Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels

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, PR = –0.30, Pβ = –1.68, t = –4.04, Pβ = 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背景：前蛋白转化酶枯草溶菌素/kexin9型（Proprotein convertase subtilisin/kexin type 9, PCSK9）是一种分泌型低密度脂蛋白（low-density lipoprotein, LDL）受体抑制剂，亦是低密度脂蛋白代谢的重要调控因子。循环PCSK9水平升高与心血管风险密切相关。本研究旨在探讨依泽替米贝、辛伐他汀单用及联合使用对循环PCSK9浓度的影响。 方法：本研究为单中心、随机、开放标签平行三组研究，纳入健康男性受试者（平均年龄32±9岁，体质量指数25.7±3.2 kg/m²），每组24名受试者，分别接受辛伐他汀40 mg/d、依泽替米贝10 mg/d或两药联合治疗，疗程为14天。采用多变量分析探究影响治疗期间PCSK9浓度变化的相关参数。 结果：总队列的基线血浆PCSK9浓度为52±20 ng/mL，各组间无统计学显著差异。辛伐他汀治疗使PCSK9水平升高68±85%（P=0.0014），依泽替米贝治疗使PCSK9水平升高10±38%（P=0.51），辛伐他汀联合依泽替米贝治疗使PCSK9水平升高67±91%（P=0.0013）。PCSK9水平的升高与基线PCSK9浓度呈负相关（斯皮尔曼相关系数R=–0.47，PR=–0.30，回归系数β=–1.68，t值=–4.04，回归系数β=1.94，t值=2.52，P=0.014）；多变量分析显示，辛伐他汀治疗（P=0.016）可显著影响PCSK9水平的变化，而依泽替米贝治疗无此作用（P=0.42）。对PCSK9浓度变化无显著影响的参数包括年龄、体质量指数、身体成分、甲状腺功能、肾功能、糖代谢参数、脂肪因子、胆固醇合成与吸收标志物以及胆固醇代谢分子标志物。 结论：依泽替米贝不会升高循环PCSK9浓度，而辛伐他汀则可升高该水平。当依泽替米贝联合辛伐他汀使用时，不会导致PCSK9浓度出现额外升高。PCSK9浓度的变化受到严格调控，主要受基线PCSK9水平及低密度脂蛋白胆固醇变化的影响。 试验注册：ClinicalTrials.gov NCT00317993