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

Abstract

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.

Fig. 1.

Effect of atorvastatin on serum TC, LDL-C, HDL-C. and TG levels. A: Baseline, 8-week, and 16-week TC levels from 74 subjects receiving atorvastatin (80 mg per day). Data are expressed as the mean ± SEM. B: Baseline, 8-week, and 16-week LDL-C levels from 74 subjects receiving atorvastatin (80 mg per day). Data are expressed as the mean ± SEM. C: Baseline, 8-week, and 16-week HDL-C levels from 74 subjects receiving atorvastatin (80 mg per day). Data are expressed as the mean ± SEM. D: Baseline, 8-week, and 16-week TG levels from 74 subjects receiving atorvastatin (80 mg per day). Data are expressed as the mean ± SEM. Abbreviations: HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.

Fig. 2.

Effect of atorvastatin on serum PCSK9 levels. A: Baseline, 4-week, 8-week, 12-week, and 16-week PCSK9 levels from 74 subjects receiving atorvastatin (80 mg per day). Data are expressed as the mean ± SEM. B: Effect of atorvastatin on PCSK9 serum isoforms. Samples were analyzed via PCSK9 immunoprecipitation and Western blotting. The predominant band indicated with the arrow represents intact PCSK9 protein. The mobility of the band immediately below is consistent with the furin cleavage product of PCSK9, while the mobility of the lowest band is consistent with PCSK9 propeptide (40). Results are representative of those from four different subjects. Abbreviation: PCSK9, proprotein convertase subtilisin kexin type 9.

Fig. 3.

Effect of atorvastatin on the correlation of PCSK9 levels with TC, LDL-C, HDL-C, and TG levels at baseline and endpoint. A: Pre- and postatorvastatin correlations between PCSK9 and TC. Baseline concentrations (▴); posttreatment concentrations (▿). B: Pre- and postatorvastatin correlations between PCSK9 and LDL-C. Baseline concentrations (▴); posttreatment concentrations (▿). C: Pre- and postatorvastatin correlations between PCSK9 and HDL-C. Baseline concentrations (▴); posttreatment concentrations (▿). D: Pre- and postatorvastatin correlations between PCSK9 and TG. Baseline concentrations (▴); posttreatment concentrations (▿). Abbreviations: HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin kexin type 9; TC, total cholesterol; TG, triglyceride.

Fig. 4.

Relationship of atorvastatin-induced changes in serum PCSK9 levels compared with changes in LDL-C. A: Comparison of atorvastatin-induced endpoint percentage changes in serum PCSK9 levels with endpoint percentage changes in serum LDL-C levels. B: Comparison of baseline serum PCSK9 levels with atorvastatin-induced endpoint changes in serum LDL-C levels. C: Comparison of atorvastatin-induced endpoint changes in serum PCSK9 levels with endpoint serum LDL-C levels. Abbreviations: LDL-C, low density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin kexin type 9.