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.
Find this article online


1. Lagace TA, Curtis DE, Garuti R, et al. Secreted pcsk9 decreases the number of ldl receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest. 2006;116:2995-3005
2. Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat a of low density lipoprotein receptor decreases receptor recycling and increases degradation. J BiolChem. 2007;282:18602-18612
3. Qian YW, Schmidt RJ, Zhang Y, et al. Secreted pcsk9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. JLipid Res. 2007;48:1488-1498
4. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med.2015;372:1489-1499
5. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-1509
6. Bergeron N, Phan BA, Ding Y, et al. Proprotein convertase subtilisin/kexin type 9 inhibition: A new therapeutic mechanism for reducing cardiovascular disease risk. Circulation. 2015;132:1648-1666
7. Hori M, Ishihara M, Yuasa Y, et al. Removal of plasma mature and furin-cleaved proprotein convertase subtilisin/kexin 9 (pcsk9) by low-density lipoprotein-apheresis in familial hypercholesterolemia: Development and application of a new assay for pcsk9. J Clin Endocrinol Metab. 2015;100:E41-E49
8. Alborn WE, Cao G, Careskey HE, et al. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum ldl cholesterol. Clin Chem. 2007;53:1814-1819