Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Chiba 272-8516, Japan.
Int J Mol Sci. 2022 Mar 22;23(7):3418. doi: 10.3390/ijms23073418.
Several randomized, double blind, placebo-controlled trials (RCTs) have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering by using statins, including high-doses of strong statins, reduced the development of cardiovascular disease (CVD). However, among the eight RCTs which investigated the effect of statins vs. placebos on the development of CVD, 56-79% of patients had the residual CVD risk after the trials. In three RCTs which investigated the effect of a high dose vs. a usual dose of statins on the development of CVD, 78-87% of patients in the high-dose statin arms still had the CVD residual risk after the trials. An analysis of the characteristics of patients in the RCTs suggests that elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C), the existence of obesity/insulin resistance, and diabetes may be important metabolic factors which determine the statin residual CVD risk. To understand the association between lipid abnormalities and the development of atherosclerosis, we show the profile of lipoproteins and their normal metabolism, and the molecular and biological mechanisms for the development of atherosclerosis by high TG and/or low HDL-C in insulin resistance. The molecular biological mechanisms for the statin residual CVD risk include an increase of atherogenic lipoproteins such as small dense LDL and remnants, vascular injury and remodeling by inflammatory cytokines, and disturbed reverse cholesterol transport. Peroxisome proliferator-activated receptor alpha (PPARα) agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and also have vascular protective effects, such as an anti-inflammatory effect and the reduction of the oxidative state. Ezetimibe, an inhibitor of intestinal cholesterol absorption, also improves TG and HDL-C, and reduces intestinal cholesterol absorption and serum plant sterols, which are increased by statins and are atherogenic, possibly contributing to reduce the statin residual CVD risk.
多项随机、双盲、安慰剂对照试验（RCT）表明，通过使用他汀类药物（包括高剂量强效他汀类药物）降低低密度脂蛋白胆固醇（LDL-C）可减少心血管疾病（CVD）的发生。然而，在八项研究他汀类药物与安慰剂对 CVD 发生影响的 RCT 中，试验后仍有 56-79%的患者存在残余 CVD 风险。在三项研究高剂量与常规剂量他汀类药物对 CVD 发生影响的 RCT 中，试验后高剂量他汀类药物组仍有 78-87%的患者存在 CVD 残余风险。对 RCT 中患者特征的分析表明，升高的甘油三酯（TG）和降低的高密度脂蛋白胆固醇（HDL-C）、肥胖/胰岛素抵抗和糖尿病的存在可能是决定他汀类药物残余 CVD 风险的重要代谢因素。为了了解脂质异常与动脉粥样硬化发展之间的关系，我们展示了脂蛋白及其正常代谢的特征，以及胰岛素抵抗时高 TG 和/或低 HDL-C 导致动脉粥样硬化发展的分子和生物学机制。他汀类药物残余 CVD 风险的分子生物学机制包括致动脉粥样硬化脂蛋白（如小而密 LDL 和残粒）的增加、炎症细胞因子引起的血管损伤和重塑，以及胆固醇逆转运的紊乱。过氧化物酶体增殖物激活受体α（PPARα）激动剂可改善致动脉粥样硬化脂蛋白，逆转胆固醇转运系统，还具有血管保护作用，如抗炎作用和氧化状态的降低。肠道胆固醇吸收抑制剂依折麦布还可改善 TG 和 HDL-C，减少肠道胆固醇吸收和血清植物固醇，这些固醇可被他汀类药物增加，且具有致动脉粥样硬化作用，可能有助于降低他汀类药物残余 CVD 风险。
