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.