Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial

Borup, Christian; Vinter‐Jensen, Lars; Jørgensen, Søren Peter; Wildt, Signe; Graff, Jesper; Gregersen, Tine; Zaremba, Anna; Andersen, Trine Borup; Nøjgaard, Camilla; Timm, Hans Bording; Rainteau, Dominique; Hansen, Steen Holger; Rumessen, Jüri Johannes; Munck, Lars Kristian

doi:10.1016/s2468-1253(22)00401-0

Cited by 24 publications

(30 citation statements)

References 32 publications

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“…A history of cholecystectomy or prior small or large intestine surgery was not reason for exclusion. Patients with inflammatory bowel disease and microscopic colitis were excluded; the complete list of participation criteria has been published 19 …”

Section: Methodsmentioning

confidence: 99%

“…At the second SeHCAT visit, a fasting morning blood sample was collected no later than 10:00 AM, with no alcohol consumption allowed 24 hours prior. The study diary was tallied, and patients fulfilling the criteria for diarrhoea: ≥ 3.0 bowel movements or ≥1.0 watery bowel movements (Bristol stool scale type 6 and 7) per day as an average over the six‐day diary were eligible for randomisation to 12 days placebo‐controlled treatment with colesevelam, as detailed and reported 19 . The patients answered a questionnaire at the end of treatment, while both treatment allocation and diagnostic results were blinded: Was your diarrhoea cured – yes or no?…”

Section: Methodsmentioning

confidence: 99%

“…In the lack of better options, diagnostic assessment of empirical treatment effect is common practice, although with unknown diagnostic performance 15,16 . Furthermore, with several treatment options available for bile acid diarrhoea, proper diagnosis is fundamental 15,17–19 . Plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4) is a surrogate marker of hepatic bile acid synthesis and a cheaper diagnostic alternative that potentially could be widely available; however, compared with SeHCAT testing, C4 has a low sensitivity of about 50% 20–22 .…”

Section: Introductionmentioning

confidence: 99%

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Prospective comparison of diagnostic tests for bile acid diarrhoea

Borup,

Vinter‐Jensen,

Jørgensen

et al. 2023

Aliment Pharmacol Ther

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SummaryBackgroundBile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic [75‐Se] acid (SeHCAT) testing has limited availability. Empirical treatment effect has unknown diagnostic performance, whereas plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4) is inexpensive but lacks sensitivity.AimsTo determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT.MethodsThis diagnostic accuracy study was part of a randomised, placebo‐controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient‐reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation.ResultsNinety‐six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%–79%) sensitivity and 65% (47%–80%) specificity; C4 > 46 ng/mL had 47% (37%–57%) and 92% (87%–96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%–85%) sensitivity and 95% (83%–99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%–90%) sensitivity and 93% (80%–98%) specificity.ConclusionsDiagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4‐based testing, offering potential widely available diagnostics. Further validation is warranted. ClinicalTrials.gov: NCT03876717.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prospective comparison of diagnostic tests for bile acid diarrhoea

Borup,

Vinter‐Jensen,

Jørgensen

et al. 2023

Aliment Pharmacol Ther

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“…41 Adjuvant medications such as bile salt binding resins, for instance, cholestyramine or colesevelam, have been proven effective in a randomized controlled trial. 42 In extreme cases, surgical intervention with reversed jejunal grafts have been attempted; however, dietary changes and medical intervention have improved significantly over time, limiting the need for surgical therapy. 28,43 Small intestinal bacterial overgrowth…”

Section: Postvagotomy Diarrheamentioning

confidence: 99%

Long‐term nutrition alterations after surgery for gastrointestinal cancers

2023

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As surgical and adjuvant therapies for gastrointestinal (GI) cancers improve in safety and efficacy, extended survival in these diseases is becoming commonplace. Surgically induced nutrition alterations are common side effects of treatment and often debilitating. This review is intended for multidisciplinary teams to better understand the postoperative anatomy, physiology, and nutrition morbidity of GI cancer operations. We have arranged this paper by the anatomic and functional changes to the GI tract intrinsic to common cancer operations. Operation-specific long-term nutrition morbidity is detailed, along with the underlying pathophysiology. We have included the most common and effective interventions for the management of individual nutrition morbidities. Finally, we highlight the importance of a multidisciplinary approach to the evaluation and treatment of these patients over the oncologic surveillance period and beyond.

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“…The current therapeutic armamentarium for the treatment of BAD is mainly limited to bile acid sequestrants (BAS). While BAS are clearly superior to placebo in the treatment of BAD,14 their use can be restricted by poor tolerance, fat-soluble vitamin deficiency, and in cases of extensive small intestinal resection—potential fat malabsorption 15–17. Equally, the efficacy of anti-diarrhoeal/antisecretory agents commonly used to reduce the diarrhoea/-ostomy output in SBS is also limited 15.…”

Section: Introductionmentioning

confidence: 99%

Emerging uses of glucagon-like peptide 1 (GLP-1) receptor agonists following ileal resection: literature review and case examples

Conley

White

Bond

et al. 2023

Frontline Gastroenterol

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Following ileal resection, the combination of severe bile acid (BA) malabsorption, rapid small bowel transit and unrestricted upper gastrointestinal (GI) secretion results in severe diarrhoea that can prove refractory to pharmacological therapies. While established therapies, including BA sequestrants and antidiarrhoeal drugs seek to ameliorate symptoms, they do not target the underlying pathophysiological mechanisms in this patient group. Their use can also be limited by both intolerance and adverse effects. The novel use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in these patients may allow restoration of the physiological negative feedback mechanisms lost in ileal resection and reduce diarrhoea by prolonging small bowel transit time, limiting upper GI secretions and perhaps by inhibiting hepatic BA synthesis. While recent evidence supports the use of GLP-1 RAs as a safe and effective therapy for bile acid diarrhoea (BAD), it remains uncertain whether those with severe BAD and subsequent short bowel syndrome secondary to extensive ileal resection will benefit. Here, we present three cases of severe diarrhoea secondary to extensive ileal resection in which the use of the GLP-1 RA, liraglutide, was well tolerated and resulted in an objective improvement in diarrhoeal symptoms. We further provide a narrative review of the emerging evidence base supporting the use of GLP therapies in this challenging condition.

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Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial

Cited by 24 publications

References 32 publications

Prospective comparison of diagnostic tests for bile acid diarrhoea

Prospective comparison of diagnostic tests for bile acid diarrhoea

Long‐term nutrition alterations after surgery for gastrointestinal cancers

Emerging uses of glucagon-like peptide 1 (GLP-1) receptor agonists following ileal resection: literature review and case examples

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