Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial.

BACKGROUND: The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS). METHOD: In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry. RESULTS: Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (-169, -28; p = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased. CONCLUSION: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with short bowel syndrome and colon in continuity: an open-label pilot study.

OBJECTIVE: Patients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group. DESIGN: In an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment. RESULTS: Of the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (-174 g/day (-1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day. CONCLUSION: Following this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.

Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome: Findings From a Randomized Trial.

BACKGROUND: Patients with short bowel syndrome (SBS) and distal-bowel resections lack neuroendocrine feedback regulations, potentially resulting in rapid gastrointestinal (GI) transit. The objective was to assess the efficacy of glepaglutide, a long-acting glucagon-like peptide-2 analog, on GI transit in patients with SBS. METHODS: In this single-center, double-blind, dose-finding, phase 2 trial, patients with SBS were randomly assigned to 3 treatments (0.1, 1, and 10 mg) in a 2-period crossover design. Each treatment period included 3 weeks of daily, subcutaneous glepaglutide injections separated by a washout period of 4-8 weeks. Endpoints were changes from baseline and included scintigraphy, wireless motility capsule (WMC, SmartPill Given Imaging, Ltd, Yokneam, Israel), and paracetamol absorption test. RESULTS: A total of 18 patients were randomized. In the 10-mg dose group (n = 9), glepaglutide significantly increased time to 10% gastric emptying (GE) of solids by 27 (4-50) minutes (adjusted mean [95% CI]), time to 50%GE of fluids by 40 (1-80) minutes, and time to 10% small bowel-emptying of solids by 21 (1-41) minutes. The WMC transit did not significantly change in any of the dose groups. The maximum paracetamol concentration significantly increased in the 10-mg dose group; however, the area under the curve remained the same. CONCLUSION: The prolonged GI transit after glepaglutide treatment, along with demonstrated positive effects on intestinal mucosal growth and potential effects on GI hypersecretions, is believed to contribute to the observed beneficial effects on fecal output (primary endpoint) and associated improvement in intestinal absorption.

Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome: findings from a randomised phase 2 trial.

BACKGROUND: With the introduction of glucagon-like peptide-2 (GLP-2) in the treatment of short bowel syndrome (SBS), there is emerging evidence that GLP-2 may play a role in the restoration of the disturbed homeostatic feedback in the gut-liver axis and may ameliorate SBS-associated liver damage. We have previously presented that daily subcutaneous injections with 1 and 10 mg of glepaglutide improved intestinal function in patients with SBS. As exploratory endpoints, we here assessed the effect of glepaglutide on liver function. METHODS: Liver tests, transient elastography (TE) with controlled attenuation parameter (CAP), indocyanine green (ICG) kinetics, soluble CD163 (sCD163), soluble mannose receptor (sMR), and lipopolysaccharide binding protein (LBP) were assessed in 18 patients with SBS in a randomised, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide. This trial is completed and registered at ClinicalTrials.gov: NCT02690025. FINDINGS: Between Feb 2016 and Jan 2017, 22 patients with SBS were screened. Of these, 18 patients were randomised and treated with glepaglutide; 16 patients completed the trial. Treatment with glepaglutide was associated with increase in TE and ICG-elimination. In the 10 mg dose group, glepaglutide increased sCD163 by 0·44 mg/mL (P = 0·0498), and alkaline phosphatase (ALP) decreased in the 1 mg dose group by 33 U/L (P = 0·032). CAP, sMR, LBP, liver transaminases, and INR were not affected. INTERPRETATION: Glepaglutide may improve hepatic excretory function, but at the same time activate resident liver macrophages and increase liver stiffness. The excretory and the stiffness findings may to some extent relate to increased splanchnic blood flow which would not influence the marker of macrophage activation. Thus, glepaglutide exerted diverse effects on liver status that call for attention in future studies. FUNDING: Zealand Pharma.

Effect of Liraglutide Treatment on Jejunostomy Output in Patients With Short Bowel Syndrome: An Open-Label Pilot Study.

BACKGROUND: An impaired hormonal "ileo-colonic brake" may contribute to rapid gastric emptying, gastric hypersecretion, high ostomy losses, and the need for parenteral support in end-jejunostomy short bowel syndrome (SBS) patients with intestinal failure (IF). Liraglutide, a glucagon-like peptide 1 receptor agonist, may reduce gastric hypersecretion and dampen gastric emptying, thereby improving conditions for intestinal absorption. MATERIALS AND METHODS: In an 8-week, open-label pilot study, liraglutide was given subcutaneously once daily to 8 end-jejunostomy patients, aged 63.4 ± 10.9 years (mean ± SD) and with small bowel lengths of 110 ± 66 cm. The 72-hour metabolic balance studies were performed before and at the end of treatment. Food intake was unrestricted. Oral fluid intake and parenteral support volume were kept constant. The primary end point was change in the ostomy wet weight output. RESULTS: Liraglutide reduced ostomy wet weight output by 474 ± 563 g/d from 3249 ± 1352 to 2775 ± 1187 g/d (P = .049, Student t test). Intestinal wet weight absorption tended to increase by 464 ± 557 g/d (P = .05), as did urine production by 765 ± 759 g/d (P = .02). Intestinal energy absorption improved by 902 ± 882 kJ/d (P = .02). CONCLUSION: Liraglutide reduced ostomy wet weight output in end-jejunostomy patients with SBS-IF and increased their intestinal wet weight and energy absorption. If larger, randomized, placebo-controlled studies confirm these effects, it adds to the hypothesis that many ileo-colonic brake hormones in conjunction may be involved in the process of intestinal adaptation. By identification of key hormones and addressing their potential synergistic effects, better treatments may be provided to patients with SBS-IF. This trial was registered at clinicaltrialsregister.eu as 2013-005499-16.