Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Perth, Australia; School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia.
School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia.
Metabolism. 2020 Jun;107:154221. doi: 10.1016/j.metabol.2020.154221. Epub 2020 Mar 30.
Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD.
The effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (>0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment.
Alirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P< 0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P <0.001) and increased the FCR of apo(a) (+28%, P< 0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P< 0.001).
In statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.
脂蛋白(a)[Lp(a)]是一种载脂蛋白(a)[apo(a)]与载脂蛋白 B-100（apoB）共价连接的低密度脂蛋白（LDL）颗粒。接受他汀类药物治疗的 Lp(a)升高的患者发生动脉粥样硬化性心血管疾病（ASCVD）的风险增加。最近的临床试验表明，前蛋白转化酶枯草溶菌素 9（PCSK9）抑制剂可降低 Lp(a)和心血管事件，特别是在 Lp(a)升高的高危患者中。我们研究了 PCSK9 抑制剂阿利西尤单抗降低他汀类药物治疗的高 Lp(a)和 ASCVD 患者的 Lp(a)的动力学机制。
对 21 名 Lp(a)浓度升高（>0.5 g/L）的患者进行了 12 周阿利西尤单抗治疗（每 2 周 150mg）对 apo(a)动力学的影响研究。采用静脉注射 D3-亮氨酸、质谱和房室模型测定 apo(a)的分解代谢率（FCR）和生成率（PR）。所有患者均长期接受他汀类药物治疗。
阿利西尤单抗显著降低了总胆固醇（-39%）、LDL-胆固醇（-67%）、apoB（-56%）、apo(a)（-25%）和 Lp(a)（-22%）的血浆浓度（所有 P<0.001）。阿利西尤单抗还显著降低了 apo(a)的血浆池大小（-26%，P<0.001），并增加了 apo(a)的 FCR（+28%，P<0.001），但并未改变 apo(a)的 PR，与接受他汀类药物治疗且 Lp(a)正常的患者参考组相比，其 PR 仍然显著更高（P<0.001）。
在他汀类药物治疗的患者中，阿利西尤单抗通过加速 Lp(a)颗粒的代谢来降低升高的血浆 Lp(a)浓度。这可能是由于肝受体（主要为 LDL）的明显上调和/或 Lp(a)与 LDL 颗粒对这些受体的竞争减少所致；这种机制可能有助于阿利西尤单抗通过抑制 PCSK9 对心血管结局的益处。
