Nagoya City University, and Institute for Consumer Science and Human Life, Kinjo, Gakuin University, Nagoya, Japan.
Toyama Jonan Onsen Daini Hospital, Toyama, Japan.
Pharmacology. 2018;101(3-4):184-218. doi: 10.1159/000486374. Epub 2018 Jan 19.
The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk. The EAS Statement proposes that any mechanism of lowering plasma LDL concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C. However, as we explain, we do not find this conclusion acceptable.
Our review points out that different interpretations are possible for the results of Mendelian randomization studies. As for prospective cohort studies, many inconsistent reports on the association of LDL-C and ASCVD were disregarded when drafting the Statement, reports with and without genetic factors related to LDL receptor function should be analyzed separately, and the term ASCVD in the Statement is used inappropriately because myocardial infarction and cerebral infarction differ in their association with LDL-C. As for RCTs, clinical reports on statins published before and after the implementation of new regulations affecting clinical trials (2004/2005) should not both be included in meta-analyses because the evaluated efficacy of statins changed markedly, and the irreversible adverse effects of statins need to be evaluated more rigorously now that their mechanisms have been elucidated. Key Messages: Apart from the EAS hypothesis that LDL causes ASCVD, recent pharmacological/biochemical studies, as summarized in this review and elsewhere, have revealed that atherosclerosis is caused by statins taken to lower LDL-C, as well as by warfarin and some types of vegetable fats and oils, in the absence of significantly elevated LDL-C levels. Thus, the promotion of statin treatment by the Statement is rather risky and we do not feel that the conclusions are justified for the prevention of ASCVD.
欧洲动脉粥样硬化学会（EAS）共识小组 2017 年的共识声明基于 3 种不同类型的临床研究得出结论，即低密度脂蛋白（LDL）会导致动脉粥样硬化性心血管疾病（ASCVD）。在孟德尔随机化研究中，发现影响 LDL 受体功能的罕见遗传突变会导致 LDL-C 水平升高或降低，而这与相应的 ASCVD 风险改变有关。在他汀类药物的前瞻性队列研究和随机对照试验（RCT）中，证明了 LDL-C 暴露的绝对水平与 ASCVD 风险之间存在显著的对数线性关联。EAS 声明提出，任何降低血浆 LDL 浓度的机制都应该按照 LDL-C 绝对降低的程度和暴露于较低 LDL-C 的累积时间来降低 ASCVD 事件的风险。然而，正如我们所解释的，我们认为这个结论不可接受。
我们的综述指出，对于孟德尔随机化研究的结果可能有不同的解释。对于前瞻性队列研究，在起草该声明时，忽略了许多关于 LDL-C 与 ASCVD 之间关联的不一致报告，应该分别分析有和没有与 LDL 受体功能相关的遗传因素的报告，而且声明中使用的 ASCVD 一词不恰当，因为心肌梗死和脑梗死与 LDL-C 的关联不同。对于 RCTs，应该分别分析发表在新的临床试验法规（2004/2005 年）实施前后的他汀类药物的临床报告，因为他汀类药物的疗效发生了显著变化，而且由于现在已经阐明了他汀类药物的作用机制，需要更严格地评估其不可逆的不良反应。关键信息：除了 LDL 导致 ASCVD 的 EAS 假设外，正如本综述和其他地方总结的那样，最近的药理学/生物化学研究表明，动脉粥样硬化是由他汀类药物降低 LDL-C 引起的，而不是由华法林和某些类型的植物油引起的，尽管 LDL-C 水平没有明显升高。因此，声明中对他汀类药物治疗的推广是相当危险的，我们认为，对于 ASCVD 的预防，这些结论是没有道理的。
