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Am J Gastroenterol
Am J Gastroenterol
AJGAST
ACG
The American Journal of Gastroenterology
0002-9270
1572-0241
Wolters Kluwer Philadelphia, PA

38668926
AJG-24-0274
10.14309/ajg.0000000000002801
00033
3
Brief Report
Efficacy and Safety of Liraglutide in Patients With an Ileal Pouch-Anal Anastomosis and Chronic High Bowel Frequency: A Placebo-Controlled, Crossover, Proof-of-Concept Study
https://orcid.org/0000-0003-4268-823X
Herfarth Hans MD, PhD, FACG 1
https://orcid.org/0000-0001-5983-2758
Long Millie D. MD, MPH, FACG 1millie_long@med.unc.edu

Hansen Jonathan J. MD, PhD 1jjhansen@med.unc.edu

https://orcid.org/0000-0001-6535-481X
Anderson Chelsea PhD 1Chelsea_Anderson@med.unc.edu

English Emily BA, MSW 1emily_english@med.unc.edu

https://orcid.org/0000-0002-9723-3876
Buse John B. MD, PhD 2jbuse@med.unc.edu

https://orcid.org/0000-0001-9894-8796
Barnes Edward L. MD, MPH, FACG 1edward_barnes@med.unc.edu

1 Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA;
2 Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina, USA.
Correspondence: Hans Herfarth, MD, PhD, FACG. E-mail: hherf@med.unc.edu.
9 2024
12 4 2024
119 9 19351938
30 1 2024
04 4 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

INTRODUCTION:

After colectomy with ileoanal pouch anastomosis (IPAA), many patients develop high bowel frequency (BF) refractory to antimotility agents, despite normal IPAA morphology. Low circulating levels of glucagon-like protein-1 (GLP-1), a modulator of gastroduodenal motility, have been reported after colectomy.

METHODS:

Double-blind crossover study of 8 IPAA patients with refractory high BF treated with daily administration of the GLP-1 receptor agonist liraglutide or placebo.

RESULTS:

Liraglutide, but not placebo, reduced daily BF by more than 35% (P < 0.03).

DISCUSSION:

Larger randomized controlled studies are warranted to delineate the treatment potential of GLP-1 receptor agonists in IPAA patients suffering from noninflammatory high BF.

KEYWORDS:

glucagon-like protein-1 receptor agonist
GLP-1
incretins
liraglutide
ileoanal pouch anastomosis (IPAA)
pouchitis
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK034987 Not ApplicableOPEN-ACCESSTRUE
SDCT
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pmcINTRODUCTION

Colectomy with Switch to Ileal pouch -anal anastomosis (IPAA) is the therapy of choice for patients with either therapy-refractory ulcerative colitis or ulcerative colitis–associated neoplasia (1). The expected daily bowel frequency (BF) in IPAA patients is around 4–8 bowel movements. However, 30%–40% of the IPAA population experience a much higher BF of 9–20 bowel movements per day, despite endoscopically normal IPAA morphology (2,3). This high BF is often associated with urgency, leakage, and incontinence, impacting the work and social life of the patients. In the absence of intestinal inflammation, the reasons for the increased BF are believed to be due to intestinal hypermotility or pouch dysmotility. However, many patients do not respond to antimotility agents such as loperamide or diphenoxylate/atropine. The pleiotropic hormone glucagon-like peptide-1 (GLP-1) is predominantly synthesized by enteroendocrine L-cells in the colon and terminal ileum (4). GLP-1 not only impacts glucose metabolism but also decreases gastroduodenal motility. Lower circulating GLP-1 levels or a delayed increase of GLP-1 after meals has been reported in patients after colectomy with IPAA or ileostomy or jejunostomy (5,6). An attenuated meal-stimulated GLP-1 secretion may be the cause for a rapid intestinal transit after colectomy with ileostomy or IPAA, and treatment with GLP-1 receptor agonist (GLP-1-RA) has been shown to normalize antroduodenal motility and to reduce the fecal wet weight (7,8).

We hypothesized that high BF in some IPAA patients is caused by decreased levels of GLP-1, leading to faster gastrointestinal transit. Therefore, we investigated the effectiveness and safety of GLP-1-RA liraglutide therapy in IPAA patients with refractory high BF.

METHODS

Between March 2022 and July 2023, patients with high BF for more than 4 weeks despite the use of antimotility agents were recruited in the pouch clinic at the University of North Carolina, Chapel Hill. After a 7-day screening period demonstrating an average daily BF of >8 bowel movements, eligible patients were included in a randomized, double-blind, placebo-controlled crossover study of therapy with either liraglutide or placebo (Figure 1). To account for daily BF variations, the patient recorded the BF each day in an electronic database, and the daily BF was then averaged over 7-day intervals. Study exclusion criteria were an endoscopic pouchitis disease activity index ≥4 (9), treatment-refractory pouch strictures, or a positive Clostridoides difficile assay. Nonresponders, defined as ≤15% decrease in BF in a treatment period, could crossover or terminate early at week 4 or 10, respectively. The study's primary endpoint was a 30% reduction of BF at week 4 or 10 compared with baseline; secondary endpoints were a reduction of BF at week 6 or 12 and tolerability and safety of liraglutide. Stool calprotectin concentrations were determined at baseline and weeks 2, 4, and 6, in each treatment period (Mayo Clinic Laboratories, Rochester, MN). Because of an interruption in the manufacturing of the placebo drug supply, the study was terminated early after 8 of 10 patients were included in the study. Statistical analyses were performed using a repeated-measures mixed model (see Supplementary Methods, Supplementary Digital Content 1, http://links.lww.com/AJG/D248). Data are reported as mean ± SD. Liraglutide and placebo pens were provided by Novo Nordisk, Bagsvaerd, Denmark. The University of North Carolina Institutional Review Board at Chapel Hill approved the study (NCT04763564).

Figure 1. Placebo-controlled, double-blind crossover study with 2 separate 6-week treatment periods with either liraglutide or placebo. Liraglutide or placebo was titrated weekly to 1.8 mg/d at week 3 and then continued at this dose. Given a half-life of 11–12 hours of liraglutide, a washout period of 5 days equal to 10 half-lives occurred between the 2 treatment periods (4). Patients not achieving a reduction in average daily bowel frequency (BF; measured as an average of 7 days of daily bowel frequency recordings) of at least 15% at week 4 or week 10 could crossover early after a 5-day washout period after week 4 to treatment period 2 or terminate the study early at week 10. BF, average daily bowel frequency, measured as an average of 7 days of daily bowel frequency recordings; Eval, evaluation of daily bowel frequency and assessment of adverse events.

RESULTS

Eight patients with a baseline BF of 12.1 ± 3.1 completed the study (Table 1); of these, 4/8 (50%) terminated the placebo treatment period early vs 1/8 (13%) on liraglutide. Liraglutide treatment significantly decreased BF starting at week 2 vs a nearly stable BF during placebo treatment (Figure 2). On liraglutide therapy, the BF compared with baseline declined by −4.6 ± 2.8 bowel movements/day (−36.3% ± 19.8%) at week 4 compared with −2.1 ± 2.2 bowel movements/day (−17.3% ± 15.7%) on placebo (P < 0.03). At week 6 on liraglutide therapy, the BF compared with baseline declined by −4.8 ± 2.7 bowel movements/day (−36.8% ± 18.7%) vs a decrease of −2.0 ± 1.9 bowel movements/day (−15.7% ± 5.3%) on placebo (P < 0.01). The reduction in BF was more pronounced during the day than at night (see Supplementary Table 1, Supplementary Digital Content 1, http://links.lww.com/AJG/D248). The proportion of patients reporting at least a 30% decrease in BF at week 6 was 6/8 (75%) patients on liraglutide vs 2/8 (25%) on placebo (P < 0.05). The most frequently observed side effect was nausea (n = 5 liraglutide vs n = 2 placebo) (see Supplementary Table 2, Supplementary Digital Content 1, http://links.lww.com/AJG/D248). Calprotectin values remained stable compared with screening and baseline values during placebo or liraglutide therapy (see Supplementary Figure 1, Supplementary Digital Content 1, http://links.lww.com/AJG/D248).

Table 1. Demographics of the study patients (6 F, 2 M; median age 51 [42–65], baseline average daily bowel frequency [mean ± SD], and endoscopic and clinical pouch activity index [PDAI])

Figure 2. Average daily bowel frequency (BF; measured as an average of 7 days of daily bowel frequency recordings) on either liraglutide or placebo compared with baseline. The dotted line represents a BF of 8 per day. The BF of nonresponders who terminated the treatment period early because of a lack of decrease of BF of at least 15% at week 4 or week 10 was carried forward.

DISCUSSION

This proof-of-concept study demonstrates that liraglutide significantly reduces the average BF in a heterogenous group of IPAA patients with noninflammatory refractory high BF by more than 35% compared with a nonsignificant decrease on placebo therapy. Although most patients on placebo terminated the treatment period early, only one patient on liraglutide had no response to therapy. On a per-patient basis, 75% of the included patients on liraglutide treatment achieved a 30% reduction by week 6.

Two previous small studies in patients with ileostomies or short bowel syndrome suggested a clinically beneficial effect of a GLP-1-RA therapy, decreasing fecal output and increasing intestinal fluid absorption (8,10,11). Similar to our findings, these previous studies reported that not all patients respond to GLP-1-RA therapy, indicating that the etiology of the high BF in IPAA patients with no significant associated mucosal inflammation is not solely due to lower levels of circulating GLP-1 levels. Alterations in bile acid metabolism may also play a pathophysiological role, and liraglutide has been shown to successfully resolve chronic bile acid diarrhea potentially by increasing bile acid absorption (12–14).

Liraglutide therapy seemed safe, with only nausea occurring more frequently on liraglutide therapy than placebo. We did not observe worsening diarrhea, a reported adverse event in diabetic patients with a colon in continuity on GLP-1-RA therapy (15). Given the overall acceptable safety profile of a GLP-1-RA therapy, this treatment has the potential to improve the quality of life for IPAA patients with high bowel frequency by re-establishing the neuroendocrine “brake mechanism,” which may be weakened after colectomy (6). The significant findings of this pilot study and the clinical need for novel treatments for noninflammatory high BF in patients with IPAA justify larger prospective randomized studies using liraglutide or other longer-acting GLP-1-RAs.

CONFLICTS OF INTEREST

Guarantor of the article: Hans Herfarth, MD, PhD, FACG.

Specific author contributions: H.H.: conceptualization and execution of the study, analysis and interpretation of data, and drafting of manuscript. M.D.L.: recruitment of patients, analysis and interpretation of data, and critically reviewed the manuscript for intellectual content and accuracy. J.J.H.: recruitment of patients, analysis, and critically reviewed the manuscript for intellectual content and accuracy. C.A.: statistical analyses. E.E.: coordination of study sites, supervision of data collection, and revised and critically reviewed the manuscript for intellectual content and accuracy. J.B.B.: conceptualization of the study, analysis and interpretation of data, and critically reviewed the manuscript for intellectual content and accuracy. E.L.B.: conceptualization of the study, analysis, and critically reviewed the manuscript for intellectual content and accuracy.

Financial support: This study was supported in part by a Novo Nordisk research grant from the Novo Nordisk (NNI) Investigator Sponsored Studies Program. The opinions in this article are those of the authors and do not necessarily represent the opinion of Novo Nordisk. This research was supported, in part, by grants from the National Institutes of Health P30DK034987.

Potential competing interests: H.H.: consultant for Alivio, AMAG, BMS, Boehringer, ExeGI, Finch, Fresenius Kabi, Galapagos, Gilead, Janssen, Lycera, Merck, Otsuka, Pfizer, PureTech, Seres, and Ventyx and research support from Artizan Biosciences, Allakos, Novo Nordisk, and Pfizer. M.D.L.: consultant for AbbVie, Takeda, Janssen, Pfizer, Lilly, Genentech, Roche, BMS, Target RWE, and Prometheus and has received research support from Pfizer, Takeda, and Lilly. J.J.H., C.A., and E.E.: no conflict of interest. J.B.B.: grant support from Bayer, Boehringer-Ingelheim, Carmot, Corcept, Dexcom, Eli Lilly, Insulet, MannKind, Novo Nordisk, and vTv Therapeutics; consulting contracts from Alkahest, Altimmune, Anji, Aqua Medical, AstraZeneca, Boehringer-Ingelheim, CeQur, Corcept Therapeutics, Eli Lilly, embecta, Fortress Biotech, GentiBio, Glyscend, Insulet, Mellitus Health, Metsera, Moderna, Novo Nordisk, Pendulum Therapeutics, Praetego, Stability Health, Tandem, Terns, and Vertex; expert witness engagement by Medtronic MiniMed and Novo Nordisk; and stock options from Glyscend, Mellitus Health, Pendulum Therapeutics, Praetego, and Stability Health. E.L.B.: consultant for AbbVie, Lilly, and Target RWE.

Supplementary Material

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/D248
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REFERENCES

1. Rubin DT Ananthakrishnan AN Siegel CA . ACG clinical guideline: Ulcerative colitis in adults. Am J Gastroenterol 2019;114 (3 ):384–413.30840605
2. Shen B Achkar JP Lashner BA . Irritable pouch syndrome: A new category of diagnosis for symptomatic patients with ileal pouch-anal anastomosis. Am J Gastroenterol 2002;97 (4 ):972–7.12003434
3. Santiago P Barnes EL Raffals LE . Classification and management of disorders of the j pouch. Am J Gastroenterol 2023;118 (11 ):1931–9.37252759
4. Knudsen LB Lau J . The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne) 2019;10 :155.31031702
5. Palnaes Hansen C Andreasen JJ Holst JJ . The release of gastric inhibitory peptide, glucagon-like peptide-I, and insulin after oral glucose test in colectomized subjects. Scand J Gastroenterol 1997;32 (5 ):473–7.9175210
6. Robertson MD Livesey G Morgan LM . The influence of the colon on postprandial glucagon-like peptide 1 (7–36) amide concentration in man. J Endocrinol 1999;161 :25–31.10194525
7. Madsen KB Askov-Hansen C Naimi RM . Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study. Regul Pept 2013;184 :30–9.23511332
8. Kunkel D Basseri B Low K . Efficacy of the glucagon-like peptide-1 agonist exenatide in the treatment of short bowel syndrome. Neurogastroenterol Motil 2011;23 (8 ):739–e328.21557790
9. Shen B Achkar JP Connor JT . Modified pouchitis disease activity index: A simplified approach to the diagnosis of pouchitis. Dis Colon Rectum 2003;46 (6 ):748–53.12794576
10. Hvistendahl M Brandt CF Tribler S . Effect of liraglutide treatment on jejunostomy output in patients with short bowel syndrome: An open-label pilot study. JPEN J Parenter Enteral Nutr 2018;42 (1 ):112–21.27875281
11. Jeppesen PB . Gut hormones in the treatment of short-bowel syndrome and intestinal failure. Curr Opin Endocrinol Diabetes Obes 2015;22 (1 ):14–20.25485516
12. Karhus ML Brønden A Forman JL . 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 ):922–31.35868334
13. Karhus ML Brønden A Røder ME . Remission of bile acid malabsorption symptoms following treatment with the glucagon-like peptide 1 receptor agonist liraglutide. Gastroenterology 2019;157 (2 ):569–71.30965026
14. Sinha SR Haileselassie Y Nguyen LP . Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 2020;27 (4 ):659–70.e5.32101703
15. Bettge K Kahle M Abd El Aziz MS . Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials. Diabetes Obes Metab 2017;19 (3 ):336–47.27860132
