High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor (LDLR), causing its subsequent degradation. We first demonstrated that a moderate dose of atorvastatin (40 mg) increases PCSK9 serum levels, suggesting why increasing statin doses may have diminished efficacy with regard to further LDL-C lowering. Since that initial observation, at least two other groups have reported statin-induced PCSK9 increases. To date, no analysis of the effect of high-dose atorvastatin (80 mg) on PCSK9 over time has been conducted. Therefore, we studied the time course of atorvastatin (80 mg) in human subjects. We measured PCSK9 and lipid levels during a 2-week lead-in baseline period and every 4 weeks thereafter for 16 weeks. We observed that atorvastatin (80 mg) caused a rapid 47% increase in serum PCSK9 at 4 weeks that was sustained throughout 16 weeks of dosing. Importantly, while PCSK9 levels were highly correlated with total cholesterol (TC), LDL-C, and triglyceride (TG) levels at baseline, atorvastatin (80 mg) completely abolished all of these correlations. Together, these results further suggest an explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering. Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor (LDLR), causing its subsequent degradation. We first demonstrated that a moderate dose of atorvastatin (40 mg) increases PCSK9 serum levels, suggesting why increasing statin doses may have diminished efficacy with regard to further LDL-C lowering. Since that initial observation, at least two other groups have reported statin-induced PCSK9 increases. To date, no analysis of the effect of high-dose atorvastatin (80 mg) on PCSK9 over time has been conducted. Therefore, we studied the time course of atorvastatin (80 mg) in human subjects. We measured PCSK9 and lipid levels during a 2-week lead-in baseline period and every 4 weeks thereafter for 16 weeks. We observed that atorvastatin (80 mg) caused a rapid 47% increase in serum PCSK9 at 4 weeks that was sustained throughout 16 weeks of dosing. Importantly, while PCSK9 levels were highly correlated with total cholesterol (TC), LDL-C, and triglyceride (TG) levels at baseline, atorvastatin (80 mg) completely abolished all of these correlations. Together, these results further suggest an explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering. Proprotein convertase subtilisin kexin type 9 (PCSK9) has been recognized as a key regulator of serum low density lipoprotein cholesterol (LDL-C) levels (1Horton J.D. Cohen J.C. Hobbs H.H. Molecular biology of PCSK9: its role in LDL metabolism.Trends Biochem. 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Konrad R.J. increases human serum levels of proprotein convertase subtilisin/kexin type Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). Since that at least two other have reported that on statins have levels of PCSK9 S.G. Lagace T.A. Cohen J.C. Horton J.D. Hobbs H.H. Genetic and metabolic determinants of plasma PCSK9 levels.J. Clin. Endocrinol. Metab. 2009; 94: 2537-2543Crossref PubMed Scopus (394) Google Scholar, G. M. G. H. Hamelin J. S. L. J. L. N.G. et al.A for of total plasma PCSK9: Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). of statin-induced PCSK9 increases in into the mechanism for the statin in that the time course of statin-induced PCSK9 increases has not been is not for PCSK9 levels during statin to increase over is that PCSK9 levels increase and then decrease as a of hepatic PCSK9 is is not with how statin the of PCSK9 levels with LDL-C levels over time PCSK9 levels to The to these not studies have been by studies have not the effects of in PCSK9 over time role in statin have the doses of statins been a in the we the time course of the effect of high-dose atorvastatin on PCSK9 the that baseline PCSK9 levels may the of the LDL-C in PCSK9 levels correlated with decreases in and the effect of high-dose atorvastatin on the between PCSK9 levels and LDL-C and other serum over has been reported effect on and in with cholesterol a 2006; PubMed Scopus Google Scholar, and in for and 2006; PubMed Scopus Google Scholar). to be at least of and not for on were a of coronary were liver two the of not have a of cholesterol that cholesterol that a interaction with A total of through a in period of two weeks no was by of atorvastatin were every 4 weeks for a total of 16 weeks on high-dose were for and effects and for PCSK9 at lipid levels total LDL-C, and were a at baseline and after and 16 weeks on PCSK9 levels were at weeks to and The two PCSK9 results for at the 2-week and to the of atorvastatin were to a baseline PCSK9 were at the of and the was by both the of and the PCSK9 levels in the serum were measured using PCSK9 antibody W.E. Cao G. Qian Y.W. Subramaniam J. Konrad R.J. proprotein convertase subtilisin kexin type 9 is correlated with serum LDL Chem. 2007; PubMed Scopus Google Scholar, Alborn W.E. Cao G. Konrad R.J. increases human serum levels of proprotein convertase subtilisin/kexin type Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar, Alborn W.E. Cao G. Konrad R.J. increases human serum proprotein convertase subtilisin kexin type 9 levels.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google with the of a PCSK9 The recognized by the in the not at PCSK9 as a in the was a human liver with a to an The not for a were in and the secreted PCSK9 protein was using an by of the protein was by and was to be on by were with anti-PCSK9 antibody at a of The were with and for with of PCSK9 of protein in were to the as a serum were in to and the was for at were with and of a of antibody anti-PCSK9 were to the for a at were with the of of were to the and to for at The was with an of and were at was for of the were on and at to of the on serum was by at the effect of to on with at least observed for all after of PCSK9 levels in serum by and was as W.E. Cao G. Qian Y.W. Subramaniam J. Konrad R.J. proprotein convertase subtilisin kexin type 9 is correlated with serum LDL Chem. 2007; PubMed Scopus Google Scholar, Alborn W.E. Cao G. Konrad R.J. increases human serum levels of proprotein convertase subtilisin/kexin type Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar, Alborn W.E. Cao G. Konrad R.J. increases human serum proprotein convertase subtilisin kexin type 9 levels.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google with of serum were to of PCSK9 was with of anti-PCSK9 antibody to were with and of were to were for and at to was using with on were for at at and to for were for at in were with PCSK9 antibody in for at were with with were with an for at a with were with and to with baseline and of serum were in the analysis of the time of the for and at the time of the for all other time and all were to be the PCSK9 was for of the were and using the analysis was using the and were by by between the using the least in were as the and analysis was to a of of atorvastatin on serum PCSK9 levels. and PCSK9 levels atorvastatin (80 as the of atorvastatin on PCSK9 serum were PCSK9 and The with the PCSK9 The of the is with the cleavage of while the of the is with PCSK9 effect on and in with cholesterol a 2006; PubMed Scopus Google Scholar). of subjects. proprotein convertase subtilisin kexin type of atorvastatin on the of PCSK9 levels with LDL-C, and levels at baseline and and between PCSK9 and and between PCSK9 and and between PCSK9 and and between PCSK9 and density lipoprotein LDL-C, low density lipoprotein proprotein convertase subtilisin kexin type total of in serum PCSK9 levels with in of in serum PCSK9 levels with in serum LDL-C levels. of baseline serum PCSK9 levels with in serum LDL-C levels. of in serum PCSK9 levels with serum LDL-C levels. LDL-C, low density lipoprotein proprotein convertase subtilisin kexin type the effect of for 16 on serum levels. baseline, the was 4 weeks of atorvastatin was a decrease in with baseline This decrease in was sustained at the time atorvastatin a effect on LDL-C levels. baseline, the LDL-C was 4 weeks of atorvastatin was a decrease in LDL-C with baseline and decrease in LDL-C was sustained at the time atorvastatin no effect on levels with baseline, and and with regard to levels, the baseline was and atorvastatin in decrease at and 16 weeks 4 and both that atorvastatin caused a rapid and sustained increase in PCSK9 levels. baseline, PCSK9 levels were 4 of atorvastatin PCSK9 levels 47% to This increase in PCSK9 levels was at the and time with PCSK9 levels of and of a recent of a of PCSK9 protein in plasma as a the PCSK9 G. M. G. H. Hamelin J. S. L. J. L. N.G. et al.A for of total plasma PCSK9: Lipid Res. Full Text Full Text PDF PubMed Scopus Google we further the increase in To we and of in which for least of these in which that atorvastatin in increases in the PCSK9 protein that with the PCSK9 protein as as the PCSK9 We the effect of atorvastatin on the of PCSK9 levels with serum lipid levels. the between PCSK9 and levels at baseline and after 16 weeks of with baseline, PCSK9 levels were correlated with 16 weeks of atorvastatin completely abolished the between PCSK9 and results were observed with regard to the effect of atorvastatin on the of PCSK9 with LDL-C levels and levels. baseline, PCSK9 levels were correlated with LDL-C 16 weeks of atorvastatin the between PCSK9 and LDL-C levels was completely at baseline, PCSK9 levels were correlated with 16 weeks of atorvastatin abolished regard to was no of PCSK9 to levels at baseline 16 weeks of these we the of in PCSK9 levels with in LDL-C levels to the increases in PCSK9 levels the decreases in LDL-C levels. the of in PCSK9 levels baseline to to in LDL-C levels baseline to was a an not achieve we the baseline PCSK9 to the in LDL-C observed baseline to to baseline PCSK9 levels to atorvastatin as was a an not achieve we in PCSK9 levels to the LDL-C after 16 weeks of with was a which that increases in PCSK9 levels to be with LDL-C levels, the was and of results that high-dose atorvastatin (80 a rapid and sustained increase in PCSK9 protein levels. 4 weeks of PCSK9 levels 47% over baseline levels, and increase was sustained at and time to we and have reported S.G. Lagace T.A. Cohen J.C. Horton J.D. Hobbs H.H. Genetic and metabolic determinants of plasma PCSK9 levels.J. Clin. Endocrinol. Metab. 2009; 94: 2537-2543Crossref PubMed Scopus (394) Google Scholar, S.E. Konrad R.J. M. Li J.A. J. A. the PCSK9 and PCSK9 plasma of Chem. 2009; PubMed Scopus Google Scholar, W.E. Cao G. Qian Y.W. Subramaniam J. Konrad R.J. proprotein convertase subtilisin kexin type 9 is correlated with serum LDL Chem. 2007; PubMed Scopus Google Scholar, Alborn W.E. Cao G. Konrad R.J. increases human serum levels of proprotein convertase subtilisin/kexin type Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google baseline PCSK9 levels were highly correlated with and LDL-C levels. We further demonstrated a between baseline PCSK9 and levels. 16 weeks of atorvastatin these were that with atorvastatin completely the between PCSK9 and these lipid have statin-induced increases in PCSK9 levels in a Alborn W.E. Cao G. Konrad R.J. increases human serum levels of proprotein convertase subtilisin/kexin type Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google we observed that a dose of atorvastatin serum PCSK9 levels after weeks. the baseline PCSK9 and LDL-C were and the was by atorvastatin Mayne et reported that of atorvastatin PCSK9 levels while lowering LDL-C levels J. A. M. A. S.A. M. M. Plasma PCSK9 levels by statins and in 2008; PubMed Scopus Google Scholar). et in with statin PCSK9 levels by M. C. C. Krempf M. Costet P. between plasma PCSK9 and levels in of Full Text Full Text PDF Scopus Google Scholar). the it was that the between PCSK9 levels and LDL-C levels was statin as statins PCSK9 levels and decreased LDL-C levels M. C. C. Krempf M. Costet P. between plasma PCSK9 and levels in of Full Text Full Text PDF Scopus Google Scholar). et G. M. G. H. Hamelin J. S. L. J. L. N.G. et al.A for of total plasma PCSK9: Lipid Res. Full Text Full Text PDF PubMed Scopus Google demonstrated that with statins a increase in PCSK9 levels and that with a a increase in et S.G. Lagace T.A. Cohen J.C. Horton J.D. Hobbs H.H. Genetic and metabolic determinants of plasma PCSK9 levels.J. Clin. Endocrinol. Metab. 2009; 94: 2537-2543Crossref PubMed Scopus (394) Google demonstrated that PCSK9 levels correlated with LDL-C levels in a and that statin was with a increase in PCSK9 levels in both and a of these it was not that a dose of atorvastatin (80 mg) cause the baseline of PCSK9 to LDL-C to be in it was to The between PCSK9 and LDL-C at baseline is not by a increasing of a a is in which hepatic LDLR expression is in for of both LDL-C and be that while in liver is decreased by the of PCSK9 is of the statin-induced of between PCSK9 and LDL-C levels PCSK9 not LDLR with dose of a the in of and PCSK9 be further and it to the of the of the between PCSK9 and LDL-C, and that we of the we to was baseline levels of PCSK9 the of decreases in We the that with the baseline PCSK9 levels have the LDL-C to atorvastatin serum PCSK9 levels were correlated with LDL-C, and atorvastatin acts to decrease LDL-C through increasing LDLR protein levels, in of increasing PCSK9 levels. with was a between baseline PCSK9 levels and in LDL-C, with baseline PCSK9 levels to be with decreases in This not achieve that we to was in PCSK9 levels with the of LDL-C We that the increases in serum PCSK9 levels have the LDL-C lowering. This not to be the Rather, that the increases in PCSK9 levels to have the decreases in serum LDL-C, to the not increases in PCSK9 were correlated with LDL-C levels. This was and to achieve the of all of the the that the not achieve it to the between in PCSK9 levels and LDL-C levels. The in may be in to the that statins increase the of a that both the LDLR and PCSK9 S. Curtis D.E. Garuti R. Anderson N.N. Y. Ho Y.K. Hammer R.E. Moon Y.A. Horton J.D. plasma cholesterol and to statins in mice Natl. Acad. Sci. USA. 2005; 102: PubMed Scopus Google Scholar, K.E. L. Leren T.P. in the PCSK9 with and to statin Biol. 2006; PubMed Scopus Google Scholar, M. Li H. N.G. Park S.W. Liu J. of PCSK9 expression through and mechanism for the to LDL-cholesterol lowering effect of statins in Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). PCSK9 and the LDLR both by statin the of PCSK9 measured in the serum may not be of statin-induced increases in hepatic PCSK9 the of PCSK9 has hepatic LDLR to which in it the This of the between serum PCSK9 levels and hepatic LDLR levels it that statin-induced increases in serum PCSK9 levels may not the effect to which statins hepatic and of PCSK9 Together, suggest that explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering may be to statin-induced rapid and sustained increases in PCSK9 protein levels. it has been that statins a of in that LDL-C is at a dose of a statin is an with of the This of for statins has to why statins LDL-C levels in a with that other have suggest that statin-induced increases in PCSK9 protein levels may for the LDL-C lowering increasing doses of This is To studies the effect of doses of a statin on PCSK9 a PCSK9 to statin results in LDL-C lowering with statin The for density lipoprotein cholesterol low density lipoprotein cholesterol low density lipoprotein receptor proprotein convertase subtilisin kexin type 9 total cholesterol triglyceride