Hausenloy D J, Yellon D M
The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, UK.
Heart. 2008 Jun;94(6):706-14. doi: 10.1136/hrt.2007.125401.
The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.6 mmol/l (100 mg/dl), the risk of a major cardiovascular event in patients with established coronary artery disease remains significant at a level approaching an annual risk of 9%, paving the way for new strategies for reducing the residual cardiovascular risk in this patient group. Early epidemiological studies have identified low levels of high-density lipoprotein cholesterol (HDL-C) (<1.0 mmol/l or 40 mg/dl), a common feature of type 2 diabetes mellitus and the metabolic syndrome, to be an independent determinant of increased cardiovascular risk. The beneficial effects of HDL-C on the cardiovascular system have been attributed to its ability to remove cellular cholesterol, as well as its anti-inflammatory, antioxidant and antithrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk. As such, raising HDL-C in patients with aggressively lowered LDL-C provides an additional strategy for addressing the residual cardiovascular risk present in these patients groups. Studies suggest that for every 0.03 mmol/l (1.0 mg/dl) increase in HDL-C, cardiovascular risk is reduced by 2-3%. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means, the former of which include smoking cessation, aerobic exercise, weight loss and dietary manipulation. Therapeutic strategies have included niacin, fibrates, thiazolidinediones and bile acid sequestrants. Newly developed pharmacological agents include apolipoprotein A-I mimetics and the cholesteryl ester transfer protein (CETP) inhibitors, JTT-705 and torcetrapib, the latter of which has been recently withdrawn from clinical testing because of serious adverse effects. Emerging experimental studies investigating the complex pathways of HDL metabolism have identified several new targets for raising HDL-C with new pharmaceutical agents currently in development. For the time being, the long-acting formulations of nicotinic acid remain the most effective and best tolerated pharmacological strategy for raising HDL-C in patients already on statin therapy to control LDL-C. Therefore, raising HDL-C represents an important strategy for reducing residual cardiovascular risk in patients already optimally treated with statins, and should lead to further improvements in clinical outcomes in these patient groups.
在过去20年中，使用3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（“他汀类药物”）降低低密度脂蛋白胆固醇（LDL-C）水平，已使心血管疾病风险显著降低。采用这种方法，LDL-C每降低1 mmol/l（39 mg/dl），主要心血管事件风险可降低21%。然而，尽管使用高剂量“他汀类药物”进行强化治疗，将LDL-C水平降至2.6 mmol/l（100 mg/dl）以下，但已确诊冠心病患者发生主要心血管事件的风险仍高达近9%的年风险水平，这为降低该患者群体残余心血管风险的新策略铺平了道路。早期流行病学研究已确定，高密度脂蛋白胆固醇（HDL-C）水平低（<1.0 mmol/l或40 mg/dl）是2型糖尿病和代谢综合征的常见特征，是心血管疾病风险增加的独立决定因素。HDL-C对心血管系统的有益作用归因于其清除细胞胆固醇的能力，以及其抗炎、抗氧化和抗血栓特性，这些特性共同作用可改善内皮功能并抑制动脉粥样硬化，从而降低心血管疾病风险。因此，在积极降低LDL-C的患者中提高HDL-C水平，为解决这些患者群体中存在的残余心血管风险提供了额外策略。研究表明，HDL-C每升高0.03 mmol/l（1.0 mg/dl），心血管疾病风险可降低2% - 3%。提高HDL-C水平可通过生活方式改变和药物手段实现，前者包括戒烟、有氧运动、减肥和饮食调整。治疗策略包括烟酸、贝特类药物、噻唑烷二酮类药物和胆汁酸螯合剂。新开发的药物制剂包括载脂蛋白A-I模拟物和胆固醇酯转运蛋白（CETP）抑制剂JTT - 705和托彻普，后者因严重不良反应最近已退出临床试验。正在进行的研究HDL代谢复杂途径的实验研究已确定了几个用目前正在研发的新型药物提高HDL-C的新靶点。目前，烟酸长效制剂仍然是在已接受他汀类药物治疗以控制LDL-C的患者中提高HDL-C最有效且耐受性最佳的药物策略。因此，提高HDL-C是降低已接受他汀类药物最佳治疗患者残余心血管风险的重要策略，应能进一步改善这些患者群体的临床结局。
