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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
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
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
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
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
(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
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).
(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
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
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.