Background

Bile acid diarrhoea is an underdiagnosed disease estimated to affect 1–2% of the general population. Case reports indicate that the glucagon-like peptide 1 receptor agonist liraglutide might be an effective treatment for bile acid diarrhoea. We aimed to investigate the safety and efficacy of liraglutide for the treatment of bile acid diarrhoea.

Methods

We conducted a randomised, double-blind, active-comparator, double-dummy, non-inferiority clinical trial at the Center for Clinical Metabolic Research at Copenhagen University Hospital–Herlev and Gentofte, Hellerup, Denmark. Patients aged 18–75 years with ⁷⁵selenium-homotaurocholic acid test (SeHCAT)-verified moderate-to-severe primary bile acid diarrhoea were randomly assigned (1:1) to receive liraglutide (one daily subcutaneous injection uptitrated from 0·6–1·8 mg per day over 3 weeks) or colesevelam (three capsules of 625 mg twice daily), the standard of care, for 6 weeks following one run-in week with no treatment. The primary endpoint was the proportion of participants experiencing a reduction in daily stool frequency of 25% or greater after 6 weeks. Data from all participants were included in the analysis of the primary outcome. The non-inferiority limit was set to 15% in favour of colesevelam. This trial is registered with EudraCT (2018-003575-34) and is completed.

Findings

Between April 1, 2019, and Jan 31, 2021, 52 patients were enrolled; 26 were assigned to liraglutide and 26 to colesevelam. 20 (77%) of 26 participants on liraglutide and 13 (50%) of 26 on colesevelam experienced a 25% or greater reduction in stool frequency, corresponding to a significant risk difference of −27% in favour of liraglutide (one-sided 95% CI −100 to −6). Liraglutide was therefore superior to colesevelam in reducing daily stool frequency. Mild nausea with a duration of 10–21 days was reported by six participants in the liraglutide group and by one participant in the colesevelam group. No other adverse events were reported.

Interpretation

The superiority of liraglutide compared with colesevelam in reducing stool frequency suggests consideration of liraglutide as a potential new treatment modality for bile acid diarrhoea, although larger confirmatory trials powered for superiority are warranted.

Funding

Novo Nordisk, Novo Nordisk Foundation, Foundation for the Advancement of Medical Science under The A.P. Møller and Chastine Mc-Kinney Møller Foundation.

中文翻译：

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利拉鲁肽与考来维仑治疗胆汁酸腹泻的安全性和有效性：一项随机、双盲、活性对照、非劣效性临床试验

背景

胆汁酸性腹泻是一种未被充分诊断的疾病，估计会影响 1-2% 的普通人群。病例报告表明，胰高血糖素样肽 1 受体激动剂利拉鲁肽可能是治疗胆汁酸腹泻的有效药物。我们旨在研究利拉鲁肽治疗胆汁酸腹泻的安全性和有效性。

方法

我们在丹麦海勒鲁普的哥本哈根大学医院临床代谢研究中心进行了一项随机、双盲、活性比较剂、双模拟、非劣效性临床试验。年龄在 18-75 岁之间的患者，其中⁷⁵硒-高牛磺胆酸试验 (SeHCAT) 验证的中度至重度原发性胆汁酸腹泻患者被随机分配 (1:1) 接受利拉鲁肽治疗（每日一次皮下注射，在 3 周内从每天 0·6–1·8 mg 递增） ) 或考来维仑（每日两次，每次 625 毫克，三粒胶囊），标准护理，在未治疗的磨合一周后持续 6 周。主要终点是 6 周后每日排便次数减少 25% 或更多的参与者比例。所有参与者的数据都包含在主要结果的分析中。非劣效性限制设置为 15%，有利于考来维仑。本试验在 EudraCT (2018-003575-34) 注册并完成。

发现

2019 年 4 月 1 日至 2021 年 1 月 31 日期间，招募了 52 名患者；26 人分配给利拉鲁肽，26 人分配给考来维仑。利拉鲁肽组的 26 名参与者中有 20 名 (77%) 和考来维仑组的 26 名参与者中有 13 名 (50%) 的大便次数减少了 25% 或更多，对应于-27% 的显着风险差异有利于利拉鲁肽（单方 95 % CI -100 至 -6)。因此，利拉鲁肽在减少每日排便次数方面优于考来维仑。利拉鲁肽组的六名参与者和考来维仑组的一名参与者报告了持续 10-21 天的轻度恶心。没有报告其他不良事件。

解释

与考来维仑相比，利拉鲁肽在减少大便次数方面的优势表明可以考虑将利拉鲁肽作为胆汁酸性腹泻的潜在新治疗方式，尽管需要更大规模的验证性试验证明其优势。

资金

Novo Nordisk、Novo Nordisk 基金会、AP Møller 医学科学促进基金会和 Chastine Mc-Kinney Møller 基金会。