J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Original Article

Volume 16, Number 2-3, March 2024, pages 33-45

Evaluation of Alternative Treatment Strategies for Bile Acid Malabsorption in Inflammatory Bowel Disease Patients: A Network Meta-Analysis

Figure 1. PRISMA flow diagram for literature search. PRISMA: the Preferred Reporting Items for Systematic Reviews and Meta-Analysis; PICO: patient, intervention, comparison, and outcome.

Figure 3. The forest network plot for the analysis of the frequency of stool per day outcome. The study demonstrated no substantial difference between the examined drugs and placebo in terms of their efficacy in decreasing daily stool frequency. MD: mean difference; CI: confidence interval.

Figure 4. The forest network plot for the analysis of the FGF19 (pg/mL) outcome. The chart illustrates that tropifexor was the most potent drug in elevating FGF19 levels, outperforming the placebo and other drugs in our study. MD: mean difference; CI: confidence interval; FGF19: fibroblast growth factor 19.

Figure 5. The network forest plot that analyses the C4 (ng/mL) outcome. This visualization demonstrates that tropifexor stands out as the most effective drug in reducing C4 levels when compared to placebo among the assessed medications. MD: mean difference; CI: confidence interval.

Figure 6. The network forest plot that analyses the Bristol Stool Form Scale (BSFS) outcome. The plot reveals no substantial difference between the tested drugs and the placebo when it comes to reducing the BSFS score in patients diagnosed with BAM. MD: mean difference; CI: confidence interval; BAM: bile acid malabsorption.

Figure 7. The forest network plot for the analysis of total fecal bile acids (µmol/g) outcome. The plot demonstrates that liraglutide was more effective than colesevelam in diminishing fecal bile acid concentrations when compared with a placebo. MD: mean difference; CI: confidence interval.

**Table 1.** Summary of the Included Studies
References	Groups	Sample size	Design	Inclusion criteria	Regimen	Underlying GI problem	Findings	Country
RCT: randomized controlled study; BMI: body mass index; GI: gastrointestinal; CD: Crohn’s disease; BSFS: Bristol Stool Form Scale; 75SeHCAT: selenium-75-homocholic acid taurine; bid: twice daily; BAD: bile acid diarrhea; CDAI: Crohn’s disease activity index; BAM: bile acid malabsorption; IBS-D: irritable bowel syndrome with diarrhea; FGF19: fibroblast growth factor 19; BA: bile acid.
Appleby et al, 2017 [16]	Cholestyramine (1 g/day)	7	RCT	Men and women aged 18 - 80 years with a BMI between 18.5 and 35: 1) three stools of BSFS 5 per day on average, calculated from 7 days off therapy; 2) SeHCAT 7-day retention of < 10% (moderate or severe impairment), within the last 5 years with no change in symptoms since; 3) 21 bowel motions in the last 7 days before randomization, of which > 50% are BSFS ≥ 5; 4) macroscopically normal colonoscopy with no histological evidence of microscopic colitis within the last 5 years.	A3384 250 mg bid. or A3384 1 g bid., or placebo for 2 weeks	-	Serum FGF19 was suppressed, and bile acid production upregulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD.	Sweden
	Cholestyramine (250 mg/day)	6
	Placebo	6
Beigel et al, 2014 [17]	Colesevelam	15	RCT	CD patients with ≥ 3 and ≤ 15 liquid stools/day in clinical remission, defined as CD activity index (CDAI) ≤ 150 points and CRP value ≤ 1 mg/dL were eligible for the study, age ≥ 18 and ≤ 65 years, contraception in women, medication with either oral aminosalicylates, azathioprine, mercaptopurine, methotrexate, oral steroids (10 mg/day), or anti-TNF alpha antibody and cholestenone serum level of ≥ 50 ng/mL, which was centrally assessed at the screening visit.	Patients received either colesevelam (3 × 2 tablets a 625 mg/day) or identically shaped placebo (3 × 2 tablets/ day).	CD	We found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency.	Germany
	Placebo	11
Camilleri et al, 2020 [18]	Tropifexor (60 µg/day) - placebo	10	Cross over RCT	Patients with primary bile acid diarrhea, who had not used bile acid sequestrants, aged ≥ 18 years weighing ≥ 50 kg, with a history of diarrheal symptoms for at least 3 months prior to dosing, as defined by average stool frequency of ≥ 3 per day when off therapy and average stool form of > 5 on the Bristol Stool Chart; laboratory or radiological confirmation of bile acid malabsorption within the last 5 years as defined by evidence of fecal bile acid loss of ≥ 2,000 µmol/48 h with or 7-day 75SeHCAT retention of < 10%.	Tropifexor 60 µg/placebo or placebo/tropifexor 60 µg. In treatment period 1, patients received either tropifexor 60 µg or placebo orally once daily for 14 days.	-	Tropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhea.	USA
	Placebo - tropifexor (60 µg/day)	10
Devarakonda et al, 2019 [19]	Colesevelam	17	RCT	-		CD	We have demonstrated that colesevelam is an effective treatment for postoperative BAM in CD. Both colesevelam and cholestyramine were associated with a reduction in stool frequency but only colesevelam was associated with a reduction in CDAI and an improvement in quality of life.	UK
	Cholestyramine	10
	Loperamide	12
	Colesevelam and loperamide	5
Karhus et al, 2022 [20]	Liraglutide	25	RCT	White individuals aged 18 - 75 years with SeHCAT verified moderate-to-severe primary bile acid diarrhea (≤ 10% 7-day bile acid retention), with no diabetes, other GI diseases including CD, ileal resection, previous history of radiation to the abdomen or the pelvis, or recent or active malignancy.	Liraglutide (one daily subcutaneous injection up-titrated from 0.6 mg to 1.8 mg over 3 weeks) or colesevelam (three capsules of 625 mg twice daily) and the opposite dummy for 6 weeks.	IBS-D	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	Denmark
	Colesevelam	25
Odunsi-Shiyanbade et al, 2010 [10]	Colesevelam	12	RCT	All participants had fasting plasma 7alpha-C4 (C4) levels measured to assess for underlying BAM and had serum FGF19 levels measured. Participants also completed the following questionnaires: Hospital Anxiety and Depression Scale,16 Symptom Checklist 90 (SCL-90) (somatization), and bowel function by validated daily diaries including BSFS scores.	Colesevelam HCl (625-mg tablets) and the placebo (312.5-mg capsules)	IBS-D	Sodium chenodeoxycholate in health and colesevelam in IBS-D patients have opposite effects on colonic transit and fecal parameters.	USA
	Placebo	12
Vijayvargiya et al, 2020 [21]	Colesevelam	15	RCT	Females and males aged 18 - 75. An IBS diagnosis based on the Rome III criteria for at least 3 months, with onset at least 6 months previously, of recurrent abdominal pain or discomfort. Biomarkers serum alpha C4 ≥ 40 ng/mL or FGF19 ≤ 80 pg/mL or fecal bile acid > 2,000 µmol/48 h	Colesevelam, 1,875mg (three tablets, 625 mg each), or matching placebo (ratio 1:1), taken orally, twice daily.	IBS-D	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.	USA
	Placebo	15

Table 1. Summary of the Included Studies

References

Groups

Sample size

Design

Inclusion criteria

Regimen

Underlying GI problem

Findings

Country

RCT: randomized controlled study; BMI: body mass index; GI: gastrointestinal; CD: Crohn’s disease; BSFS: Bristol Stool Form Scale; 75SeHCAT: selenium-75-homocholic acid taurine; bid: twice daily; BAD: bile acid diarrhea; CDAI: Crohn’s disease activity index; BAM: bile acid malabsorption; IBS-D: irritable bowel syndrome with diarrhea; FGF19: fibroblast growth factor 19; BA: bile acid.

Appleby et al, 2017 [16]

Cholestyramine (1 g/day)

RCT

Men and women aged 18 - 80 years with a BMI between 18.5 and 35: 1) three stools of BSFS 5 per day on average, calculated from 7 days off therapy; 2) SeHCAT 7-day retention of < 10% (moderate or severe impairment), within the last 5 years with no change in symptoms since; 3) 21 bowel motions in the last 7 days before randomization, of which > 50% are BSFS ≥ 5; 4) macroscopically normal colonoscopy with no histological evidence of microscopic colitis within the last 5 years.

A3384 250 mg bid. or A3384 1 g bid., or placebo for 2 weeks

Serum FGF19 was suppressed, and bile acid production upregulated on conventional bile acid sequestrants, but not with A3384. This colonic-release formulation of colestyramine produced symptomatic benefit in patients with BAD.

Sweden

Cholestyramine (250 mg/day)

Placebo

Beigel et al, 2014 [17]

Colesevelam

RCT

CD patients with ≥ 3 and ≤ 15 liquid stools/day in clinical remission, defined as CD activity index (CDAI) ≤ 150 points and CRP value ≤ 1 mg/dL were eligible for the study, age ≥ 18 and ≤ 65 years, contraception in women, medication with either oral aminosalicylates, azathioprine, mercaptopurine, methotrexate, oral steroids (10 mg/day), or anti-TNF alpha antibody and cholestenone serum level of ≥ 50 ng/mL, which was centrally assessed at the screening visit.

Patients received either colesevelam (3 × 2 tablets a 625 mg/day) or identically shaped placebo (3 × 2 tablets/ day).

We found significant differences in favor for colesevelam treatment compared to placebo treatment for CD patients with BAM regarding the reduction of the number of liquid stools/day and stool consistency.

Germany

Placebo

Camilleri et al, 2020 [18]

Tropifexor (60 µg/day) - placebo

Cross over RCT

Patients with primary bile acid diarrhea, who had not used bile acid sequestrants, aged ≥ 18 years weighing ≥ 50 kg, with a history of diarrheal symptoms for at least 3 months prior to dosing, as defined by average stool frequency of ≥ 3 per day when off therapy and average stool form of > 5 on the Bristol Stool Chart; laboratory or radiological confirmation of bile acid malabsorption within the last 5 years as defined by evidence of fecal bile acid loss of ≥ 2,000 µmol/48 h with or 7-day 75SeHCAT retention of < 10%.

Tropifexor 60 µg/placebo or placebo/tropifexor 60 µg. In treatment period 1, patients received either tropifexor 60 µg or placebo orally once daily for 14 days.

Tropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhea.

USA

Placebo - tropifexor (60 µg/day)

Devarakonda et al, 2019 [19]

Colesevelam

RCT

We have demonstrated that colesevelam is an effective treatment for postoperative BAM in CD. Both colesevelam and cholestyramine were associated with a reduction in stool frequency but only colesevelam was associated with a reduction in CDAI and an improvement in quality of life.

Cholestyramine

Loperamide

Colesevelam and loperamide

Karhus et al, 2022 [20]

Liraglutide

RCT

White individuals aged 18 - 75 years with SeHCAT verified moderate-to-severe primary bile acid diarrhea (≤ 10% 7-day bile acid retention), with no diabetes, other GI diseases including CD, ileal resection, previous history of radiation to the abdomen or the pelvis, or recent or active malignancy.

Liraglutide (one daily subcutaneous injection up-titrated from 0.6 mg to 1.8 mg over 3 weeks) or colesevelam (three capsules of 625 mg twice daily) and the opposite dummy for 6 weeks.

IBS-D

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

Denmark

Colesevelam

Odunsi-Shiyanbade et al, 2010 [10]

Colesevelam

RCT

All participants had fasting plasma 7alpha-C4 (C4) levels measured to assess for underlying BAM and had serum FGF19 levels measured. Participants also completed the following questionnaires: Hospital Anxiety and Depression Scale,16 Symptom Checklist 90 (SCL-90) (somatization), and bowel function by validated daily diaries including BSFS scores.

Colesevelam HCl (625-mg tablets) and the placebo (312.5-mg capsules)

IBS-D

Sodium chenodeoxycholate in health and colesevelam in IBS-D patients have opposite effects on colonic transit and fecal parameters.

USA

Placebo

Vijayvargiya et al, 2020 [21]

Colesevelam

RCT

Females and males aged 18 - 75. An IBS diagnosis based on the Rome III criteria for at least 3 months, with onset at least 6 months previously, of recurrent abdominal pain or discomfort. Biomarkers serum alpha C4 ≥ 40 ng/mL or FGF19 ≤ 80 pg/mL or fecal bile acid > 2,000 µmol/48 h

Colesevelam, 1,875mg (three tablets, 625 mg each), or matching placebo (ratio 1:1), taken orally, twice daily.

IBS-D

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.

USA

Placebo

**Table 2.** Mechanism of Action of Colestyramine, Colesevelam, Tropifexor, Loperamide, and Liraglutide for Treatment of Bile Acid Malabsorption
Drug	Mechanism of action
Colestyramine	Cholestyramine resin adsorbs and combines with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by preventing their absorption.
Colesevelam	Colesevelam hydrochloride is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption.
Tropifexor	Activation of tropifexor inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in tropifexor as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis.
Loperamide	Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency.
Liraglutide	Through liraglutide-induced prolongation of small intestinal transit time allowing a greater degree of passive and active bile acid reabsorption through the small intestine and thereby reducing spillover of bile acids.

Table 2. Mechanism of Action of Colestyramine, Colesevelam, Tropifexor, Loperamide, and Liraglutide for Treatment of Bile Acid Malabsorption

Drug

Mechanism of action

Colestyramine

Cholestyramine resin adsorbs and combines with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by preventing their absorption.

Colesevelam

Colesevelam hydrochloride is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption.

Tropifexor

Activation of tropifexor inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in tropifexor as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis.

Loperamide

Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency.

Liraglutide

Through liraglutide-induced prolongation of small intestinal transit time allowing a greater degree of passive and active bile acid reabsorption through the small intestine and thereby reducing spillover of bile acids.