Farmer J A, Torre-Amione G
Section of Cardiology, Ben Taub General Hospital and Baylor College of Medicine, Houston, Texas 77030, USA.
Drug Saf. 2000 Sep;23(3):197-213. doi: 10.2165/00002018-200023030-00003.
The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has revolutionised the treatment of lipid abnormalities in patients at risk for the development of coronary atherosclerosis. The relatively widespread experience with HMG-CoA therapy has allowed a clear picture to emerge concerning the relative tolerability of these agents. While HMG-CoA reductase inhibitors have been shown to decrease complications from atherosclerosis and to improve total mortality, concern has been raised as to the long term safety of these agents. They came under close scrutiny in early trials because ocular complications had been seen with older inhibitors of cholesterol synthesis. However, extensive evaluation demonstrated no significant adverse alteration of ophthalmological function by the HMG-CoA reductase inhibitors. Extensive experience with the potential adverse effect of the HMG-CoA reductase inhibitors on hepatic function has accumulated. The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1 to 3% of patients experience an increase in hepatic enzyme levels. The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring. Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive HMG-CoA reductase inhibitor monotherapy. However, the incidence is increased when HMG-CoA reductase inhibitors are used in combination with agents that share a common metabolic path. The role of the cytochrome P450 (CYP) enzyme system in drug-drug interactions involving HMG-CoA reductase inhibitors has been extensively studied. Atorvastatin, cerivastatin, lovastatin and simvastatin are predominantly metabolised by the CYP3A4 isozyme. Fluvastatin has several metabolic pathways which involve the CYP enzyme system. Pravastatin is not significantly metabolised by this enzyme and thus has theoretical advantage in combination therapy. The major interactions with HMG-CoA reductase inhibitors in combination therapy involving rhabdomyolysis include fibric acid derivatives, erythromycin, cyclosporin and fluconazole. Additional concern has been raised relative to overzealous lowering of cholesterol which could occur due to the potency of therapy with these agents. Currently, there is no evidence from clinical trials of an increase in cardiovascular or total mortality associated with potent low density lipoprotein reduction. However, a threshold effect had been inferred by retrospective analysis of the Cholesterol and Recurrent Events study utilising pravastatin and the role of aggressive lipid therapy is currently being addressed in several large scale trials.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂的出现彻底改变了对有冠状动脉粥样硬化发展风险患者的脂质异常治疗。HMG-CoA疗法相对广泛的应用经验使得这些药物的相对耐受性情况得以清晰呈现。虽然HMG-CoA还原酶抑制剂已被证明可降低动脉粥样硬化并发症并改善总死亡率，但人们对这些药物的长期安全性提出了担忧。在早期试验中，它们受到密切关注，因为在较老的胆固醇合成抑制剂中曾观察到眼部并发症。然而，广泛评估表明HMG-CoA还原酶抑制剂对眼科功能没有显著的不良改变。关于HMG-CoA还原酶抑制剂对肝功能潜在不良影响的广泛经验已经积累。各种HMG-CoA还原酶抑制剂对肝功能的影响大致与剂量相关，1%至3%的患者会出现肝酶水平升高。大多数肝脏异常发生在治疗的前3个月内，需要进行监测。横纹肌溶解是一种罕见的综合征，在接受HMG-CoA还原酶抑制剂单一疗法的患者中发生率约为0.1%。然而，当HMG-CoA还原酶抑制剂与具有共同代谢途径的药物联合使用时，发生率会增加。细胞色素P450（CYP）酶系统在涉及HMG-CoA还原酶抑制剂的药物相互作用中的作用已得到广泛研究。阿托伐他汀、西立伐他汀、洛伐他汀和辛伐他汀主要由CYP3A4同工酶代谢。氟伐他汀有几种涉及CYP酶系统的代谢途径。普伐他汀不被该酶显著代谢，因此在联合治疗中有理论优势。联合治疗中与HMG-CoA还原酶抑制剂发生的主要相互作用包括横纹肌溶解，涉及的药物有纤维酸衍生物、红霉素、环孢素和氟康唑。对于这些药物治疗效力可能导致的过度降低胆固醇，人们也提出了更多担忧。目前，临床试验中没有证据表明强效降低低密度脂蛋白会增加心血管或总死亡率。然而，通过对使用普伐他汀的胆固醇和再发事件研究进行回顾性分析推断出了一种阈值效应，积极降脂治疗的作用目前正在几项大规模试验中得到探讨。
