Department of Medical Gastroenterology and Hepatology, Rigshospitalet, Copenhagen, Denmark.
Department of Medical Gastroenterology and Hepatology, Rigshospitalet, Copenhagen, Denmark.
EBioMedicine. 2019 Aug;46:444-451. doi: 10.1016/j.ebiom.2019.07.016. Epub 2019 Jul 17.
With the introduction of glucagon-like peptide-2 (GLP-2) in the treatment of short bowel syndrome (SBS), there is emerging evidence that GLP-2 may play a role in the restoration of the disturbed homeostatic feedback in the gut-liver axis and may ameliorate SBS-associated liver damage. We have previously presented that daily subcutaneous injections with 1 and 10 mg of glepaglutide improved intestinal function in patients with SBS. As exploratory endpoints, we here assessed the effect of glepaglutide on liver function.
Liver tests, transient elastography (TE) with controlled attenuation parameter (CAP), indocyanine green (ICG) kinetics, soluble CD163 (sCD163), soluble mannose receptor (sMR), and lipopolysaccharide binding protein (LBP) were assessed in 18 patients with SBS in a randomised, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide. This trial is completed and registered at ClinicalTrials.gov: NCT02690025.
Between Feb 2016 and Jan 2017, 22 patients with SBS were screened. Of these, 18 patients were randomised and treated with glepaglutide; 16 patients completed the trial. Treatment with glepaglutide was associated with increase in TE and ICG-elimination. In the 10 mg dose group, glepaglutide increased sCD163 by 0·44 mg/mL (P = 0·0498), and alkaline phosphatase (ALP) decreased in the 1 mg dose group by 33 U/L (P = 0·032). CAP, sMR, LBP, liver transaminases, and INR were not affected.
Glepaglutide may improve hepatic excretory function, but at the same time activate resident liver macrophages and increase liver stiffness. The excretory and the stiffness findings may to some extent relate to increased splanchnic blood flow which would not influence the marker of macrophage activation. Thus, glepaglutide exerted diverse effects on liver status that call for attention in future studies.
Zealand Pharma.
随着胰高血糖素样肽-2（GLP-2）在短肠综合征（SBS）治疗中的引入，有越来越多的证据表明 GLP-2 可能在恢复肠道-肝脏轴中失调的稳态反馈方面发挥作用，并可能改善 SBS 相关的肝损伤。我们之前已经提出，每天皮下注射 1 毫克和 10 毫克的 glepaglutide 可改善 SBS 患者的肠道功能。作为探索性终点，我们在此评估了 glepaglutide 对肝功能的影响。
在一项随机、交叉、剂量发现的 2 期临床试验中，我们评估了 18 例 SBS 患者在使用 glepaglutide 治疗前和治疗 3 周后的肝功能试验、瞬态弹性成像（TE）与受控衰减参数（CAP）、吲哚菁绿（ICG）动力学、可溶性 CD163（sCD163）、可溶性甘露糖受体（sMR）和脂多糖结合蛋白（LBP）。这项试验已经完成并在 ClinicalTrials.gov 上注册：NCT02690025。
2016 年 2 月至 2017 年 1 月期间，共筛查了 22 例 SBS 患者。其中，18 例患者被随机分配并接受 glepaglutide 治疗；16 例患者完成了试验。glepaglutide 治疗与 TE 和 ICG 消除的增加有关。在 10mg 剂量组中，glepaglutide 使 sCD163 增加了 0.44mg/mL（P=0.0498），而 1mg 剂量组的碱性磷酸酶（ALP）下降了 33U/L（P=0.032）。CAP、sMR、LBP、肝转氨酶和 INR 没有受到影响。
glepaglutide 可能改善肝脏排泄功能，但同时激活肝内驻留的巨噬细胞并增加肝硬度。排泄和硬度的发现可能在一定程度上与增加的内脏血流有关，而这不会影响巨噬细胞激活的标志物。因此，glepaglutide 对肝脏状态产生了多种影响，这在未来的研究中需要引起关注。
丹麦制药公司 Zealand Pharma。
