1. Rosuvastatin, Proprotein Convertase
Subtilisin/Kexin Type 9 Concentrations,
and LDL Cholesterol Response: the
JUPITER Trial
Z. Awan, N.G. Seidah, J.G. MacFadyen, S. Benjannet,
D.I. Chasman, P.M. Ridker, and J. Genest
January 2012
www.clinchem.org/content/58/1/183.full
© Copyright 2012 by the American Association for Clinical Chemistry

2. Introduction
PCSK9 function
PCSK9 is a protein secreted predominantly by the liver
that has a substantial effect on LDL-C concentration
PCSK9 has both an active form and an inactive (furin
cleaved) form circulating in the blood
Gain-of-function and loss-of-function mutations in PCSK9
gene cause a high and low LDL-C phenotype, respectively
The mechanism is not fully understood, but it is thought
that PCSK9 promotes degradation of the LDL receptor
© Copyright 2009 by the American Association for Clinical Chemistry

3. Introduction (cont’d)
PCSK9 regulation
Both the LDL receptor and PCSK9 are up regulated by
statins through sterol regulatory element binding protein-2
(SREBP-2) ti l ti
(SREBP 2) stimulation
PCSK9 targeting
Given these interrelationships, there has been considerable
interest in understanding the effect of statins on PCSK9
concentrations, particularly since agents designed to inhibit
p y g g
PCSK9 are likely to be used as adjuncts to statin therapy
Phase II and III clinical trials are currently being conducted
using PCSK9 antisense and inhibitors to lower LDL-C
g
© Copyright 2009 by the American Association for Clinical Chemistry

4. Questions
Is there a difference in mean PCSK9
concentration between men and women?
Is the PCSK9 concentration stable over time?
What is the relation between LDL-C reduction
and PCSK9 concentration after a dose of 20mg
rosuvastatin?
© Copyright 2009 by the American Association for Clinical Chemistry

5. Method
PCSK9 measurement
Total plasma PCSK9 concentration was measured by
ELISA at baseline and after one year in 500 men and 500
women participating in the Justification for Use of Statins in
Prevention: an Intervention Trial Evaluating Rosuvastatin
(
(JUPITER) trial that randomly allocated p
) y participant to
p
rosuvastatin 20 mg daily or placebo
>Genetic evaluation
rs11591147 (R46L), a single nucleotide polymorphism known
to have a lowering effect on plasma PCSK9 concentrations,
was evaluated
© Copyright 2009 by the American Association for Clinical Chemistry

6. Results
R lt
Table 1.
a Data are median (25th–75th percentile) or n (%). No statistical difference exists between the 2 groups in
either sex (n = 250 in each gro p)
se group).
b As defined by the consensus criteria of the American Heart Association.
© Copyright 2009 by the American Association for Clinical Chemistry

7. Results (
R lt (cont’d)
t’d)
© Copyright 2009 by the American Association for Clinical Chemistry

8. Results (
R lt (cont’d)
t’d)
Figure 1. Stability of PCSK9 concentrations over 1 year in the JUPITER placebo arm vs the
rosuvastatin arm. PCSK9 concentrations in men and women at baseline and over 1 year.
Vertical bars minimum and maximum values; box interquartile range (IQR); horizontal bar median; NS
bars, box, bar, NS,
nonsignificant; t=0, baseline values; t=12, 1-year values. *P 0.0001.
© Copyright 2009 by the American Association for Clinical Chemistry

9. Questions
Can PCSK9 concentrations be used to
determine LDL-C response to statins?
Will carriers of the SNP (R46L) respond better to
rosuvastatin 20mg than non carriers?
© Copyright 2009 by the American Association for Clinical Chemistry

10. Results (
R lt (cont’d)
t’d)
Figure 1 suppl.
(A), Correlation between baseline LDL-C and PCSK9 values in the placebo and rosuvastatin arm.
(B), After one year in the rosuvastatin arm (disruption of correlation).
© Copyright 2009 by the American Association for Clinical Chemistry

11. Results
R lt
(cont’d)
Figure 2. Rosuvastatin increased plasma concentrations of PCSK9 in proportion to the magnitude of
LDL-C reduction. (A), Individual percentage LDL-C change in response to rosuvastatin ranked by magnitude
of effect. (B), Corresponding change in PCSK9 concentrations for each study subject ranked by the
magnitude of LDL-C change. (C), Changes in PCSK9 ranked by quintiles of LDL-C change on rosuvastatin.
(D), LDL-C percentage change on rosuvastatin correlates significantly with PCSK9 percentage change.
© Copyright 2009 by the American Association for Clinical Chemistry

12. Results (
R lt (cont’d)
t’d)
Figure 2 suppl.
(A), Baseline PCSK9 values in the placebo and rosuvastatin arm for men and women separately (n=954).
(B), LDL-C reduction after one year on the rosuvastatin arm for men and women together (n=478).
© Copyright 2009 by the American Association for Clinical Chemistry

13. Summary
This study is the largest to demonstrate that
rosuvastatin at a 20 mg dosage increases plasma
concentrations of PCSK9 by 28% and 34% in men
and women, respectively
Women have a higher baseline concentration than
men and this difference is exaggerated further when
20 mg rosuvastatin is given
Circulating PCSK9 as a biomarker is stable over
time in apparently healthy individuals
© Copyright 2009 by the American Association for Clinical Chemistry

14. Summary (cont’d)
Carriers of the SNP (R46L) respond similarly to
rosuvastatin LDL-C reduction as non carriers
Total PCSK9 concentrations cannot be used to
determine individual LDL-C response to
rosuvastatin
Rosuvastatin use was not associated with LDL-
LDL
C response blunting as the PCSK9
concentration increased
© Copyright 2009 by the American Association for Clinical Chemistry

15. Discussion
Statin effect on PCSK9
There is a need to understand the paradoxical
relationship between statin-mediated PCSK9 increase and
LDL-C. A ratio between PCSK9 active and inactive forms
may be the key for understanding this relationship.
A strategy based on the measurement of LDL-C
response and PCSK9 concentrations may help identify
those statin-resistant subjects with increased PCSK9
statin resistant
concentration whom may benefit from PCSK9 modulation.
© Copyright 2009 by the American Association for Clinical Chemistry

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© Copyright 2009 by the American Association for Clinical Chemistry