Effects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial

doi:10.1016/j.cgh.2020.02.027

Clinical Gastroenterology and Hepatology

Volume 18, Issue 13, December 2020, Pages 2962-2970.e6

https://doi.org/10.1016/j.cgh.2020.02.027 Get rights and content

Background & Aims

Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent with luminal BA sequestration by colesevelam. We compared the effects of colesevelam vs placebo on symptoms and gene expression patterns in the sigmoid colon mucosa in patients with BA diarrhea associated with IBS-D.

Methods

We performed a double-blind, parallel-group study of 30 adults with IBS-D and evidence of increased BA synthesis or fecal excretion, from December 2017 through December 2018 at a single center. Patients were randomly assigned (1:1) to groups given colesevelam (3 tablets, 625 mg each) or matching placebo, orally twice daily for 4 weeks. Stool diaries documented bowel functions for 8 days before and 28 days during colesevelam or placebo. Stool and fasting serum samples were collected for analyses of fecal BAs and serum levels of C4 and FGF19. We measured colonic transit by scintigraphy, mucosal permeability by in vivo excretion of saccharide probes, and mRNA levels in rectosigmoid biopsies. All measurements were made at baseline and on the last days of treatment. The primary endpoints were change in total fecal BA concentration and stool consistency.

Results

Compared with placebo, colesevelam was associated with significant changes in sequestered fecal total BA excretion (P < .001) and serum levels of C4 and FGF19 (both P < .001), and with a mean increase in fecal level of deoxycholic acid (10%; P = .07) compared to placebo. Colesevelam decreased colon mucosal expression of NR1H4 and P2RY4 and increased expression of GPBAR1, compared with baseline. Stool frequency and consistency, colonic transit, and permeability did not differ significantly between groups. Colesevelam was well tolerated.

Conclusions

In a randomized trial, we found that colesevelam increases delivery of total and secondary BAs to stool, hepatic BA synthesis, and colonic mucosal expression of genes that regulate BA, farnesoid X, and GPBAR1 receptors. Larger studies are needed to determine the effects on clinical responses. ClinicalTrials.gov no: NCT03270085

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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Bile acid diarrhoea is a common but overlooked cause of chronic watery diarrhoea. Plasma 7α-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic [⁷⁵Se] acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including colesevelam. We aimed to determine the efficacy and safety of colesevelam in bile acid diarrhoea.
In this randomised, double-blind, placebo-controlled, investigator-initiated phase 4 trial of the sequestrant colesevelam in bile acid diarrhoea (SINBAD), we enrolled consecutive patients aged 18–79 years without inflammatory bowel disease attending SeHCAT testing for suspected bile acid diarrhoea at four Danish secondary care centres. Participants were randomly allocated 1:1 to receive 12 days of treatment with colesevelam (overencapsulated tablets of 625 mg) or placebo, with the starting dose of two capsules twice daily and titrated to effect during the first 5 days of treatment. A pharmacist independent of the clinical investigators generated a randomisation list on the web page randomization.com using block randomisation (randomisation was not stratified). C4 and SeHCAT diagnostic results were blinded during treatment. We treated all patients with diarrhoea, with a daily mean of 3·0 or more bowel movements or 1·0 or more watery bowel movements (Bristol stool scale type 6 and 7). Remission was defined as the absence of both these criteria during treatment days 6–12. The primary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by C4 concentration greater than 46 ng/mL. A secondary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by SeHCAT retention of 10% or less. This trial is registered with ClinicalTrials.gov, NCT03876717.
Between Oct 25, 2018, and July 1, 2021, 168 patients were randomly assigned to receive colesevelam (n=84) or placebo (n=84). 41 patients had C4 concentration greater than 46 ng/mL (22 assigned to the colesevelam group and 19 to the placebo group). For the C4-defined primary outcome, 14 (64%) of 22 participants receiving colesevelam versus three (16%) of 19 participants receiving placebo achieved remission (adjusted odds ratio 9·1, 95% CI 1·9–62·8; p=0·011). For the SeHCAT-defined secondary outcome, 75 of the 168 participants had retention of less than 10% (37 assigned to the colesevelam group and 38 assigned to the placebo group); 22 (59%) of 37 participants receiving colesevelam achieved remission versus five (13%) of 38 participants receiving placebo (adjusted odds ratio 11·1, 95% CI 3·4–45·6; p=0·00020). There were no serious adverse events. Common adverse events were transient. For patients receiving colesevelam within the primary outcome population, five had abdominal pain, nine had bloating, and four had nausea. For patients receiving placebo, four had abdominal pain, four had bloating, and one had nausea. No participants with bile acid diarrhoea withdrew due to adverse events.
Colesevelam was superior to placebo at inducing remission of bile acid diarrhoea diagnosed with C4 concentration greater than 46 ng/mL. Secondary outcome data suggest similar efficacy treating SeHCAT-defined bile acid diarrhoea. Colesevelam was safe during the treatment.
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Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial
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Citation 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.
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.
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.
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.
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.
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Bile acid malabsorption (BAM) is a debilitating disease characterized by loose stools and high stool frequency. The pathophysiology of BAM is not well-understood. We investigated postprandial enterohepatic and gluco-metabolic physiology, as well as gut microbiome composition and fecal bile acid content in patients with BAM.
Twelve participants with selenium-75 homocholic acid taurine test–verified BAM and 12 healthy controls, individually matched on sex, age, and body mass index, were included. Each participant underwent 2 mixed meal tests (with and without administration of the bile acid sequestrant colesevelam) with blood sampling and evaluation of gallbladder motility; bile acid content and microbiota composition were evaluated in fecal specimens.
Patients with BAM were characterized by increased bile acid synthesis as assessed by circulating 7-alpha-hydroxy-4-cholesten-3-one, fecal bile acid content, and postprandial concentrations of glucose, insulin, C-peptide, and glucagon. The McAuley index of insulin sensitivity was lower in patients with BAM than that in healthy controls. In patients with BAM, colesevelam co-administered with the meal reduced postprandial concentrations of bile acids and fibroblast growth factor 19 and increased 7-alpha-hydroxy-4-cholesten-3-one concentrations but did not affect postprandial glucagon-like peptide 1 responses or other gluco-metabolic parameters. Patients with BAM were characterized by a gut microbiome with low relative abundance of bifidobacteria and high relative abundance of Blautia, Streptococcus, Ruminococcus gnavus, and Akkermansia muciniphila.
Patients with BAM are characterized by an overproduction of bile acids, greater fecal bile acid content, and a gluco-metabolic profile indicative of a dysmetabolic prediabetic-like state, with changes in their gut microbiome composition potentially linking their enterohepatic pathophysiology and their dysmetabolic phenotype. ClinicalTrials.gov number NCT03009916.

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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.

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Original ArticleAlimentary TractEffects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Design, Randomization, and Experimental Protocol

Demographics

Discussion

Conclusion

Acknowledgments

Gastroenterology

Gastroenterology

Gastroenterology

J Crohns Colitis

Gastroenterology

Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis

Clin Gastroenterol Hepatol

Quality of life in patients with irritable bowel syndrome

J Clin Gastroenterol

Prospective study of motor, sensory, psychological and autonomic functions in 119 patients with irritable bowel syndrome

Clin Gastroenterol Hepatol

The brain-gut axis in abdominal pain syndromes

Annu Rev Med

Peripheral mechanisms in irritable bowel syndrome

N Engl J Med

Serotonin signalling in the gut-functions, dysfunctions and therapeutic targets

Nat Rev Gastroenterol Hepatol

The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype

Am J Gastroenterol

Update on bile acid malabsorption: finally ready for prime time?

Curr Gastroenterol Rep

Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis

Gut

Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome

Aliment Pharmacol Ther

Original Article
Alimentary Tract
Effects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial