies were deemed eligible if they: [1] included participants of any age across different countries; [2] had PCSK9 levels in plasma or serum at baseline as exposure of interest; [3] had clinical outcomes including major adverse cardiovascular events (MACEs) and/or stroke and/or allcause mortality; [4] were prospective cohort studies or nested case-control studies performed within prospective cohort with a minimum follow-up of 1 year; [5]were full-text publications; [6] had a multivariable-adjusted relative risk (RR) or hazard ratio (HR) or odds ratio (OR) and the corresponding 95% confidence interval (CI) or provision of available information to calculate them
A total of 12 studies reported risk estimates according to tertiles, two studies according to quartiles, and 16 studies according to continuous levels of PCSK9
Summary
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a circulating serine protease, has a fundamental role in low-density lipoprotein cholesterol (LDL-C) metabolism by enhancing the endosomal and lysosomal degradation of hepatic LDL-Receptor, thereby resulting in increased LDL-C concentration.Over the past years, PCSK9 has been validated to be an established target for cholesterol-lowering therapies. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a circulating serine protease, has a fundamental role in low-density lipoprotein cholesterol (LDL-C) metabolism by enhancing the endosomal and lysosomal degradation of hepatic LDL-Receptor, thereby resulting in increased LDL-C concentration. In recent years, mounting studies have explored the association between circulating PCSK9 and the risk of CV events; the results remained divergent. We conducted the current meta-analysis to add substantive new data and insights into the predictive ability of circulating PCSK9 level in terms of major adverse cardiovascular events (MACEs), stroke, and all-cause mortality from the eligible prospective studies. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a pivotal protein in low-density lipoprotein cholesterol metabolism, has been validated to be an established target for cardiovascular (CV) risk reduction. Prospective studies concerning the associations between circulating PCSK9 and the risk of CV events and mortality have yielded, so far, inconsistent results. We conducted a meta-analysis to evaluate the association systemically
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