Rosuvastatin, Proprotein Convertase Subtilisin/Kexin Type 9 Concentrations, and LDL Cholesterol Response: the JUPITER Trial

BACKGROUND: Although statin therapy is known to increase concentrations of PCSK9, whether this effect is related to the magnitude of LDL reduction is uncertain. This study was undertaken to understand the extent of this effect and examine the relationship between PCSK9 and LDL cholesterol (LDL-C) reduction. METHODS: We measured plasma PCSK9 concentrations by ELISA at baseline and at 1 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 participants to rosuvastatin 20 mg daily or placebo. We also evaluated rs11591147, a single nucleotide polymorphism known to have an impact on plasma PCSK9 concentrations. RESULTS: At baseline, median (interquartile range) PCSK9 concentrations were higher in women 73 (62-90) ng/mL than in men 69 (57-81) ng/mL (P<0.005). During 1 year, there was no change in PCSK9 concentrations in the placebo arm, suggesting stability in time. In contrast, the rosuvastatin increased PCSK9 by 35% in women 101 (82-117) ng/mL and 28% in men 89 (71-109) ng/mL (P<0.0001). Among those allocated to rosuvastatin, greater reductions in LDL-C were associated with greater increases in PCSK9 on both absolute and relative scales (r=-0.15, P<0.0005). Furthermore PCSK9 (rs11591147) did not alter the magnitude of LDL-C reduction associated with rosuvastatin use. CONCLUSIONS: In this randomized trial, rosuvastatin increased plasma concentration of PCSK9 in proportion to the magnitude of LDL-C reduction; the LDL-C response to statin could not be inferred by PCSK9 concentrations.