脂蛋白(a)[Lp(a)]是心血管疾病的公认危险因素,易患主要心血管事件,包括冠心病,中风,主动脉瓣钙化和腹主动脉瘤。Lp(a)通过载脂蛋白(a)与其他脂蛋白分子区分,具有归因于其结构的动脉粥样硬化和抗血栓溶解特性。Lp(a)水平主要是遗传预先确定的,并受LPA基因变体大小的影响,具有较小的同工型,导致apo(a)的合成速率更高,最终,Lp(a)水平升高。因此,血清Lp(a)水平可能从极低到极高变化很大。高脂蛋白血症(a)定义为Lp(a)水平在美国>30mg/dL,在欧洲>50mg/dL。因为它与CVD有关,Lp(a)水平应至少在成人一生中测量一次。最终目标是确定心血管疾病风险增加的个体并进行相应的干预。传统的药物干预措施,如烟酸,他汀类药物,ezetimibe,阿司匹林,PCSK-9抑制剂,mipomersen,雌激素和CETP抑制剂尚未获得令人满意的结果。平均Lp(a)减少,如果有的话,对所有特工来说只有50%,随着他汀类药物升高Lp(a)水平,而主要心血管事件的显著减少似乎需要减少80-90%.特异性靶向肝细胞的新型RNA干扰剂旨在这个方向。Pelacarsen是一种反义寡核苷酸,而olpasiran,LY3819469和SLN360是小干扰RNA,都与N-乙酰半乳糖胺分子缀合。他们的最终目标是基因沉默LPA,减少载脂蛋白(a)的产生和降低血清Lp(a)水平。迄今为止的证据表明,每月一次皮下给药单剂量可产生最佳结果,并持续大幅降低Lp(a)水平。潜在增强心血管疾病风险降低。用新型RNA试剂实现的Lp(a)降低可超过95%。正在进行和未来的临床试验的结果令人热切期待,希望针对这些新型试剂的Lp(a)水平的量身定制管理指南可能不会太远。
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.