Evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating PCSK9 levels

Abstract

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted inhibitor of the low-density lipoprotein (LDL) receptor and an important regulator of LDL metabolism. Elevated PCSK9 levels have been associated with cardiovascular risk. The purpose of this study was to investigate how ezetimibe and simvastatin, alone and in combination, affect PCSK9 circulating concentrations.

Methods: A single center, randomized, open-label parallel 3-group study in healthy men (mean age 32±9 years, body mass index 25.7±3.2 kg/m(2)) was performed. Each group of 24 subjects was treated for 14 days with either simvastatin 40 mg/d, ezetimibe 10 mg/d, or with both drugs. Multivariate analysis was used to investigate parameters influencing the change in PCSK9 concentrations under treatment.

Results: The baseline plasma PCSK9 concentrations in the total cohort were 52±20 ng/mL with no statistically significant differences between the groups. They were increased by 68±85% by simvastatin (P = 0.0014), by 10±38% by ezetimibe (P = 0.51) and by 67±91% by simvastatin plus ezetimibe (P = 0.0013). The increase in PCSK9 was inversely correlated with baseline PCSK9 concentrations (Spearman's R = -0.47, P<0.0001) and with the percent change in LDL cholesterol concentrations (Spearman's R = -0.30, P<0.01). In multivariate analyses, only baseline PCSK9 concentrations (β = -1.68, t = -4.04, P<0.0001), percent change in LDL cholesterol from baseline (β = 1.94, t = 2.52, P = 0.014), and treatment with simvastatin (P = 0.016), but not ezetimibe (P = 0.42), significantly influenced changes in PCSK9 levels. Parameters without effect on PCSK9 concentration changes were age, body mass index, body composition, thyroid function, kidney function, glucose metabolism parameters, adipokines, markers of cholesterol synthesis and absorption, and molecular markers of cholesterol metabolism.

Conclusions: Ezetimibe does not increase circulating PCSK9 concentrations while simvastatin does. When added to simvastatin, ezetimibe does not cause an incremental increase in PCSK9 concentrations. Changes in PCSK9 concentrations are tightly regulated and mainly influenced by baseline PCSK9 levels and changes in LDL cholesterol.

Trial registration: ClinicalTrials.gov NCT00317993.

Conflict of interest statement

Competing Interests: The authors would like to extend their declaration of funding from a commercial source by the following statement: This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. In addition, HKB is serving as an academic editor for PLOS ONE. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT flow diagram: Flow of participants through the trial.

Figure 2. Change in LDL cholesterol and PCSK9 from baseline according to treatment groups.

Data are means ± SEM. The decrease in LDL cholesterol was significant in all groups (all P<0.0001), the increase in PCSK9 was significant in the simvastatin and in the combination groups (P<0.005), but not in the ezetimibe group.

Figure 3. Change in PCSK9 from baseline according to baseline PCSK9 and baseline LDL cholesterol.

(A) Correlation between baseline PCSK9 concentrations (log-transformed) and percent change in PCSK9 from baseline in the total cohort (N = 72). (B) Correlation between percent change in LDL cholesterol and percent change in PCSK9 from baseline in the total cohort (N = 72). The R values shown are the ones from linear regression analyses. The corresponding R values from Spearman’s rank correlation analyses are –0.47 (P<0.0001) or –0.30 (P<0.001), respectively.

Figure 4. Change in PCSK9 concentrations (in percent from baseline) according to baseline PCSK9 concentrations and change in LDL cholesterol (in percent from baseline).

Subjects were divided approximately in tertiles: baseline PCSK9

Figure 5. Correlation between baseline PCSK9 concentrations (left panels) and percent change in PCSK9 from baseline (right panels) and percent change in LDL cholesterol from baseline.

(A) ezetimibe, (B) simvastatin, (C) ezetimibe plus simvastatin.