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 Slide 2 Copyright 2009
by the American Association for Clinical Chemistry 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 Slide 3
Copyright 2009 by the American Association for Clinical Chemistry
Introduction (contd) PCSK9 regulation Both the LDL receptor and
PCSK9 are up regulated by statins through sterol regulatory element
binding protein-2 (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 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 Slide 4 Copyright 2009 by the American
Association for Clinical Chemistry 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? Slide 5 Copyright 2009 by the American Association
for Clinical Chemistry 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 participant to
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 Slide
6 Copyright 2009 by the American Association for Clinical Chemistry
Table 1. a Data are median (25th75th percentile) or n (%). No
statistical difference exists between the 2 groups in either sex (n
= 250 in each group). b As defined by the consensus criteria of the
American Heart Association. Results Slide 7 Copyright 2009 by the
American Association for Clinical Chemistry Results (contd) Slide 8
Copyright 2009 by the American Association for Clinical Chemistry
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, nonsignificant; t=0, baseline values;
t=12, 1-year values. *P 0.0001. Results (contd) Slide 9 Copyright
2009 by the American Association for Clinical Chemistry 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? Slide 10 Copyright 2009 by the
American Association for Clinical Chemistry 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). Results (contd) Slide 11 Copyright
2009 by the American Association for Clinical Chemistry 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. Results(contd) Slide 12 Copyright
2009 by the American Association for Clinical Chemistry 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). Results (contd) Slide 13 Copyright 2009 by the American
Association for Clinical Chemistry 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 Summary Slide 14 Copyright 2009 by
the American Association for Clinical Chemistry Summary (contd)
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- C response blunting as the PCSK9
concentration increased Slide 15 Copyright 2009 by the American
Association for Clinical Chemistry 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 concentration whom may
benefit from PCSK9 modulation. Slide 16 Copyright 2009 by the
American Association for Clinical Chemistry Thank you for
participating in this months Clinical Chemistry Journal Club.
Additional Journal Clubs are available at www.clinchem.org Follow
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