Department of Cardiovascular Medicine, Research Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
Trends Cardiovasc Med. 2024 May;34(4):215-222. doi: 10.1016/j.tcm.2023.01.008. Epub 2023 Feb 5.
Optimal management of low-density lipoprotein cholesterol (LDL-C) is a central tenet in the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). However, significant residual cardiovascular risk remains despite achieving guideline-directed LDL-C levels, in part due to mixed hyperlipidemia with elevated fasting and non-fasting triglyceride-rich lipoprotein levels. Advances in human genetics have identified angiopoietin-like 3 (ANGPTL3) as a promising therapeutic target to lower cardiovascular risk. Evidence accrued from genetic epidemiological studies demonstrate that ANGPTL3 loss of function is strongly associated with lowering of circulating LDL-C, triglyceride-rich lipoproteins and concurrent risk reduction in development of coronary artery disease. Pharmacological inhibition of ANGPTL3 with monoclonal antibodies, antisense oligonucleotides and gene editing are in development with early studies showing their safety and efficacy in lowering in both, LDL-C and TGs, circumventing a key limitation of previous therapies. Monoclonal antibodies targeting ANGPTL3 are approved for clinical use in homozygous familial hypercholesteremia in USA and Europe. Although promising, future studies focusing on long-term beneficial effect in reducing cardiovascular events with inhibition of ANGPTL3 are warranted.
优化低密度脂蛋白胆固醇（LDL-C）的管理是动脉粥样硬化性心血管疾病（ASCVD）一级和二级预防的核心原则。然而，尽管达到了指南指导的 LDL-C 水平，但仍存在显著的心血管残余风险，部分原因是混合性高脂血症伴有空腹和非空腹富含甘油三酯的脂蛋白水平升高。人类遗传学的进展将血管生成素样 3（ANGPTL3）确定为降低心血管风险的有前途的治疗靶点。遗传流行病学研究的证据表明，ANGPTL3 功能丧失与循环 LDL-C、富含甘油三酯的脂蛋白降低以及冠心病发病风险降低密切相关。单克隆抗体、反义寡核苷酸和基因编辑抑制 ANGPTL3 的药物正在开发中，早期研究表明它们在降低 LDL-C 和 TGs 方面的安全性和有效性，规避了先前治疗的一个关键局限性。针对 ANGPTL3 的单克隆抗体在美国和欧洲已获准用于治疗纯合子家族性高胆固醇血症。尽管前景广阔，但仍需要进行未来的研究，重点关注抑制 ANGPTL3 对减少心血管事件的长期有益效果。
