吡格列酮改善非酒精性脂肪性肝炎的晚期纤维化

StephenW

Pioglitazone improves advanced fibrosis in nonalcoholic steatohepatitis
Musso G, et al. JAMA Intern Med. 2017;doi:10.1001/jamainternmed.2016.9607.
Yee HF. JAMA Intern Med. 2017;doi:10.1001/jamainternmed.2016.9669.
February 27, 2017

In patients with advanced liver fibrosis with or without diabetes, pioglitazone may halt disease progression to end-stage liver disease, according to data published in JAMA Internal Medicine.

“Nonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020,” Giovanni Musso, MD, from Humanitas Gradenigo Hospital in Italy, and colleagues wrote. “Advanced fibrosis (stage F3-F4) on liver biopsy independently predicts all-cause and liver-related mortality in NASH. There are no known efficacious treatments for advanced fibrosis related to NASH.”

The researchers searched several databases, registries and scientific meeting presentations through Aug. 15, 2016 for data from randomized clinical trials that analyzed the efficacy of thiazolidinedione therapy for NASH to determine its effect in advanced liver fibrosis. They evaluated whether a dichotomous improvement in advanced fibrosis on liver biopsy (improving from fibrosis stage F3-F4 to F0-F2) and at least a one-point improvement in fibrosis of any stage and NASH resolution resulted from thiazolidinedione therapy. Adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer and anemia were also assessed.

A total of 516 patients with biopsy-proven NASH from eight randomized clinical trials conducted between 6 and 24 months were studied of which five trials evaluated pioglitazone use and three evaluated rosiglitazone maleate use. Results from all studies indicated that thiazolidinedione therapy improved advanced fibrosis (OR = 3.15; 95% CI, 1.25-7.93; P = .01; I² = 0%), fibrosis of any stage (OR = 1.66; 95% CI, 1.12-2.47; P = .01; I² = 0%) and NASH resolution (OR = 3.22; 95% CI, 2.17-4.79; P < .001; I² = 0%). Patients without diabetes displayed similar results for improvement in advanced fibrosis (OR = 2.95; 95% CI, 1.04-10.9; P = .02; I² = 0%), improvement in fibrosis of any stage (OR = 1.76; 95% CI, 1.02-3.03; P = .02; I² = 0%) and NASH resolution (OR = 3.40; 95% CI, 1.95-5.93; P < .001; I² = 0%).

Thiazolidinedione therapy resulted in more frequent occurrence of weight gain and lower limb edema (initial body weight +2.7%; 95% CI, 1.96-4.34; P = .001). Musso and colleagues noted that they were unable to evaluate more serious adverse effects of thiazolidinedione therapy due to the small sample size of trials studied.

“Recent guidelines recommend identification of patients with [nonalcoholic fatty liver disease] with advanced fibrosis to target them for more intensive monitoring of the onset of complications but acknowledge the lack of therapeutic options that effectively reverse advanced stages of liver disease,” Musso and colleagues concluded. “The new finding in this meta-analysis is that treatment with the antidiabetic drug pioglitazone reverses the more advanced stages of liver disease in NASH regardless of the presence of diabetes, which provides a rationale for evaluating the effect of this drug on clinical outcomes in this subgroup of patients at higher risk of liver-related complications.”

In a related editorial, Hal F. Yee Jr, MD, PhD, from the department of medicine at the University of California, San Francisco, wrote that although this study enhances the understanding of the role that thiazolidinedione therapy may have in the management of NASH, essential questions, such as if pioglitazone alters clinical outcomes or has any potential risks, need to be answered before clinicians can recommend the drug as a treatment for patients with NASH.

“Pioglitazone has been approved by the FDA, alone or in combination with other medications, for the treatment of type 2 diabetes based on extensive clinical trials showing benefits that outweigh risks,” he added. “Therefore, it may make sense to consider the use of pioglitazone in patients with type 2 diabetes who have NASH and evidence of advanced fibrosis. Treating such patients would not incur any incremental risk of adverse events because they might already be taking pioglitazone as part of the management of their diabetes, while potentially benefiting from its putative benefits in NASH. For most patients with NASH, prior guidance to reduce weight, exercise, and refrain from heavy consumption of alcohol would seem prudent until we have data showing therapies that improve clinical outcomes.” – by Alaina Tedesco

Disclosures: Musso and Yee reports no relevant financial disclosures.

StephenW

吡格列酮改善非酒精性脂肪性肝炎的晚期纤维化
Musso G，et al。 JAMA Intern Med。 2017; doi：10.1001 / jamainternmed.2016.9607。
Yee HF。 JAMA Intern Med。 2017; doi：10.1001 / jamainternmed.2016.9669。
2017年2月27日

在有或没有糖尿病的晚期肝纤维化患者中，吡格列酮可以阻止疾病进展为终末期肝病，根据JAMA内科中公布的数据。

意大利Humanitas Gradenigo医院的Giovanni Musso，MD和同事写道：“非酒精性脂肪性肝炎（NASH）预计将是2020年肝移植的主要原因。 “肝活检的高级纤维化（阶段F3-F4）独立预测NASH中的全因死亡和肝相关死亡。对于与NASH相关的晚期纤维化没有已知的有效治疗。

研究人员在2016年8月15日之前搜索了几个数据库，登记册和科学会议记录，用于随机临床试验的数据，分析了噻唑烷二酮治疗NASH的疗效，以确定其对晚期肝纤维化的影响。他们评估肝活检（从纤维化阶段F3-F4到F0-F2改善）的晚期纤维化的二分性改善和任何阶段和NASH决定的纤维化中的至少一点改善是否由噻唑烷二酮治疗引起。还评估了噻唑烷二酮治疗的不良作用，包括体重增加，下肢水肿，充血性心力衰竭，骨折，癌症和贫血。

研究了总共516个活检证实的NASH患者从8个随机临床试验进行6和24个月之间，其中五个试验评估吡格列酮使用和三个评估马来酸罗格列酮使用。所有研究的结果表明噻唑烷二酮治疗改善晚期纤维化（OR = 3.15; 95％CI，1.25-7.93; P = 0.01; I 2 = 0％），任何阶段的纤维化（OR = 1.66; 95％CI， 2.47; P = 0.01; I 2 = 0％）和NASH分辨率（OR = 3.22; 95％CI，2.17-4.79; P <0.001; I 2 = 0％没有糖尿病的患者对于晚期纤维化的改善（OR = 2.95; 95％CI，1.04-10.9; P = 0.02; I 2 = 0％）显示相似的结果，任何阶段的纤维化的改善（OR = 1.76; 95％CI， 1.02-3.03; P = 0.02; I 2 = 0％）和NASH分辨率（OR = 3.40,95％CI，1.95-5.93; P <0.001; I 2 = 0％

噻唑烷二酮治疗导致体重增加和下肢水肿更频繁发生（初始体重+ 2.7％; 95％CI，1.96-4.34; P = 0.001）。 Musso和他的同事指出，由于研究的试验样本量很小，他们无法评估噻唑烷二酮治疗的更严重的不良反应。

“最近的指南建议确定患有晚期纤维化的[非酒精性脂肪性肝病]患者，目标是更密切监测并发症的发生，但承认缺乏有效逆转肝脏疾病晚期的治疗选择，”Musso和同事总结。 “这项荟萃分析的新发现是，用抗糖尿病药物吡格列酮治疗可逆转NASH肝病的更晚期，而不管糖尿病的存在，这为评价该药对临床结果的影响提供了一个基础。亚组患者肝脏相关并发症的高风险。

在一篇相关的社论中，来自旧金山加州大学医学系的Hal F. Yee Jr，MD博士写道，尽管这项研究增强了对噻唑烷二酮治疗可能在NASH的治疗中的作用的理解，基本问题，如如果吡格列酮改变临床结果或有任何潜在风险，需要回答，临床医生可以推荐该药物作为NASH患者的治疗。

“Pioglitazone已被FDA批准，单独或与其他药物联合用于治疗2型糖尿病，基于广泛的临床试验，显示超过风险的益处，”他补充说。 “因此，考虑在患有NASH和晚期纤维化证据的2型糖尿病患者中使用吡格列酮是有意义的。治疗这些患者不会引起任何不良事件的增加风险，因为他们可能已经服用吡格列酮作为其糖尿病管理的一部分，而可能从其在NASH中的推定利益受益。对于大多数NASH患者，在我们有数据显示改善临床结果的治疗方法之前，减轻体重，锻炼和避免大量饮酒的预先指导似乎是谨慎的。“ - 通过Alaina Tedesco

披露：Musso和Yee没有报告相关财务披露。

MP4

吡格列酮中国已经上市

baobao7676

不介绍原理，这个研究有点耍流氓。