Vitamin E therapy proved superior to placebo in improving nonalcoholic steatohepatitis by significantly reducing steatosis, lobular inflammation, and disease activity, according to a study published online April 28 in the New England Journal of Medicine.
Pioglitazone also improved these factors as well as insulin resistance, but its histologic benefits did not reach the prespecified level of significance in the multicenter, phase III clinical trial, said Dr. Arun J. Sanyal of Virginia Commonwealth University, Richmond, and his associates.
The study findings are particularly important because until now, no treatment has been shown to improve the disorder, they noted.
The investigators compared the two agents with placebo in 247 adults who had biopsy-confirmed nonalcoholic steatohepatitis. The study participants were randomly assigned to receive oral vitamin E (800 IU daily, 84 patients), pioglitazone (30 mg daily, 80 patients), or placebo (83 patients) for 96 weeks. They then were followed an additional 24 weeks after discontinuing treatment.
Patients with diabetes were excluded from the trial to ensure that antidiabetic therapy wouldn’t confound the study findings.
The primary outcome was a composite of histologic features: improvement in hepatocellular ballooning score, no increase in fibrosis score, and either a decrease in the activity score for nonalcoholic fatty liver disease to three or less or at least a two-point decrease in disease activity score that included improvement in inflammation or steatosis subscores.
Vitamin E was associated with a significantly higher rate of improvement in the primary outcome (43%) than was placebo (19%).
Pioglitazone also was associated with a higher rate of improvement (34%), compared with placebo, but this outcome did not reach statistical significance.
“Given the subjectivity of histologic analysis,” the researchers performed further analyses and found that there had been an excess of patients with no hepatocellular ballooning at baseline in the pioglitazone group. Such patients could not show the improvement in hepatocellular ballooning that was required in the primary outcome. When these patients were excluded from the analysis, pioglitazone was associated with a significantly higher rate of improvement in the primary outcome (47%), Dr. Sanyal and his colleagues said (N. Engl. J. Med. 2010 [doi:10.1056/NEJMoa0907929]).
In addition to these benefits, both active treatments were associated with an early and highly significant reduction in mean aspartate aminotransferase and alanine aminotransferase levels, which persisted throughout the treatment phase of the trial. “Serum concentrations of alkaline phosphatase and gamma-glutamyl transpeptidase also improved in the two active-treatment groups, but bilirubin levels did not change significantly,” they said.
Neither agent improved fibrosis scores.
Only subjects in the pioglitazone group showed a significant improvement in insulin resistance, but this group also was the only one to show a significant (4.7 kg) weight gain, which began by week 24 and progressed with further treatment. Insulin resistance returned to baseline levels when pioglitazone was discontinued, but the associated weight gain persisted, the investigators noted.
Other than weight gain, the distribution of adverse events did not differ significantly among the three groups. There were 19 severe adverse events: 10 with placebo, 7 with vitamin E, and 2 with pioglitazone.
“It is important not to overinterpret the data on adverse events because the study was not powered to test any safety-related hypothesis,” Dr. Sanyal and his colleagues noted.
There were no cases of serious hepatotoxicity requiring discontinuation of treatment.
The investigators emphasized that “enthusiasm for the potential benefits of pioglitazone and vitamin E must be tempered by the finding that there was an improvement in histologic features in only 34% of the subjects who received pioglitazone and 43% of those who received vitamin E, and steatohepatitis resolved in only 47% and 36% of the subjects in those two groups, respectively.
“Neither agent was associated with a significant improvement in the mean fibrosis score after 96 weeks of treatment. There was also no significant reduction in portal inflammation,” Dr. Sanyal and his associates noted.
These treatments would have to be taken for the rest of the patient’s lifetime, and their potential for long-term adverse effects is not known. “The weight gain among the subjects receiving pioglitazone – which did not resolve after discontinuation of the drug – also detracts from its long-term usefulness,” they added.
This study was supported by the U.S. National Institutes of Health, the U.S. National Cancer Institute, and Takeda Pharmaceuticals North America. The vitamin E and one placebo were provided by Pharmavite; the pioglitazone and another placebo were provided by Takeda Pharmaceuticals North America. Dr. Sanyal and his associates reported financial ties to 38 drug companies, including Takeda, maker of pioglitazone.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
据4月28日《新英格兰医学杂志》在线发表的一项研究，维生素E疗法可显著减少脂肪变性、小叶内炎症和肝炎活动度，在改善非酒精性脂肪性肝炎方面优于安慰剂。
里士满弗吉尼亚联邦大学Arun J. Sanyal博士及其同事说，在这项多中心、III期临床试验中，吡格列酮也使上述因素及胰岛素抵抗有所改善，但其组织学改善并未达到预设的显著性水平。
他们指出，由于至今尚无研究显示有改善该病的疗法，故该研究结果特别重要。
研究者在247例活检证实为非酒精性脂肪性肝炎的成人中对这两种药物与安慰剂进行比较。研究受试者被随机安排接受口服维生素E (800 IU/d，84例患者)、吡格列酮(30 mg/d，80例患者)或安慰剂 (83例患者)，历时96周。停止治疗后对受试者再随访24周。
为确保抗糖尿病治疗不会干扰研究结果，本试验排除了糖尿病患者。
主要结局为由下列组织学特征构成的复合终点：肝细胞气球样变评分提高、纤维化评分无增加，以及非酒精性脂肪性肝病的活动度评分减至≤3分，或者该病活动度 (包括炎症改善) 或脂肪变性评分至少减少2分。
服用维生素E组主要结局的改善率(43%)显著高于安慰剂对照组(19%)。
服用吡格列酮组的改善率(34%)亦高于对照组，但未达到统计学意义。
“鉴于组织学分析存在主观性，”故研究者做了进一步分析，并发现吡格列酮组基线时无肝细胞气球样变的患者过多，这类患者无法显示肝细胞气球样变的改善情况，而此指标为主要结局的必需组分。分析中排除这些患者时，吡格列酮与主要结局改善率明显提高具有相关性，Sanyal博士及其同事说(N. Engl. J. Med. 2010 [doi:10.1056/NEJMoa0907929])。
除上述收益外，两种阳性药物治疗均与早期天冬氨酸氨基转移酶和丙氨酸氨基转移酶的平均水平显著降低有关，这种收益贯穿试验的整个治疗期。“血清碱性磷酸酶和γ-谷氨酰转肽酶水平在两组阳性药物治疗组中亦有改善，但胆红素水平无显著变化，”他们说。
两种药物均未改善纤维化评分。
仅吡格列酮组受试者显示胰岛素抵抗有显著改善，但该组亦为显示明显(4.7 kg)增重的惟一一组，增重始于第24周，随治疗的推进而加重。吡格列酮停药后，胰岛素抵抗回归基线水平，但体重仍在增加，研究者指出。
除增重外，其他不良事件的分布无明显组间差异。共发生19例不良事件：安慰剂对照组10例，维生素E组7例，吡格列酮组2例。
“本研究不具备检验安全性相关假设的效能，故不要对不良事件相关数据做过度的解读，这很重要，”Sanyal博士及其同事指出。
研究中未出现因严重肝毒性而需终止治疗的病例。
研究中强调指出，切勿过于热衷于吡格列酮和维生素E的潜在收益，毕竟研究结果显示服用吡格列酮的受试者中仅有34%、服用维生素E的受试者中仅有43%在组织学特征方面有改善，这两组脂肪性肝炎好转率分别仅为47%和36%。
“两种药物与96周治疗后平均纤维化评分显著改善均无相关性，门脉炎症亦无显著减少，”Sanyal博士及其同事指出。
这些治疗可能需要患者终生进行，尚不清楚是否有发生长期不良反应的可能。“服用吡格列酮的受试者体重增加 (在停药后仍无缓解)亦减损了该药的长期效果，”他们补充道。
该研究得到美国国立卫生研究院、美国国家癌症研究所及武田制药北美分公司资助。维生素E和一种安慰剂由Pharmavite公司惠赠；吡格列酮和另一种安慰剂由武田制药北美分公司惠赠。Sanyal及其同事报告与38家制药公司有经济关系，其中包括吡格列酮生产商武田制药。
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