Physicians' Academy for Cardiovascular Education

PCSK9 serum concentrations associated with CV risk

Literature - Leander K, et al. Circulation 2016

Circulating PCSK9 Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors

Leander K, Mälarstig A, van’t Hooft FM, et al.
Circulation 2016; published online ahead of print


The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) can bind the hepatocyte LDL receptor (LDLR) and direct the LDLR-LDL cholesterol complex to the lysosome for degradation [1]. As a result, LDLR cannot recirculate on the surface of the hepatocyte [2-3]. Clinical data have shown that the inhibition of PCSK9 leads to significant decreases of plasma LDL-C in patients with familial hypercholesterolemia and statin intolerance [4,5]. Consequently, PCSK9 inhibition has been associated with lower CV mortality and morbidity, and PCSK9 lowering antibodies have been approved for use in patients who fail to achieve LDL cholesterol lowering through diet and maximally-tolerated statin therapy [5,6].
Based on the above facts, it was hypothesised that circulating PCSK9 might predict future CV events. To test this hypothesis, the serum PCSK9 concentrations were matched with incident CVD in a prospective cohort study including 4,232 individuals, aged 60 years.

Main results

Association between serum PCSK9 levels and incident CVD:
• Crude HR: 1.22; 95% CI: 1.11–1.34; P for trend < 0.0001
• Adjusted HR: 1.15; 95% CI: 1.05–1.26; P for trend 0.0032
• Adjusted HRs for increasing PCSK9 quartiles (lowest to highest, p for trend 0.0063)
  • HR Q2: 1.15; 95% CI: 0.88–1.50
  • HR Q3: 1.24; 95% CI: 0.94–1.63
  • HR Q4: 1.48; 95% CI: 1.12–1.95
(Adjusted for sex, LDL cholesterol, HDL cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes, obesity, overweight, physical inactivity, current smoking, statin use)
• HRs in quartile 4 as compared to quartile 1:
  • HR adjusted for sex: 1.69; 95% CI: 1.30–2.19
  • HR adjusted further for LDL cholesterol,HDL-cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes, smoking, overweight, obesity, physical inactivity and statin use: 1.48; 95% CI: 1.12–1.95


In a prospective cohort of 60-year old individuals, serum PCSK9 concentration was associated with risk of incident CVD. The association persisted after multiple adjustments for established CV risk factors.
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