Original ArticleAlimentary TractEffects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial
Section snippets
Study Design, Randomization, and Experimental Protocol
We conducted a single-center, randomized, double-blind, single dose–level, parallel-group, controlled, 28-day trial of the effects of colesevelam, 1875mg (3 tablets, 625 mg each), or matching placebo (ratio 1:1), taken orally, twice daily, in 30 patients with IBS-D and prior evidence of increased BA synthesis or fecal excretion. Placebo consisted of gelatin, titanium dioxide, and FDA/E172 red iron oxide.
The study was conducted at Mayo Clinic (Rochester, Minnesota), and participants were
Demographics
Table 1 shows the demographics and baseline data of participants in the study and documents the absence of any statistically significant differences between the 2 groups.
The CONSORT flow chart and participant disposition are shown in Supplemental Figure 1. One person withdrew from the study secondary to personal reasons but was included within the analysis in accordance with intention to treat principles. Within this cohort, 30% (n = 9 of 30) were diagnosed with BAD based on elevated total
Discussion
Our study demonstrates expected pharmacodynamic effects of colesevelam such as increase in sequestered total fecal BAs, increase in fasting serum C4 reflecting compensatory BA synthesis, and the expected reciprocal reduction in serum FGF19. There was also a numerical increase in sequestration of deoxycholic acid in stool with colesevelam (P = .07). However, there were no significant effects on stool frequency and consistency with colesevelam compared with placebo, although there was variable
Conclusion
Our study is consistent with the literature documenting that, to date, the optimal dosing of BA sequestrants is unclear, despite the significant pharmacodynamics effects of serum C4, FGF19, and BA sequestration with colesevelam in this study, and the positive correlation between improved stool frequency and consistency and the binding and fecal excretion of BAs. However, stool frequency and consistency were not significantly different between colesevelam and placebo treatment. Larger studies
Acknowledgments
The authors thank Mrs Cindy Stanislav for excellent secretarial assistance.
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2022, The Lancet Gastroenterology and HepatologyCitation Excerpt :Furthermore, liraglutide treatment reduced stool frequency more effectively than colesevelam (ETD 0·76 stools per day), increased reabsorption of bile acids (assessed by SeHCAT), and decreased bile acid synthesis (assessed by circulating C4), thus exerting beneficial effects on the core pathophysiological features of bile acid diarrhoea. The mainstay pharmacological treatment of bile acid diarrhoea, bile acid sequestration (originally developed for the treatment of hypercholesterolaemia, as sequestering bile in the intestine causes loss of bile acids through faeces and compensatory conversion of cholesterol into bile acids in the liver), mainly rests on empirical data and a few studies investigating the bile acid sequestrants cholestyramine, colestipol, and colesevelam.20–23 In a retrospective chart review and patient questionnaire, Wedlake and colleagues24 found that the majority of colesevelam-treated individuals with cancer and SeHCAT-verified bile acid diarrhoea experienced symptom relief.
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Conflicts of interest These authors disclose the following: Michael Camilleri has received funding from Allergan, NGM Pharmaceuticals, and Novartis to study treatment of patients with bile acid disorders and irritable bowel syndrome and from Takeda for studies in gastroparesis; he has no other personal conflicts of interest. The remaining authors disclose no conflicts.
Funding Michael Camilleri’s research on bile acid diarrhea, and specifically this clinical trial, were supported by grant R01-DK115950 from National Institutes of Health and by the Mayo Foundation (Atherton and Winifred W. Bean Endowed Professorship). The study was conducted with the help of the Nursing Core of Mayo Clinic CCaTS grant #UL1-TR000135 from National Institutes of Health.