Department of Internal Medicine, University Hospital of Heraklion, Heraklion, Crete, Greece.
Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece.
Curr Vasc Pharmacol. 2019;17(4):332-340. doi: 10.2174/1570161116666180209112351.
Over the last 3 decades, hypolipidaemic treatment has significantly reduced both Cardiovascular (CV) risk and events, with statins being the cornerstone of this achievement. Nevertheless, residual CV risk and unmet goals in hypolipidaemic treatment make novel options necessary. Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested. Other effective and well tolerated drugs affect known paths of lipid synthesis and metabolism, such as bempedoic acid blocking acetyl-coenzyme A synthesis at a different level than statins, pemafibrate selectively acting on peroxisome proliferator-activated receptor (PPAR)- alpha receptors and oligonucleotides against apolipoprotein (a). Additionally, other novel hypolipidaemic drugs are in early phase clinical trials, such as the inhibitors of apolipoprotein C-III, which is located on triglyceride (TG)-rich lipoproteins, or the inhibitors of angiopoietin-like 3 (ANGPTL3), which plays a key role in lipid metabolism, aiming to beneficial effects on TG levels and glucose metabolism. Among others, gene therapy substituting the loss of essential enzymes is already used for Lipoprotein Lipase (LPL) deficiency in autosomal chylomicronaemia and is expected to eliminate the lack of Low- Density Lipoprotein (LDL) receptors in patients with homozygous familial hypercholesterolaemia. Experimental data of High-Density Lipoprotein (HDL) mimetics infusion therapy have shown a beneficial effect on atherosclerotic plaques. Thus, many novel hypolipidaemic drugs targeting different aspects of lipid metabolism are being investigated, although they need to be assessed in large trials to prove their CV benefit and safety.
在过去的 30 年中，降脂治疗显著降低了心血管（CV）风险和事件，他汀类药物是这一成就的基石。然而，降脂治疗中仍然存在残余的 CV 风险和未满足的目标，这使得有必要探索新的治疗方法。最近上市的针对前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）的单克隆抗体为创新指明了方向，而其他抑制 PCSK9 的方法，如小干扰 RNA（Inclisiran），已经在进行测试。其他有效且耐受良好的药物作用于已知的脂质合成和代谢途径，如阻断他汀类药物不同作用靶点乙酰辅酶 A 合成的贝马布汀，选择性作用于过氧化物酶体增殖物激活受体（PPAR）-α受体的 pemafibrate，以及针对载脂蛋白（a）的寡核苷酸。此外，其他新型降脂药物正在进行早期临床试验，如位于富含甘油三酯（TG）脂蛋白上的载脂蛋白 C-III 抑制剂，或在脂质代谢中起关键作用的血管生成素样蛋白 3（ANGPTL3）抑制剂，旨在对 TG 水平和葡萄糖代谢产生有益影响。除此之外，用替代必需酶的基因治疗来治疗常染色体性乳糜微粒血症中的脂蛋白脂肪酶（LPL）缺乏症已经在使用，并有望消除纯合家族性高胆固醇血症患者 LDL 受体缺乏的问题。高密度脂蛋白（HDL）模拟物输注治疗的实验数据表明，它对动脉粥样硬化斑块有有益的影响。因此，许多针对脂质代谢不同方面的新型降脂药物正在被研究，尽管它们需要在大规模临床试验中进行评估，以证明它们对心血管的益处和安全性。
