Ishay Yuval, Neutel Joel, Kolben Yotam, Gelman Ram, Arbib Orly Sneh, Lopez Oliver, Katchman Helena, Mohseni Rizwana, Kidron Miriam, Ilan Yaron
Department of Medicine, Hadassah Medical Center and Faculty of Medicine Hebrew University, Jerusalem, Israel.
Orange County Research Center, Tustin, California.
Gastro Hep Adv. 2023 Dec 7;3(3):417-425. doi: 10.1016/j.gastha.2023.11.016. eCollection 2024.
Metabolic dysfunction-associated steatohepatitis is an advanced form of nonalcoholic fatty liver disease and a leading cause of end-stage liver disease and transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease.
This double-blind, randomized, placebo-controlled, multicenter feasibility clinical trial aimed to determine the safety of oral 8 mg insulin in patients with metabolic dysfunction-associated steatohepatitis and type 2 diabetes mellitus. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n = 21) or placebo (n = 11) capsule. Safety was monitored throughout the study. MRI-proton density fat fraction assessed liver fat content, and Fibroscan® measured liver fibrosis and steatosis levels at screening and after 12 weeks of treatment.
No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2% vs -6.5%, respectively) and liver segment 3 (-11.7% vs +0.1%, respectively) fat content was higher in the insulin than in the placebo arm. Patients receiving insulin showed a median -1.2 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively, while placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, oral insulin was associated with a mean of 0.27% reduction and placebo with a 0.23% increase from baseline hemoglobin A1c levels. Mean percent changes from baseline alanine aminotransferase, and aspartate aminotransferase levels were -10% and -0.8%, respectively, in the oral insulin and 3.0% and 13.4%, in the placebo arm.
The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes (NIH Clinical Trials No. NCT04618744).
代谢功能障碍相关脂肪性肝炎是非酒精性脂肪性肝病的一种晚期形式，是终末期肝病和肝移植的主要原因。胰岛素抵抗和炎症是该疾病发病机制的基础。
这项双盲、随机、安慰剂对照、多中心可行性临床试验旨在确定口服8毫克胰岛素对代谢功能障碍相关脂肪性肝炎和2型糖尿病患者的安全性。患者每天服用两次8毫克胰岛素胶囊（n = 21）或安慰剂胶囊（n = 11），持续12周。在整个研究过程中监测安全性。磁共振成像 - 质子密度脂肪分数评估肝脏脂肪含量，Fibroscan®在筛查时和治疗12周后测量肝脏纤维化和脂肪变性水平。
研究期间未报告严重的药物相关不良事件。治疗12周后，胰岛素组全肝（分别为-11.2%对-6.5%）和肝段3（分别为-11.7%对+0.1%）脂肪含量的平均百分比降低高于安慰剂组。接受胰岛素治疗的患者纤维化和脂肪变性水平较基线分别中位数降低1.2 kPa和21.0 dB/m，而接受安慰剂治疗的患者分别中位数增加0.3 kPa和13.0 dB/m。在第12周时，口服胰岛素使糖化血红蛋白水平较基线平均降低0.27%，安慰剂使糖化血红蛋白水平较基线平均增加0.23%。口服胰岛素组谷丙转氨酶和谷草转氨酶水平较基线的平均百分比变化分别为-10%和-0.8%，安慰剂组分别为3.0%和13.4%。
这项可行性研究的结果支持口服胰岛素对肝纤维化、脂肪堆积和炎症过程的安全性和潜在治疗效果（美国国立卫生研究院临床试验编号：NCT04618744）。
