Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY 10467, USA.
Cardiology Clinic, Cardiology Unlimited, PC, New York, NY 10033, USA.
Int J Mol Sci. 2023 Sep 3;24(17):13622. doi: 10.3390/ijms241713622.
Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.
脂蛋白(a) [Lp(a)] 是心血管疾病的一个公认的危险因素，易导致主要心血管事件，包括冠心病、中风、主动脉瓣钙化和腹主动脉瘤。通过载脂蛋白(a) 将 Lp(a) 与其他脂蛋白分子区分开来，载脂蛋白(a) 具有致动脉粥样硬化和抗血栓形成的特性，归因于其结构。Lp(a) 水平主要由遗传决定，并受 LPA 基因变异体的大小影响，较小的异构体导致 apo(a) 的合成速率增加，最终导致 Lp(a) 水平升高。因此，血清 Lp(a) 水平可能从极低到极高差异很大。美国将脂蛋白(a)水平>30mg/dL 定义为高脂蛋白(a)血症，欧洲将脂蛋白(a)水平>50mg/dL 定义为高脂蛋白(a)血症。由于其与 CVD 的关联，应至少在一生中测量一次成年人的 Lp(a) 水平。最终目标是识别具有 CVD 风险增加的个体并进行相应干预。烟酸、他汀类药物、依折麦布、阿司匹林、PCSK-9 抑制剂、米泊美生、雌激素和 CETP 抑制剂等传统药物干预措施尚未取得令人满意的结果。所有药物的平均 Lp(a) 降低率仅为 50%左右，他汀类药物增加 Lp(a) 水平，而需要降低 80-90%才能显著降低主要心血管事件的发生。专门针对肝细胞的新型 RNA 干扰药物正在朝着这个方向发展。Pelacarsen 是一种反义寡核苷酸，而 olpasiran、LY3819469 和 SLN360 是小干扰 RNA，均与 N-乙酰半乳糖胺分子缀合。它们的最终目标是基因沉默 LPA，减少 apo(a) 的产生并降低血清 Lp(a) 水平。到目前为止，证据表明每月皮下注射一剂可获得最佳效果，持续显著降低 Lp(a) 水平，可能增强 CVD 风险降低。新型 RNA 药物实现的 Lp(a) 降低率可能超过 95%。正在进行和未来的临床试验结果备受期待，希望不久后就能制定出使用这些新型药物针对 Lp(a) 水平进行个体化管理的指南。
