Ahn Chang Ho, Choi Sung Hee
Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
Diabetes Metab J. 2015 Apr;39(2):87-94. doi: 10.4093/dmj.2015.39.2.87.
Statins have been shown to be very effective and safe in numerous randomized clinical trials, and became the implacable first-line treatment against atherogenic dyslipidemia. However, even with optimal statin treatment, 60% to 80% of residual cardiovascular risk still exists. The patients with familial hypercholesterolemia which results in extremely high level of low density lipoprotein cholesterol (LDL-C) level and the patients who are intolerant or unresponsive to statins are the other hurdles of statin treatment. Recently, new classes of lipid-lowering drugs have been developed and some of them are available for the clinical practice. The pro-protein convertase subtilisin/kexintype 9 (PCSK9) inhibitor increases the expression of low density lipoprotein (LDL) receptor in hepatocytes by enhancing LDL receptor recycling. The microsomal triglyceride transport protein (MTP) inhibitor and antisense oligonucleotide against apolipoprotein B (ApoB) reduce the ApoB containing lipoprotein by blocking the hepatic very low density lipoprotein synthesis pathway. The apolipoprotein A1 (ApoA1) mimetics pursuing the beneficial effect of high density lipoprotein cholesterol and can reverse the course of atherosclerosis. ApoA1 mimetics had many controversial clinical data and need more validation in humans. The PCSK9 inhibitor recently showed promising results of significant LDL-C lowering in familial hypercholesterolemia (FH) patients from the long-term phase III trials. The MTP inhibitor and antisesnse oligonucleotide against ApoB were approved for the treatment of homozygous FH but still needs more consolidated evidences about hepatic safety such as hepatosteatosis. We would discuss the benefits and concerns of these new lipid-lowering drugs anticipating additional benefits beyond statin treatment.
他汀类药物在众多随机临床试验中已被证明非常有效且安全，并成为治疗致动脉粥样硬化性血脂异常的一线治疗药物。然而，即使采用最佳的他汀类药物治疗，仍有60%至80%的心血管残留风险存在。家族性高胆固醇血症患者会导致极低密度脂蛋白胆固醇（LDL-C）水平极高，以及对他汀类药物不耐受或无反应的患者是他汀类药物治疗的其他障碍。最近，已开发出新型降脂药物，其中一些已可用于临床实践。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）抑制剂通过增强LDL受体再循环来增加肝细胞中低密度脂蛋白（LDL）受体的表达。微粒体甘油三酯转运蛋白（MTP）抑制剂和抗载脂蛋白B（ApoB）反义寡核苷酸通过阻断肝脏极低密度脂蛋白合成途径来减少含ApoB的脂蛋白。载脂蛋白A1（ApoA1）模拟物具有高密度脂蛋白胆固醇的有益作用，并可逆转动脉粥样硬化进程。ApoA1模拟物有许多有争议的临床数据，需要在人体中进行更多验证。PCSK9抑制剂最近在长期III期试验中显示出在家族性高胆固醇血症（FH）患者中显著降低LDL-C的有前景结果。MTP抑制剂和抗ApoB反义寡核苷酸已被批准用于治疗纯合子FH，但仍需要更多关于肝脏安全性（如肝脂肪变性）的确凿证据。我们将讨论这些新型降脂药物的益处和关注点，期望获得超越他汀类药物治疗的额外益处。
