Articles
Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial

https://doi.org/10.1016/S2468-1253(22)00198-4Get rights and content

Summary

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.

Introduction

Bile acid diarrhoea is an underdiagnosed disease estimated to affect up to 1–2% of the general population.1 The main symptoms of bile acid diarrhoea are high stool frequency, defecation urgency, and faecal incontinence, making it a socially debilitating disease.2 Bile acid diarrhoea can be divided into three groups: types 1 and 3 are secondary to other conditions, such as Crohn's disease, coeliac disease, intestinal resection, and post-cholecystetomy diarrhoea, among others, whereas type 2, also known as primary bile acid diarrhoea, does not have a known underlying pathophysiology.1

In normal physiology, bile acids are synthesised in the liver, stored in the gallbladder, secreted to the duodenum upon food ingestion, and reabsorbed from the small intestine.3 Bile synthesis is regulated in a negative feedback loop where bile acids in the small intestine induce the release of fibroblast growth factor 19 (FGF19), thereby inhibiting the synthesis of bile in the liver. Symptoms of bile acid diarrhoea are caused by excessive spillover of unabsorbed bile acids from the small intestine to the colon, causing the abovementioned symptoms.3, 4 It has been speculated whether overproduction of bile acids due to defective negative inhibition is part of the pathophysiology of type 2 bile acid diarrhoea.5 The reference standard for diagnosing bile acid diarrhoea is the 75selenium-homotaurocholic acid test (SeHCAT), where the 7-day retention of orally administered 75selenium-labelled homotaurocholic acid is measured with a gamma camera.6 Retention greater than 15% is considered normal, 10–15% is defined as mild bile acid diarrhoea, 5–10% is defined as moderate bile acid diarrhoea, and less than 5% is defined as severe bile acid diarrhoea.6 Interestingly, emerging evidence suggests that patients with bile acid diarrhoea, in addition to their enterohepatic pathophysiology, are also characterised by a glucometabolic profile indicative of a dysmetabolic prediabetic-like state.7

Research in context

Evidence before this study

Bile acid diarrhoea is estimated to affect 1–2% of the general population. The main symptoms of bile acid diarrhoea are high stool frequency, defecation urgency, and faecal incontinence, making it a socially debilitating disease. Evidence shows that individuals with bile acid diarrhoea are also characterised by a dysmetabolic, prediabetes-like state. Bile acid diarrhoea is usually treated with bile acid sequestrants, but many individuals with bile acid diarrhoea experience an inadequate effect or intolerable side-effects from these drugs. Therefore, new treatment modalities are highly needed. Liraglutide is a glucagon-like peptide 1 receptor agonist that is approved for the treatment of type 2 diabetes and obesity, and has been shown to interfere with the enterohepatic circulation of bile acids and gastrointestinal motility. Case reports indicate that liraglutide might be an effective treatment for bile acid diarrhoea, but the effectiveness of liraglutide has never formally been investigated as a treatment modality for bile acid diarrhoea. We searched PubMed and ClinicalTrials.gov using the terms “bile acid malabsorption” and “liraglutide” for English language publications; the first search was done on Sept 1, 2017, and searches were repeated on a monthly basis. We found two case reports and the published protocol for the present study along with its records on ClinicalTrials.gov.

Added value of this study

In this randomised controlled trial we compared head to head the effectiveness of liraglutide and the current standard of care (ie, the bile acid sequestrant colesevelam) on stool frequency in patients with moderate-to-severe bile acid diarrhoea. Liraglutide was superior to colesevelam in reducing stool frequency in patients with bile acid diarrhoea. Liraglutide treatment was also associated with added glucometabolic benefits. One participant from each group dropped out because of nausea, which is a common side-effect of both liraglutide and colesevelam; otherwise, no safety issues were observed. Taken together, the results of the present study point to liraglutide as a potential new treatment modality for bile acid diarrhoea. The study also provides valuable data on the enterohepatic and glucometabolic effects of the two drugs, providing novel insights into their mode of action.

Implications of all the available evidence

Liraglutide is a well-known, safe, and commonly used drug for the treatment of type 2 diabetes and obesity. It is administered once daily as a subcutaneous injection and is well tolerated (the most common side-effect is temporary, mild-to-moderate nausea). The observed superiority of liraglutide compared to colesevelam in reducing stood frequency in patients with bile acid diarrhoea suggests consideration of liraglutide as a new treatment for bile acid diarrhoea, although larger confirmatory trials powered for superiority are warranted. Future research should focus on understanding the long-term effects of liraglutide on bile acid diarrhoea and the potential beneficial glucometabolic effects of liraglutide in these patients.

Currently, patients with bile acid diarrhoea are treated with bile acid sequestrants that bind to bile acids in the gut, thus alleviating symptoms. However, the efficacy of bile acid sequestrants is highly variable,5 and in some studies bile acid sequestrant therapy had no effect on high stool frequency, one of the core symptoms of bile acid diarrhoea. High stool frequency has been shown to be directly related to impaired quality of life.8 Furthermore, common adverse effects of bile acid sequestrants include constipation and overflow diarrhoea, stomach pain, bloating, flatulence, nausea, and vomiting. Hence, better modalities for the treatment of bile acid diarrhoea are needed.

The present study was inspired by case reports of two patients who experienced total remission of their bile acid diarrhoea symptoms after treatment with the glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) liraglutide,9 which they initiated because of concomitant overweight and type 2 diabetes. Liraglutide is a commonly used drug for treating type 2 diabetes and obesity. Apart from improving glycaemic control and reducing bodyweight, liraglutide slows gastric emptying and small intestinal motility.10 GLP-1RA therapy has also been reported to reduce gallbladder emptying11 and delay gallbladder refilling,12 an effect that might contribute to the beneficial effects of liraglutide in primary bile acid diarrhoea. Reduced gallbladder emptying combined with increased small intestinal transit time, and thus increased time for passive reabsorption of bile acids in the small intestine, might reduce spillover of bile acids to the colon. Based on this notion and the abovementioned cases, we hypothesised that treatment of bile acid diarrhoea with liraglutide would reduce the exposure of the colonic mucosa to bile acids and thus ameliorate symptoms of bile acid diarrhoea to the same extent as bile acid sequestrants (ie, liraglutide would be non-inferior to the best-in-class bile acid sequestrant). We aimed to investigate the safety and efficacy of liraglutide compared to the current standard of care (ie, treatment with the bile acid sequestrant colesevelam) in patients with bile acid diarrhoea.

Section snippets

Study design and participants

We conducted an investigator-initiated randomised, double-blind, active-comparator, double-dummy, parallel-group, non-inferiority clinical trial that was designed to evaluate the safety and efficacy of liraglutide compared to colesevelam for the treatment of moderate-to-severe bile acid diarrhoea. The trial was done at the Center for Clinical Metabolic Research at Copenhagen University Hospital–Herlev and Gentofte, Hellerup, Denmark. The trial protocol has previously been published13 and was

Results

Between April 1, 2019, and Jan 31, 2021, 52 individuals with moderate-to-severe bile acid diarrhoea were enrolled; 26 were assigned to liraglutide and 26 to colesevelam (table 1, figure 1). The mean age was 50·2 years, mean BMI was 29·9 kg/m2, and mean SeHCAT was 4·0%. 32 participants were female and 18 were male; two participants dropped out (one female participant from the liraglutide group and one male participant from the colesevelam group).

Liraglutide reduced daily stool frequency by 25%

Discussion

In this investigator-initiated, randomised, double-blind, placebo-controlled, double-dummy, parallel-group, non-inferiority clinical trial, we confirmed our primary hypothesis that liraglutide would be non-inferior to colesevelam (the standard of care) in reducing daily stool frequency by 25% or greater during 6 weeks of treatment in patients with moderate-to-severe bile acid diarrhoea. In fact, liraglutide-treated participants had a 27% greater chance of achieving a reduction in daily stool

Data sharing

At present, data from this study are not publicly available.

Declaration of interests

FKK received honorarium for consulting, lecturing, and teaching from the manufacturers of liraglutide (Novo Nordisk) and support for attending American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) meetings, including paid meeting registration, accommodation, and travel. All other authors declare no competing interests.

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