Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study
Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study
复制标题
DOI：
10.1016/s0140-6736(15)00803-x
复制
发表时间：
2016-02-13
期刊：
影响因子：
168.9
通讯作者：
Newsome, Philip N.
中科院分区：
文献类型：
--
作者：
Armstrong, Matthew James;Gaunt, Piers;Newsome, Philip N.
背景：胰高血糖素样肽-1 （GLP-1）类似物可降低脂肪性肝病小鼠模型中的肝脂肪变性、肝酶浓度和胰岛素抵抗。这些类似物已被批准用于治疗2型糖尿病，但其对非酒精性脂肪性肝炎患者的疗效尚不清楚。我们评估了长效GLP-1类似物利拉鲁肽在非酒精性脂肪性肝炎患者中的安全性和有效性。这项多中心、双盲、随机、安慰剂对照的2期试验在英国4个医疗中心进行，以评估皮下注射利拉鲁肽（每日1.8 mg）与安慰剂对超重和有临床证据的非酒精性脂肪性肝炎患者的疗效。患者使用计算机生成的中央管理程序随机分配（1:1），按试验中心和糖尿病状况分层。该试验采用A'Hern的单组方法设计，利拉鲁肽组21例成功患者中需要8例（38%）才能认为利拉鲁肽的效果具有临床意义。在整个研究过程中，患者、研究者、临床试验现场工作人员和病理学家对治疗分配进行了掩饰。主要结局指标是明确的非酒精性脂肪性肝炎的消退，从基线到治疗结束（48周）没有纤维化恶化，由两名独立的病理学家进行集中评估。通过意向治疗分析进行分析，其中包括所有接受治疗结束活检的患者。该试验已在ClinicalTrials.gov注册，编号NCT01237119。在2010年8月1日至2013年5月31日期间，26名患者被随机分配接受利拉鲁肽治疗，26名接受安慰剂治疗。接受利拉鲁肽治疗并在治疗结束时进行肝活检的23例患者中有9例（39%）确诊为非酒精性脂肪性肝炎，而安慰剂组22例患者中有2例（9%）确诊为非酒精性脂肪性肝炎（相对危险度为4.3 [95% CI 1.0-17.7]; p= 0.019）。利拉鲁肽组23例患者中有2例（9%）出现纤维化进展，而安慰剂组22例患者中有8例（36%）出现纤维化进展（0.2 [0.1-1.0];p= 0.04）。大多数不良事件的严重程度为1级（轻度）至2级（中度），在两个治疗组中，所有器官类别和症状均相似，但利拉鲁肽组23例患者中有21例（81%）出现胃肠道疾病，安慰剂组22例患者中有17例（65%）出现胃肠道疾病，其中包括腹泻（利拉鲁肽组10例（38%）对安慰剂组5例（19%）），便秘（7例（27%）对无）。食欲不振（8人（31%）vs 2人（8%））。利拉鲁肽是安全的，耐受性良好，并导致非酒精性脂肪性肝炎的组织学解决，值得广泛，长期的研究。
Background Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the longacting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.Methods This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1.8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1: 1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119.Findings Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4.3 [95% CI 1.0-17.7]; p= 0.019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0.2 [0.1-1.0]; p= 0.04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]).Interpretation Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.