Abstract
BackgroundProprotein 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.MethodsA 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/m2) 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.ResultsThe 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.ConclusionsEzetimibe 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 RegistrationClinicalTrials.gov NCT00317993
Highlights
Both, statins, which are cholesterol synthesis inhibitors, and ezetimibe, a cholesterol absorption inhibitor, lower low-density lipoprotein (LDL) cholesterol by 40–60% and 20%, respectively
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein produced mainly in the liver, which binds to the hepatic LDL receptor (LDLR) and targets it for degradation [2]
Gain-of-function mutations of PCSK9 are associated with familial hypercholesterolemia and premature cardiovascular disease [3], while PCSK9 deficiency leads to low LDL cholesterol concentrations and protection against cardiovascular disease [4]
Summary
Statins, which are cholesterol synthesis inhibitors, and ezetimibe, a cholesterol absorption inhibitor, lower low-density lipoprotein (LDL) cholesterol by 40–60% and 20%, respectively. These drugs are often administered together in order to achieve a further decrease in LDL cholesterol levels, when clinically necessary [1]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein produced mainly in the liver, which binds to the hepatic LDL receptor (LDLR) and targets it for degradation [2]. 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. The purpose of this study was to investigate how ezetimibe and simvastatin, alone and in combination, affect PCSK9 circulating concentrations
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