Aims Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P < 0.001 for main effect). As monotherapy, evolocumab significantly decreased the production of Lp(a)-apo(a) (-36%, P < 0.001). In contrast, in combination with atorvastatin, evolocumab significantly increased the fractional catabolism of Lp(a)-apo(a) (+59%, P < 0.001), but had no effect on the production of Lp(a)-apo(a). There was a highly significant association between the changes in the fractional catabolism of Lp(a)-apo(a) and Lp(a)-apoB in the substudy of 16 subjects (r = 0.966, P < 0.001). Conclusions Evolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance. Clinical Trial Registration Information NCT02189837.

中文翻译：

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evolocumab对前蛋白转化酶枯草杆菌蛋白酶9抑制作用对脂蛋白(a)颗粒动力学影响的对照研究

目的 脂蛋白 (a) [Lp(a)] 是一种与载脂蛋白 (a) [apo(a)] 共价结合的低密度脂蛋白 (LDL) 颗粒，是心血管疾病的潜在有效遗传风险因素。我们研究了 evolocumab（一种针对前蛋白转化酶枯草杆菌蛋白酶 9 型（PCSK9）的单克隆抗体）降低 Lp(a) 的机制。方法和结果 我们研究了 63 名健康男性中 Lp(a) 颗粒的动力学，血浆 apo(a) 浓度 >5 nmol/L，参与了一项为期 8 周的 evolocumab（每 2 周 420 毫克）影响的析因试验）和阿托伐他汀（每天 80 毫克）对脂蛋白代谢的影响。使用静脉内 D3-亮氨酸给药、质谱法和区室模型研究了脂蛋白 (a)-apo(a) 动力学；还在从治疗组中随机选择的 16 名受试者中测定了 Lp(a)-apoB 动力学。Evolocumab，但不是阿托伐他汀，显着降低了 Lp(a)-apo(a) 的血浆池大小（-36%，主效应 P < 0.001）。作为单一疗法，evolocumab 显着降低 Lp(a)-apo(a) 的产生（-36%，P < 0.001）。相比之下，与阿托伐他汀联用，依洛尤单抗显着增加了 Lp(a)-apo(a) 的分解代谢（+59%，P < 0.001），但对 Lp(a)-apo(a) 的产生没有影响）。在 16 名受试者的子研究中，Lp(a)-apo(a) 和 Lp(a)-apoB 的部分分解代谢变化之间存在高度显着的相关性（r = 0.966，P < 0.001）。结论 Evolocumab 单药治疗通过减少 Lp(a) 颗粒的产生来降低血浆 Lp(a) 池大小。与阿托伐他汀合用，evolocumab 通过加速 Lp(a) 颗粒的分解代谢来降低血浆 Lp(a) 池大小。这种双重机制可能与 PCSK9 抑制对 Lp(a)-apo(a) 产生的影响以及 LDL 受体活性对 Lp(a) 全颗粒清除率的显着上调有关。临床试验注册信息 NCT02189837。