Rosuvastatin, Proprotein ConvertaseSubtilisin/Kexin Type 9 Concentrations, and LDL Cholesterol Response: theand 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
IntroductionIntroductionPCSK9 functionPCSK9 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 receptorthat PCSK9 promotes degradation of the LDL receptor
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Introduction (cont’d)Introduction (cont’d)PCSK9 regulationPCSK9 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 targetingGiven 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 gPCSK9 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
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g
QuestionsQuestionsIs there a difference in mean PCSK9Is 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?rosuvastatin?
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MethodMethodPCSK9 measurementPCSK9 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 ( ) y p prosuvastatin 20 mg daily or placebo
>Genetic evaluation>Genetic evaluationrs11591147 (R46L), a single nucleotide polymorphism known to have a lowering effect on plasma PCSK9 concentrations, was evaluated
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was evaluated
R ltR ltResults Results
Table 1. a Data are median (25th–75th percentile) or n (%). No statistical difference exists between the 2 groups in either se (n 250 in each gro p)
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either sex (n = 250 in each group).b As defined by the consensus criteria of the American Heart Association.
R lt ( t’d)R lt ( t’d)Results (cont’d)Results (cont’d)
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R lt ( t’d)R lt ( t’d)Results (cont’d)Results (cont’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
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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.
QuestionsQuestionsCan PCSK9 concentrations be used toCan 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
R lt ( t’d)R lt ( t’d)Results (cont’d)Results (cont’d)
Figure 1 suppl.(A), Correlation between baseline LDL-C and PCSK9 values in the placebo and rosuvastatin arm.
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(B), After one year in the rosuvastatin arm (disruption of correlation).
R ltR ltResults Results (cont’d)(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
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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.
R lt ( t’d)R lt ( t’d)Results (cont’d)Results (cont’d)
Figure 2 suppl.(A), Baseline PCSK9 values in the placebo and rosuvastatin arm for men and women separately (n=954).
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(B), LDL-C reduction after one year on the rosuvastatin arm for men and women together (n=478).
This study is the largest to demonstrate that
SummarySummary 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 thanWomen 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
time in apparently healthy individuals
SummarySummary (cont’d)(cont’d)Carriers of the SNP (R46L) respond similarly toCarriers 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 LDLRosuvastatin use was not associated with LDL-C response blunting as the PCSK9 concentration increased
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concentration increased
DiscussionDiscussionStatin effect on PCSK9Statin 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 PCSK9those statin-resistant subjects with increased PCSK9 concentration whom may benefit from PCSK9 modulation.
© Copyright 2009 by the American Association for Clinical Chemistry
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