Department of Internal Medicine, Faculty of Health Sciences, Division of Endocrinology and Metabolism, University of the Witwatersrand, Johannesburg, South Africa.
Curr Atheroscler Rep. 2022 Dec;24(12):959-967. doi: 10.1007/s11883-022-01071-1. Epub 2022 Nov 11.
Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) or remnants are important risk factors for the development of atherosclerotic cardiovascular disease (ASCVD). The ongoing challenge of not being able to achieve recommended LDL-C targets despite maximally tolerated lipid-lowering therapy (LLT) has led to the development of novel therapeutic agents including angiopoietin-like 3 (ANGPTL3) inhibitors.
ANGPTL3 is a glycoprotein produced by the liver that inhibits lipoprotein lipase and endothelial lipase. Data from genetic and clinical studies have shown that a lower ANGPTL3 level is associated with lower plasma LDL-C, triglyceride (TG), and other lipoproteins. Pharmacological inactivation of ANGPTL3 with the monoclonal antibody, evinacumab, results in a 50% reduction in LDL-C, even in patients with homozygous familial hypercholesterolemia (HoFH). The safe and effective targeted delivery of nucleic acid-based therapies will shape the future of the lipid arena. ANGPTL3 is a novel target in lipoprotein metabolism, targeting not only LDL-C via an LDL-receptor (LDLR) independent mechanism but also TRLs and carries a significant promise for further ASCVD risk reduction.
升高的低密度脂蛋白胆固醇（LDL-C）和富含甘油三酯的脂蛋白（TRLs）或残粒是动脉粥样硬化性心血管疾病（ASCVD）发展的重要危险因素。尽管进行了最大限度耐受的降脂治疗（LLT），但仍无法达到推荐的 LDL-C 目标，这一持续存在的挑战导致了新型治疗药物的发展，包括血管生成素样 3（ANGPTL3）抑制剂。
ANGPTL3 是一种由肝脏产生的糖蛋白，可抑制脂蛋白脂肪酶和内皮脂肪酶。遗传和临床研究的数据表明，ANGPTL3 水平较低与血浆 LDL-C、甘油三酯（TG）和其他脂蛋白较低相关。单克隆抗体依维莫司（evinacumab）对 ANGPTL3 的药理学失活可使 LDL-C 降低 50%，即使在纯合家族性高胆固醇血症（HoFH）患者中也是如此。基于核酸的治疗方法的安全有效靶向递送将塑造脂质领域的未来。ANGPTL3 是脂蛋白代谢的一个新靶点，不仅通过 LDLR 独立机制靶向 LDL-C，还靶向 TRLs，并为进一步降低 ASCVD 风险带来了巨大希望。
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