Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina 27715, USA.
Gastroenterology. 2010 Apr;138(4):1365-73, 1373.e1-2. doi: 10.1053/j.gastro.2009.12.003. Epub 2010 Feb 13.
BACKGROUND & AIMS: Farglitazar (GI262570), an insulin-sensitizing agent, selectively binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibits stellate cell activation. We evaluated its antifibrotic effect in patients with chronic hepatitis C that did not respond to standard-of-care therapy.
Patients with fibrosis of Ishak stages 2-4 (n = 265), based on analysis of liver biopsy samples, were randomly assigned to groups given once-daily doses of 0.5 mg farglitazar, 1.0 mg farglitazar, or placebo for 52 weeks; repeat liver biopsy samples were then obtained. The primary end points were changes in levels of alpha-smooth muscle actin (SMA) expression and collagen, based on morphometry and ranked histologic assessments.
Two hundred nine patients had paired biopsy specimens adequate for analysis (81.5% with pretreatment Ishak scores of stage 2 or 3). There was no overall difference in SMA (P = .58) or collagen (P = .99) levels at week 52. SMA levels increased by a median of 49% in samples from patients given placebo, 58% in patients given 0.5 mg farglitizar and 52% in patients given 1.0 mg farglitizar, respectively. Collagen increased by 27% in placebo samples and 31% in samples from patients given either dose of farglitizar. There were no significant differences between treatment groups in the ranked assessment of paired biopsy specimens or in the proportion of patients with a change in fibrosis score > or = Ishak stage.
In patients with chronic hepatitis C and moderate fibrosis, 52 weeks of treatment with farglitazar does not affect stellate cell activation or fibrosis (measured by morphometry or comparison of paired biopsy specimens).
法格列他（GI262570）是一种胰岛素增敏剂，选择性结合并激活过氧化物酶体增殖物激活受体γ（PPARγ），并抑制星状细胞激活。我们评估了其在未对标准治疗有反应的慢性丙型肝炎患者中的抗纤维化作用。
根据肝活检样本分析，将纤维化程度为 Ishak 分期 2-4 期（n=265）的患者随机分为三组，分别接受每天一次的 0.5mg 法格列他、1.0mg 法格列他或安慰剂治疗 52 周；然后再次获得肝活检样本。主要终点是基于形态计量学和分级组织学评估的α-平滑肌肌动蛋白（SMA）表达和胶原变化。
209 例患者有足够的配对活检标本进行分析（81.5%的患者治疗前 Ishak 评分处于 2 或 3 期）。在第 52 周时，SMA（P=0.58）或胶原（P=0.99）水平没有总体差异。安慰剂组患者的 SMA 水平中位数增加了 49%，0.5mg 法格列他组增加了 58%，1.0mg 法格列他组增加了 52%。安慰剂组胶原增加了 27%，两种剂量的法格列他组胶原均增加了 31%。在配对活检标本的分级评估或纤维化评分变化≥Ishak 期的患者比例方面，治疗组之间没有显著差异。
在慢性丙型肝炎和中度纤维化患者中，52 周的法格列他治疗不会影响星状细胞激活或纤维化（通过形态计量学或比较配对活检标本测量）。
