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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

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@article{421de8508f1e4adc8e97c719ddba4461,
title = "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",
abstract = "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.",
keywords = "Aged, Biomarkers, Denmark, Elasticity Imaging Techniques, Female, Glucagon-Like Peptide 2/pharmacology, Humans, Liver/diagnostic imaging, Male, Middle Aged, Short Bowel Syndrome/diagnosis, Treatment Outcome",
author = "Naimi, {Rahim Mohammad} and Mark Hvistendahl and Nikolaj Nerup and Rikard Ambrus and Achiam, {Michael Patrick} and Svendsen, {Lars Bo} and Henning Gr{\o}nb{\ae}k and M{\o}ller, {Holger Jon} and Hendrik Vilstrup and Adam Steensberg and Jeppesen, {Palle Bekker}",
note = "Copyright {\circledC} 2019 The Authors. Published by Elsevier B.V. All rights reserved.",
year = "2019",
month = "8",
doi = "10.1016/j.ebiom.2019.07.016",
language = "English",
volume = "46",
pages = "444--451",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome

T2 - findings from a randomised phase 2 trial

AU - Naimi, Rahim Mohammad

AU - Hvistendahl, Mark

AU - Nerup, Nikolaj

AU - Ambrus, Rikard

AU - Achiam, Michael Patrick

AU - Svendsen, Lars Bo

AU - Grønbæk, Henning

AU - Møller, Holger Jon

AU - Vilstrup, Hendrik

AU - Steensberg, Adam

AU - Jeppesen, Palle Bekker

N1 - Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

PY - 2019/8

Y1 - 2019/8

N2 - 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.

AB - 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.

KW - Aged

KW - Biomarkers

KW - Denmark

KW - Elasticity Imaging Techniques

KW - Female

KW - Glucagon-Like Peptide 2/pharmacology

KW - Humans

KW - Liver/diagnostic imaging

KW - Male

KW - Middle Aged

KW - Short Bowel Syndrome/diagnosis

KW - Treatment Outcome

U2 - 10.1016/j.ebiom.2019.07.016

DO - 10.1016/j.ebiom.2019.07.016

M3 - Journal article

VL - 46

SP - 444

EP - 451

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -

ID: 59085445