Scheen A J
Department of Medicine, CHU Sart Tilman, Liège, Belgium.
Drug Saf. 2001;24(12):873-88. doi: 10.2165/00002018-200124120-00002.
Decreased insulin sensitivity plays a major role in various human diseases. particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (> or =3 x upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.
胰岛素敏感性降低在多种人类疾病中起主要作用，尤其是2型糖尿病，并且与动脉粥样硬化和心血管并发症的较高风险相关。噻唑烷二酮类药物，更通常被称为格列酮类药物，是首批专门针对肌肉胰岛素抵抗的药物。它们已被证明对单用饮食、磺脲类药物、二甲双胍或胰岛素治疗的2型糖尿病患者降低血糖水平有效。此外，它们与心血管风险状况的一定改善相关。然而，美国食品药品监督管理局批准的首个化合物曲格列酮被证明具有肝毒性，在报告了几十例死亡或严重肝衰竭需要肝移植的病例后退出市场。肝毒性是该类药物的共同作用还是与曲格列酮的独特性质有关仍不清楚。与曲格列酮相比，另外两种格列酮类药物罗格列酮和吡格列酮在2型糖尿病患者血糖控制方面似乎具有相似疗效。在对照临床试验中，与安慰剂相比，罗格列酮或吡格列酮导致肝酶水平（尤其是谷丙转氨酶）显著升高（≥正常上限3倍）的发生率相似，而曲格列酮的发生率高出3倍。与接受曲格列酮治疗的患者出现大量急性肝衰竭病例报告相反，到目前为止，接受罗格列酮治疗的患者仅有少数肝毒性病例报告，因果关系仍不确定。此外，尚未有吡格列酮导致严重肝毒性的单个病例报告。应该提及的是，与吡格列酮和罗格列酮不同，曲格列酮诱导细胞色素P450同工酶3A4，这部分负责其代谢，并且可能易于发生药物相互作用。足够重要的是，肥胖、胰岛素抵抗和2型糖尿病与肝脏异常相关，尤其是非酒精性脂肪性肝炎，与任何药物治疗无关。这种关联显然使选择适合格列酮类药物治疗的患者以及在开始使用任何噻唑烷二酮类化合物治疗后监测肝功能检查变得复杂。虽然仍建议定期监测肝酶且需要更多长期数据，但美国临床试验和上市后经验的当前证据支持以下结论：罗格列酮和吡格列酮不具有曲格列酮的肝毒性特征。
