Cupido Arjen J, Reeskamp Laurens F, Kastelein John J P
Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Curr Opin Lipidol. 2017 Aug;28(4):367-373. doi: 10.1097/MOL.0000000000000428.
Statins have long been the cornerstone for the prevention of cardiovascular disease (CVD). However, because of perceived adverse effects and insufficient efficacy in certain groups of patients, considerable interest exists in the search for alternatives to lower LDL-cholesterol (LDL-C), and the recent approvals of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors underlines the success of this quest. Here, we give an updated overview on the most recent developments in the area of LDL-C lowering agents.
The clinical effects of the PCSK9 inhibitors are promising, especially now that the FOURIER and SPIRE programmes are published. Most cholesterylester-transfer protein inhibitors, however, except anacetrapib, have been discontinued because of either toxicity or lack of efficacy in large cardiovascular outcome trials. Other agents - like mipomersen, lomitapide, ETC-1002, and gemcabene - aim to lower LDL-C in different ways than solely through the LDL receptor, opening up possibilities for treating patients not responding to conventional therapies. New discoveries are also being made at the DNA and RNA level, with mipomersen being the first approved therapy based on RNA intervention in the United States for homozygous familial hypercholesterolemia.
Recent years have witnessed a new beginning for cholesterol-lowering compounds. With increased knowledge of lipid metabolism a score of new therapeutic targets has been identified. Mechanisms for modulation of those targets are also becoming more diverse while statins remain the backbone of CVD prevention, the new alternatives, such as PCSK9 monoclonals will probably play an important additional role in treatment of patients at risk for CVD.
长期以来，他汀类药物一直是预防心血管疾病（CVD）的基石。然而，由于某些患者群体存在不良反应和疗效不足的问题，人们对寻找降低低密度脂蛋白胆固醇（LDL-C）的替代药物兴趣浓厚，最近前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）抑制剂的获批凸显了这一探索的成功。在此，我们对LDL-C降低药物领域的最新进展进行更新综述。
PCSK9抑制剂的临床效果令人期待，尤其是在FOURIER和SPIRE项目公布之后。然而，除阿那曲匹外，大多数胆固醇酯转运蛋白抑制剂因毒性或在大型心血管结局试验中缺乏疗效而被停用。其他药物，如米泊美生、洛美他派、ETC-1002和吉卡贝尼，旨在通过不同于单纯通过LDL受体的方式降低LDL-C，为治疗对传统疗法无反应的患者开辟了可能性。在DNA和RNA水平也有新发现，米泊美生是美国首个基于RNA干预获批用于纯合子家族性高胆固醇血症的疗法。
近年来，降胆固醇化合物迎来了新起点。随着对脂质代谢认识的增加，已确定了一系列新的治疗靶点。调节这些靶点的机制也日益多样化。虽然他汀类药物仍是CVD预防的支柱，但新的替代药物，如PCSK9单克隆抗体，可能在治疗有CVD风险的患者中发挥重要的辅助作用。
