Introduction

Bile acid diarrhoea is a common cause of chronic watery diarrhoea. Recent randomised studies have demonstrated the effect of the sequestrant colesevelam and the glucagon-like peptide-1 analogue, liraglutide (1, 2). The colesevelam dose was titrated to effect, while liraglutide was increased to the maximum dose of 1.8 mg daily. No therapeutic guidelines have incorporated these findings, and the optimal dosing is not settled.

Aims & Methods

We aimed to describe the effect of second-line treatment with liraglutide with pragmatic dose-escalation on remission of bile acid diarrhoea refractory to sequestrant therapy.
From the 1^st of April 2022 to the 3^rd of March 2023, patients with bile acid diarrhoea either diagnosed by SeHCAT retention of less than 15% or by a history of small bowel resection were included from our outpatient clinic. The patients were either intolerant to or had treatment failure of sequestrants (colestyramine and/or colesevelam) and fulfilled the Hjortswang diarrhoea criteria (3 or more stools or 1 or more watery stool per day). Diary-recorded bowel habits were evaluated by the mean daily total number and the daily mean number of watery stools (Bristol stool chart type 6 and 7). A dose of 0.6 mg/day liraglutide was initiated at baseline. Patients were evaluated every two to three weeks; patients without remission and no significant adverse events had the dose increased in increments of 0.6 mg/day liraglutide, possibly to a maximum dose of 1.8 mg/day liraglutide. Remission was defined as a daily mean of < 1 watery bowel movement and < 3 total bowel movements. The total number of bowel movements and the number of watery bowel movements were log-normally distributed. Geometric means of the baseline were compared with values at the final treatment dose using paired t-test. Clopper-pearson’s confidence interval was used for the binary remission data.

Results

A total of 27 patients were included, of whom 19 (70%) were female and the mean weight at baseline was 93 kilograms (range 58-183).
Twenty-one (78%) were diagnosed by SeHCAT testing (median retention value 4%, range 0-11%), while six (22%) were diagnosed by a history of bowel resection, four of whom were due to Crohn’s disease. Three patients had a history with cholecystectomy and six patients had a concurrent diagnosis of microscopic colitis.
In total 15 (56%) of the 27 patients achieved remission. Five patients had 0.6 mg/day liraglutide as the final dose, with four achieving remission; seven of nine achieved remission at 1.2 mg, and 4 of 13 patients on the maximum dose of 1.8 mg. Two patients not in remission on 1.8 mg liraglutide/day obtained remission with the addition of colestyramin 4 g once daily.
The geometric mean total bowel movements at baseline of 6.5 (95% CI, 5.1-8.3) was reduced to 2.8 (95% CI, 2.2-3.5) at the end of follow up (p < 0.0001). The geometric mean number of watery bowel movements at baseline of 5.1 (95% CI, 3.7-7.0) was reduced at end of follow up to 0.8 (95% CI, 0.6-1.1, p < 0.0001).

Conclusion

Second-line liraglutide with pragmatic dose-escalation achieved remission in 15 of 27 patients with bile acid diarrhoea intolerant or with insufficient treatment response to conventional sequestrants. Of the 15 in remission, 11 did not need maximum liraglutide dosing. Proper diagnosis of bile acid diarrhoea is needed to enable second-line therapy.

References

1. Karhus ML, Bronden A, Forman JL, Haaber A, Knudsen E, Langholz E, et al. Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial. Lancet Gastroenterol Hepatol. 2022;7(10):922-31.
2. Borup C, Vinter-Jensen L, Jørgensen SPG, Wildt S, Graff J, Gregersen T, et al. Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial. The Lancet Gastroenterology & Hepatology. 2023;8(4):321-31.

Introduction

Coexistence of bile acid diarrhoea (BAD) and microscopic colitis (MC) has been described (1), and treating this with sequestrants could reduce the need for budesonide. Fasting plasma 7α-hydroxy-4-cholesten-3-one (C4) values >46 ng/mL are specific for BAD but sensitivity is only 47% (37-57%) compared with tauroselcholic [75-Se]
acid (SeHCAT) retention <10% (2). C4 values between 33 and 46 are in a diagnostic grey zone. Budesonide directly affects the bile acid homeostasis making the temporal relation between treatment and testing important. Fortunately, unlike SeHCAT testing, C4 may be sampled immediately when a patient presents with a flare of MC.

Aims & Methods

To assess the prevalence of coexisting BAD in patients with active MC.
Consequtive patients with MC and a flare fulfilling the Hjortswang diarrhoea criteria (≥3 stools or ≥1 watery stool per day) and a negative test for infectious diarrhoea were included. Patients were treated with budesonide 9 mg once daily for 6 weeks. Clinical assessment, Bristol stool charts, and fasting C4 were obtained at baseline, during the last treatment week and 4 weeks after end of treatment. Remission was defined as a daily mean of <1 watery bowel movement and <3 total bowel movements [EudraCT: 2019-002762-12].

Results

49 patients were included; 26 (53%) with collagenous colitis. Mean age was 60 (range 55-70) years, 22% current smoker, none on NSAIDs. Six (12%; 95%CI: 5–25%) of 49 patients had BAD diagnosed by C4. Another 3 patients had grey zone C4 values. Mean C4 did not change during budesonide treatment, 22 and 23 ng/mL at baseline and at week 6, respectively. SeHCAT was performed outside the study in 26 patients of whom 3 had retention of <10% and 6 of <15%. The mean total number of stools per day declined from baseline 7.9 to 1.9 and watery stools from 3.7 to 0.3 during budesonide treatment. Remission was obtained in 45. Twenty-nine had relapsed four weeks after end of budesonide treatment, 5 of 6 (83%; 95%CI: 36–100%) with MC and BAD, and 24 of 43 (56%; 95%CI: 40–71%) with MC and not BAD.

Conclusion

During an inflammatory flare of MC, 12% (5–25%) had C4-defined BAD. However, C4 only identifies about half of patients with BAD compared with the diagnostic gold standard SeHCAT, meaning about 25% of patients with MC could have coexisting BAD. Screening for BAD may have merit in MC patients with relapse of diarrhoea after budesonide treatment.

References

1 Bjørnbak C, Engel PJH, Nielsen PL, Munck LK. Microscopic colitis: clinical findings, topography, and persistence of histopathological subgroups. Aliment Pharmacol Ther. 2011, 34: 1225-34.
2. Borup C, Vinter-Jensen L, Jørgensen SPG, Wildt S, Graff J, Gregersen T, Zaremba A, Andersen TB, Nøjgaard C, Timm HB, Lamazière A, Rainteau D, Hansen SH, Rumessen JJ, Munck LK. Prospective comparison of diagnostic tests for bile acid diarrhoea. Aliment Pharmacol Ther. 2024; 59: 39-50.

Disclosure

Budesonide was donated for study use by Tillotts Pharma as an unrestricted scientific grant. Tillotts Pharma had no influence on the planning, conduct, or reporting of the study.

Introduction

SBS-IF is a severe organ failure with long-term parenteral support (PS) dependence. GLP-2 stimulates intestinal adaptation resulting in increased absorptive capacity. Apraglutide (APRA) is a novel long-acting GLP-2 analog in development for SBS-IF. This multicenter, open-label, phase 2 study in SBS-IF-CiC aims to investigate the safety and clinical efficacy of APRA at 52 weeks (W).

Aims & Methods

STARS Nutrition is a 52W open-label study in 9 adult SBS-IF–CiC pts receiving once-weekly subcutaneous APRA injections (5 mg). Metabolic balance studies were performed at baseline and 4W with stable PS, followed by a 48-W PS adjustment period. During monthly 48-hour fluid balance assessments, oral fluid intake was kept constant by adhering to an individual predefined drinking menu while measuring urine volume. PS was reduced according to an algorithm if an increase in mean daily urinary output of ≥10% was observed. As part of patient-reported outcomes (PRO), Patient Global Impression of Change (PGIC) v2.0 (5-point verbal response scale from 2= much better to -2= much worse) was used to assess overall change in pts’ status since APRA use. Safety was the primary endpoint. Secondary endpoints included changes in weekly PS volume, energy content, and PS days, proportion of clinical responders (≥20% PS reduction) and changes in PGIC at 52W. Data are presented as mean (95% CI) unless otherwise specified. Nominal p-values are calculated using paired T-tests with significance set at 0.05.

Results

APRA had an acceptable safety profile. All pts experienced ≥1 adverse event (AE); a total of 127 AEs were reported. Three pts experienced serious AEs. APRA was interrupted for 1 week in one pt with acute cholangitis and restarted successfully to trial completion. Absolute weekly PS volume decreased significantly by -4702 (-6539 to -2865) mL/week representing a 52% reduction from baseline (p=0.0004). Accordingly, PS energy content significantly decreased by -3510 (-4991 to -2029) kcal/week (p=0.0006). All pts qualified as clinical responders. Seven pts (78%) achieved ≥1 day off PS of whom two pts (22%) reached enteral autonomy. Pts gained an additional 2.1 (0.7–3.6) days off per week. Total body and lean body weight; and daily urine output remained stable despite PS reductions. All pts experienced a subjective improvement of their general condition based on the PGIC: eight pts reported a score of 2 (much better) and one pt reported a score of 1 (little better).

Conclusion

STARS Nutrition prospectively shows evidence for clinical benefit of a long-acting GLP-2 analog in SBS-IF–CiC. APRA has an acceptable safety profile and is associated with significant reductions in PS needs in pts with SBS-IF–CiC resulting in days without PS and subjective improvement based on PRO.

Disclosure

Astrid Verbiest, Mark Krogh Hvistendahl – nothing to declare.
Palle Bekker Jeppesen – received grants/research support/honoraria or consultation fees from Agomab, Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast, Ferring, Fresenius Kabi, GLyPharma, Naia Pharma, NPS Pharmaceuticals, NorthSea Therapeutics, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectivBio and Zealand Pharma.
Francisca Joly – has received grants/research support/honoraria or consultation fees from Agomab, Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile3e Consulting, Carembouche, NPS Pharmaceuticals, NorthSea Therapeutics, Shire, Takeda, Therachon, VectivBio and Zealand Pharma.
Tim Vanuytsel – has served on the speaker bureau for Abbott, Agomab, Baxter, Biocodex, Dr. Falk Pharma, Fresenius Kabi, Ipsen, Menarini, Microbiotica, MyHealth, Remedus, Takeda, Truvion, VectivBio and Zealand Pharma. TV has provided clinical advice to Baxter, Danone, Dr. Falk Pharma, MyHealth, NorthSea Therapeutics, Shire, Therachon, Takeda, VectivBio, Zealand Pharma. TV has received research grants from Danone, MyHealth, Takeda and VectivBio.
Federico Bolognani, Carrie Li and Nader N. Youssef – employees of VectivBio/Ironwood.
This research was supported by VectivBio AG/Ironwood.

Introduction

SBS-IF is a severe organ failure with long-term parenteral support (PS) dependence. GLP-2 stimulates intestinal adaptation resulting in increased absorptive capacity. Apraglutide (APRA) is a novel, long-acting GLP-2 analog in development for SBS-IF. This study investigated the safety and efficacy of APRA in patients with SBS-IF and CiC.

Aims & Methods

STARS Nutrition is a 52-Week (W) multicenter, open-label, phase 2 study in 9 adult SBS-IF-CiC patients (pts) receiving weekly subcutaneous APRA injections (5mg). 72-h metabolic balance studies (MBS) were performed at baseline (BL), 4W and 48W; with stable PS at BL and 4W. During MBS, oral fluid intake was kept constant by adhering to an individual predefined drinking menu. Duplicates of meals and fluids (wet weight intake) were collected as well as urine and feces (fecal wet weight output). Pts were advised to keep oral food intake at 4W similar to BL, but not at 48W to explore the effect of APRA on spontaneous dietary intake. Safety was the primary endpoint. Secondary endpoints included changes in wet weight, energy and macronutrient absorption at 4W and 48W. Data are presented as mean (95% CI) unless specified otherwise. Nominal p-values are calculated using paired T-tests with significance set at 0.05.

Results

Small bowel length was 19 (range 0-50) cm and median estimated residual colon was 79 (range 43-100) %. At BL, pts received a PS volume of 10 (range 4-21) L/W. APRA had an acceptable safety profile. At 4W, fecal output reduced significantly by 253 (68 – 437) g/day (p=0.013); resulting in a trend to increased wet weight absorption of 256 (-9 – 520) g/day (p=0.057) while energy absorption remained unaltered. At 48W, pts significantly increased their overall wet weight intake (p=0.047), carbohydrate (p=0.042) and nitrogen intake (p=0.024) resulting in a significantly increased energy intake (p=0.027). Fecal wet weight output remained constant despite the increased oral intake. There was a significant increase in wet weight absorption by 316 (21 – 611) g/day (p=0.039), energy absorption by 1134 (58 – 2210) kJ/day (p=0.041) and carbohydrate absorption by 56.1 (8.8 – 94.3) g/day (p= 0.024). Urine output and body weight remained stable throughout the study.

Conclusion

The STARS Nutrition MBS findings confirm the role of the colon in energetic recovery of carbohydrates and maintenance of the fluid balance in SBS-IF-CiC. In pts with SBS-IF-CiC, APRA treatment resulted in an early reduced fecal output and improved wet weight absorption. After 48 weeks, oral intake was increased despite stable fecal output, leading to increased energy and carbohydrate absorption.

Disclosure

Astrid Verbiest, Mark Krogh Hvistendahl – nothing to declare.
Palle Bekker Jeppesen – received grants/research support/honoraria or consultation fees from Agomab, Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast, Ferring, Fresenius Kabi, GLyPharma, Naia Pharma, NPS Pharmaceuticals, NorthSea Therapeutics, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectivBio and Zealand Pharma.
Francisca Joly – has received grants/research support/honoraria or consultation fees from Agomab, Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile3e Consulting, Carembouche, NPS Pharmaceuticals, NorthSea Therapeutics, Shire, Takeda, Therachon, VectivBio and Zealand Pharma.
Tim Vanuytsel – has served on the speaker bureau for Abbott, Agomab, Baxter, Biocodex, Dr. Falk Pharma, Fresenius Kabi, Ipsen, Menarini, Microbiotica, MyHealth, Remedus, Takeda, Truvion, VectivBio and Zealand Pharma. TV has provided clinical advice to Baxter, Danone, Dr. Falk Pharma, MyHealth, NorthSea Therapeutics, Shire, Therachon, Takeda, VectivBio, Zealand Pharma. TV has received research grants from Danone, MyHealth, Takeda and VectivBio.
Federico Bolognani, Carrie Li and Nader N. Youssef – employees of VectivBio/Ironwood.
This research was supported by VectivBio AG/Ironwood.