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Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?
Journal of Cardiovascular Pharmacology and Therapeutics ( IF 2.5 ) Pub Date : 2021-06-17 , DOI: 10.1177/10742484211023632
Ruihai Zhou 1 , George A Stouffer 1 , Sidney C Smith 1
Affiliation  

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as “bad” cholesterol and high-density lipoprotein cholesterol (HDL-C) as “good” cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.



中文翻译:

针对降低动脉粥样硬化性心血管疾病风险的胆固醇范式:药物治疗的作用机制对临床结果是否重要?

高胆固醇血症是动脉粥样硬化性心血管疾病 (ASCVD) 公认的危险因素。低密度脂蛋白胆固醇 (LDL-C) 被标记为“坏”胆固醇,高密度脂蛋白胆固醇 (HDL-C) 被标记为“好”胆固醇。普遍的假设是,降低血液中的胆固醇水平,尤其是 LDL-C,可以减少血管沉积和胆固醇或含有载脂蛋白 B (apoB) 的致动脉粥样硬化的脂蛋白的滞留。我们在此回顾了降低血液胆固醇的不同药理学方法的临床试验数据,并提出降低胆固醇的作用机制以及降低胆固醇的幅度对于改善 ASCVD 的临床结果至关重要。胆汁酸螯合剂、贝特类、烟酸、胆固醇酯转移蛋白 (CETP) 抑制剂、载脂蛋白 AI 和 HDL 模拟物、apoB 调节剂、酰基辅酶 A:胆固醇酰基转移酶 (ACAT) 抑制剂、胆固醇吸收抑制剂、他汀类药物和前蛋白转化酶枯草杆菌蛋白酶 kexin 9 (PCSK9) 抑制剂等策略包括审查。临床证据支持不同类别的胆固醇降低或脂蛋白调节方法对 ASCVD 结果产生不同的影响,特别是在心血管和全因死亡率方面。他汀类药物是最广泛使用的降胆固醇药物,并具有最佳证明的心血管事件和生存益处。通过特异性靶向载脂蛋白或脂蛋白来控制胆固醇水平并没有产生临床益处。

更新日期:2021-06-18
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