Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA.
Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia.
Pharmacotherapy. 2023 Oct;43(10):1051-1063. doi: 10.1002/phar.2851. Epub 2023 Jul 26.
Lipoprotein(a), or Lp(a), is structurally like low-density lipoprotein (LDL) but differs in that it contains glycoprotein apolipoprotein(a) [apo(a)]. Due to its prothrombotic and proinflammatory properties, Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are genetically determined, and it is estimated that 20%-25% of the global population has an Lp(a) level ≥50 mg/dL (or ≥125 nmol/L). Diet and lifestyle interventions have little to no effect on Lp(a) levels. Lipoprotein apheresis is the only approved treatment for elevated Lp(a) but is time-intensive for the patient and only modestly effective. Pharmacological approaches to reduce Lp(a) levels and its associated risks are of significant interest; however, currently available lipid-lowering therapies have limited effectiveness in reducing Lp(a) levels. Although statins are first-line agents to reduce LDL cholesterol levels, they modestly increase Lp(a) levels and have not been shown to change Lp(a)-mediated ASCVD risk. Alirocumab, evolocumab, and inclisiran reduce Lp(a) levels by 20-25%, yet the clinical implications of this reduction for Lp(a)-mediated ASCVD risk are uncertain. Niacin also lowers Lp(a) levels; however, its effectiveness in mitigating Lp(a)-mediated ASCVD risk remains unclear, and its side effects have limited its utilization. Recommendations for when to screen and how to manage individuals with elevated Lp(a) vary widely between national and international guidelines and scientific statements. Three investigational compounds targeting Lp(a), including small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen), are in various stages of development. These compounds block the translation of messenger RNA (mRNA) into apo(a), a key structural component of Lp(a), thereby substantially reducing Lp(a) synthesis in the liver. The purpose of this review is to describe current recommendations for screening and managing elevated Lp(a), describe the effects of currently available lipid-lowering therapies on Lp(a) levels, and provide insight into emerging therapies targeting Lp(a).
脂蛋白(a)，或 Lp(a)，在结构上与低密度脂蛋白 (LDL) 相似，但不同之处在于它含有糖蛋白载脂蛋白(a) [apo(a)]。由于其促血栓形成和促炎特性，Lp(a) 是动脉粥样硬化性心血管疾病 (ASCVD) 和主动脉瓣狭窄的独立危险因素。Lp(a) 水平是由遗传决定的，据估计全球有 20%-25%的人 Lp(a) 水平≥50mg/dL（或≥125nmol/L）。饮食和生活方式干预对 Lp(a) 水平几乎没有影响。脂蛋白吸附术是升高的 Lp(a) 的唯一批准治疗方法，但对患者来说时间密集且效果适中。降低 Lp(a) 水平及其相关风险的药物治疗方法具有重要意义；然而，目前可用的降脂疗法在降低 Lp(a) 水平方面效果有限。虽然他汀类药物是降低 LDL 胆固醇水平的一线药物，但它们适度增加 Lp(a) 水平，并且尚未显示可改变 Lp(a) 介导的 ASCVD 风险。Alirocumab、evolocumab 和 inclisiran 可降低 20-25%的 Lp(a) 水平，但这种降低对 Lp(a) 介导的 ASCVD 风险的临床意义尚不确定。烟酸也可降低 Lp(a) 水平；然而，其降低 Lp(a) 介导的 ASCVD 风险的效果尚不清楚，其副作用限制了其应用。关于何时进行筛查以及如何管理 Lp(a) 升高的个体，各国和国际指南和科学声明之间存在很大差异。三种针对 Lp(a) 的研究化合物，包括小干扰 RNA (siRNA) 制剂（olpasiran、SLN360）和一种反义寡核苷酸 (pelacarsen)，处于不同的开发阶段。这些化合物可阻断信使 RNA (mRNA) 翻译成载脂蛋白(a)，这是 Lp(a) 的关键结构成分，从而大大减少肝脏中 Lp(a) 的合成。本综述的目的是描述目前筛查和管理升高的 Lp(a) 的建议，描述目前可用的降脂疗法对 Lp(a) 水平的影响，并提供针对 Lp(a) 的新兴疗法的见解。
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