Colesevelam boosts likelihood for clinical remission in patients with bile acid diarrhea
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Colesevelam was superior to placebo in inducing remission in patients with bile acid diarrhea with no serious adverse events reported, according to results published in The Lancet Gastroenterology & Hepatology.
“Bile acid diarrhea is a common yet underrecognized cause of chronic watery diarrhea. In most countries, including the U.S., the diagnostic nuclear medicine tauroselcholic [Se] acid (SeHCAT) retention test is unavailable. The biochemical Plasma 7alpha-hydroxy-4-cholesten-3-one (C4) test has lower sensitivity compared with SeHCAT but is much cheaper and potentially widely available,” Christian Borup, MD, of Zealand University Hospital in Denmark, told Healio. “Treatment with bile acid binding sequestrants such as colestyramine, colestipol and colesevelam appears effective in observational studies, but the few placebo-controlled trials were underpowered to show superiority over placebo regarding bowel symptoms.
He continued, “Without clear evidence of treatment benefit, the reason for diagnosing bile acid diarrhea, and to some extent also the diagnostic entity of bile acid diarrhea, were uncertain.”
In a phase 4 trial of colesevelam, Borup and colleagues enrolled 168 patients aged 18 to 79 years who were referred for SeHCAT testing for suspected bile acid diarrhea. Results of C4 and SeHCAT testing were blinded and participants received either colesevelam (n = 84) or placebo (n = 84) for 12 days.
The primary outcome of interest was intention-to-treat remission rate, defined as resolution of three or more bowel movements and one or more watery bowel movements per day, in patients diagnosed by C4 concentration greater than 46 ng/mL. The secondary outcome was remission rate in patients diagnosed by SeHCAT retention of 10% or less.
Forty-one participants had C4 concentration greater than 46 ng/mL, of whom 22 were in the colesevelam group and 19 were in the placebo group, and 75 participants had retention of less than 10% for the SeHCAT-defined secondary outcome (colesevelam, n = 37; placebo, n = 38).
Results showed 64% of patients in the colesevelam group and 16% in the placebo group achieved remission of C4-defined bile acid diarrhea (adjusted OR = 9.1; 95% CI, 1.9-62.8). Adjusted remission rates were 65% (95% CI, 41-83) and 17% (95% CI, 5-44), respectively, with an estimated treatment difference of 48%.
For secondary outcomes, 59% and 13% of patients, respectively, achieved remission (aOR = 11.1; 95% CI, 3.4-45.6) with adjusted remission rates of 66% (95% CI, 43-83) and 15% (95% CI, 6-32). The estimated treatment difference was 51% (95% CI, 28-74).
Researchers observed no serious adverse events.
“Colesevelam treatment of C4-diagnosed bile acid diarrhea proved safe and superior to placebo,” Borup said. “Testing for bile acid diarrhea to establish the diagnosis should be considered in patients presenting with chronic watery diarrhea and in patients presenting with symptoms compatible with mixed and diarrhea types of irritable bowel syndrome.”
Perspective
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Adrienna Jirik, MD
Bile acid diarrhea is recognized as a fairly common but frequently underdiagnosed cause of diarrhea. It is caused by either bile salt malabsorption in the terminal ileum or bile salt overproduction in the liver. Excess bile acids that are not properly absorbed subsequently act as colonic irritants and essentially behave as unwanted, persistent osmotic laxatives.
Conditions that can predispose to this include post-cholecystectomy anatomy, bowel resections involving the ileum, inflammatory lesions of the small bowel (such as from Crohn’s disease and celiac disease), other inflammatory/ infectious enteropathies, radiation therapy and bariatric surgery. It has been reported that up to 30% of patients with diarrhea-predominant irritable bowel syndrome have bile acid diarrhea.
Objective measures to confirm bile acid-induced diarrhea are quite limited at many medical centers, and initiation of treatment with bile acid sequestrants tends to be empiric and delayed after workup for other causes of chronic diarrhea has been exhausted. Having an adequately powered, placebo-controlled study to confirm observational studies of clinical improvement and remission in a significant portion of patients with confirmed bile acid diarrhea is a helpful development.
Expanding capacity to formally test patients for suspected bile acid diarrhea would be a welcome next step for earlier diagnosis and treatment.
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