Centre for Preventative Medicine, Ullevål University Hospital, University of Oslo, Oslo, Norway.
Am J Cardiovasc Drugs. 2010;10 Suppl 1:10-7. doi: 10.2165/1158822-S0-000000000-00000.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are extremely effective at reducing low-density lipoprotein (LDL) cholesterol and have been demonstrated to reduce mortality and the risk of major cardiovascular events in a number of large primary and secondary prevention studies. The linear relationship between LDL-cholesterol and cardiovascular risk suggests statins work solely by reducing LDL-cholesterol, and that ancillary properties do not contribute to cardiovascular risk reduction. In recent years, however, a number of additional non-lipid-lowering, or 'pleiotropic', effects of statins have been suggested to contribute to their efficacy in cardiovascular disease. The first data to suggest that statins may have benefits beyond lipid lowering came from the Heart Protection Study, in which simvastatin reduced mortality and morbidity even in patients with 'normal' LDL-cholesterol levels (2.6 mmol/L or 100 mg/dL). It has since been demonstrated, however, that cardiovascular risk remains high at this LDL concentration, but is substantially reduced in those achieving levels below 2.0 mmol/L (77 mg/dL). Evidence for the pleiotropic effects of statins in heart failure comes largely from retrospective and subgroup analyses of large studies. When statin therapy is compared with placebo, or when high-dose statin therapy is compared with low-dose treatment, a lower incidence of heart failure or hospitalization is observed. Despite promising retrospective data, however, two prospective studies of rosuvastatin in the treatment of patients with New York Heart Association class II-IV heart failure showed no impact on the primary endpoint and only one of the studies showed a lower rate of hospitalization favouring rosuvastatin. A number of small studies has shown evidence for mechanisms of action of statins outside of LDL-cholesterol lowering, including improvements in endothelial function, halting or retardation of atheroma development, reduction in inflammation and antithrombotic effects. The linear relationship between LDL-cholesterol lowering and reduction in coronary heart disease risk, as well as a lack of conclusive evidence for other mechanisms of action raise the question of whether any cholesterol-lowering agent is equally effective for reducing cardiovascular risk, but recent data from the torcetrapib clinical trial programme suggest this is not the case. Future cholesterol-lowering modalities must be able to demonstrate efficacy and good tolerability in large-scale clinical trials.
3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）在降低低密度脂蛋白（LDL）胆固醇方面非常有效，并已在多项大型一级和二级预防研究中证明可降低死亡率和主要心血管事件的风险。LDL 胆固醇与心血管风险之间的线性关系表明，他汀类药物仅通过降低 LDL 胆固醇起作用，并且辅助特性不会降低心血管风险。然而，近年来，人们提出了他汀类药物的一些其他非降脂作用或“多效性”，这些作用可能有助于其在心血管疾病中的疗效。他汀类药物可能具有除降脂作用以外的益处的第一个数据来自心脏保护研究，其中辛伐他汀降低了死亡率和发病率，即使在 LDL 胆固醇水平“正常”（2.6mmol/L 或 100mg/dL）的患者中也是如此。然而，此后已经证明，在这种 LDL 浓度下，心血管风险仍然很高，但在 LDL 浓度低于 2.0mmol/L（77mg/dL）的患者中则大大降低。他汀类药物在心力衰竭中的多效性作用的证据主要来自大型研究的回顾性和亚组分析。当将他汀类药物治疗与安慰剂进行比较，或当高剂量他汀类药物治疗与低剂量治疗进行比较时，观察到心力衰竭或住院的发生率较低。然而，尽管有有希望的回顾性数据，但两项关于 rosuvastatin 治疗纽约心脏协会 II-IV 级心力衰竭患者的前瞻性研究均未对主要终点产生影响，只有一项研究显示 rosuvastatin 更有利于降低住院率。一些小型研究表明，他汀类药物在 LDL 胆固醇降低以外的作用机制的证据，包括改善内皮功能、阻止或延缓动脉粥样硬化发展、减少炎症和抗血栓作用。LDL 胆固醇降低与冠心病风险降低之间的线性关系，以及缺乏其他作用机制的明确证据，提出了一个问题，即是否任何降脂药对于降低心血管风险同样有效，但最近来自 torcetrapib 临床试验计划的数据表明并非如此。未来的降脂方式必须能够在大规模临床试验中证明疗效和良好的耐受性。
