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Glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide (Victoza, Saxenda) may be superior to colesevelam (Welchol) for reducing stool frequency in patients with moderate-to-severe bile acid diarrhea, a small randomized trial in Denmark suggested.

In the non-inferiority trial of 52 patients, a significantly higher proportion of patients taking liraglutide experienced a reduction in daily stool frequency of 25% or greater at 6 weeks versus those assigned to standard-of-care colesevelam (77% vs 50%, respectively), reported Filip Knop, MD, PhD, of Copenhagen University Hospital, and colleagues in .

This absolute risk difference of 27% (one-sided 95% CI -100 to -6) in the study's primary endpoint met criteria for noninferiority and superiority, though the latter should be interpreted with caution due to the trial's low power, the researchers noted.

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

After 6 weeks, stool frequency decreased by 1.83 stools per day in the liraglutide group versus 1.08 per day in the colesevelam group, for an estimated treatment difference of 0.76 stools per day (P=0.0042).

The GLP-1 receptor agonist also increased reabsorption of bile acids more effectively than colesevelam (as assessed by ⁷⁵selenium-homotaurocholic acid test [SeHCAT]), and also decreased bile acid synthesis (assessed by circulating C4). Both treatment groups reported reduced symptom scores and an improvement in their quality of life without any significant between-group differences.

Bile acid diarrhea is caused by an excessive spillover of bile acids that remain unabsorbed from the small intestine, Knop's group noted, and it commonly results in defecation urgency, high stool frequency, and fecal incontinence.

Prior have suggested liraglutide -- a GLP-1 receptor agonist approved for type 2 diabetes and weight management -- as a possible treatment for the condition, which is estimated to affect about 1% to 2% of people and can be secondary to other conditions, such as Crohn's disease.

"Gastric emptying and intestinal transit have been shown to be slowed by liraglutide, with an increase in intestinal residue seen by capsule enteroscopy," stated Julian R.F. Walters, MA, MB, of Hammersmith Hospital in London, in an . "The most likely current explanation for the beneficial effect of liraglutide is that the slower intestinal motility gives greater time for bile acid absorption."

Walters added that "it will be important to see whether the most severely symptomatic patients, with bowel frequency in excess of eight watery stools per day, and who have not responded to colesevelam therapy, are able to have a meaningful response."

Knop and colleagues enrolled patients with moderate-to-severe primary bile acid diarrhea and randomized them 1:1 to receive a 6-week course of liraglutide or colesevelam at the Copenhagen University Hospital from April 2019 to January 2021. After the first week of the study without treatment, liraglutide was given as a once-daily subcutaneous injection (uptitrated from 0.6 to 1.8 mg over 3 weeks), whereas colesevelam was provided in three 625 mg capsules twice daily.

Average patient age was 50.2 years, and the mean body mass index was 29.9. All patients met Rome IV criteria for irritable bowel syndrome with diarrhea. Excluded were those with other gastrointestinal diseases, diabetes, ileal resection, or hepatobiliary disorders (other than simple non-alcoholic steatosis), among others.

A post-hoc analysis showed that more patients in the liraglutide group achieved normal stool frequency of two or fewer daily stools (65% vs 42% in the colesevelam group), and both groups had firmer stools after 6 weeks on the Bristol Stool Form scale.

Liraglutide was well tolerated, the researchers reported. Six patients experiencing mild nausea with the drug, lasting 10 to 21 days, versus one patient in the colesevelam arm. One patient from each group discontinued because of nausea. No additional adverse events were reported.

Study limitations included the small sample size and short treatment duration.

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