TY - JOUR

T1 - Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome

T2 - Findings from a randomized phase 2 trial

AU - Naimi, Rahim Mohammad

AU - Hvistendahl, Mark Krogh

AU - Poulsen, Steen Seier

AU - Kissow, Hannelouise

AU - Pedersen, Jens

AU - Nerup, Nikolaj Albeck

AU - Ambrus, Rikard

AU - Achiam, Michael Patrick

AU - Svendsen, Lars Bo

AU - Jeppesen, Palle Bekker

N1 - This article is protected by copyright. All rights reserved.

PY - 2023

Y1 - 2023

N2 - BACKGROUND: The pro-adaptive effects of glucagon-like peptide-2 (GLP-2) include stimulation of intestinal mucosal growth as well as intestinal blood flow and angiogenesis. We have recently reported that daily subcutaneous injections of glepaglutide, a long-acting GLP-2 analog, improved intestinal absorptive function in patients with short bowel syndrome (SBS). As secondary and exploratory endpoints, the effects of glepaglutide on intestinal morphology and perfusion are reported.METHODS: The following assessments were done in 18 patients with SBS in a randomized, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide: Plasma citrulline; Mucosa biopsies to assess changes in 1) intestinal morphology by immunohistochemistry, and 2) gene expressions associated with absorption, proliferation, and markers of tight junction integrity by quantitative polymerase chain reaction. Intestinal perfusion was assessed in stoma nipples by laser speckle contrast imaging and quantitative fluorescence angiography with indocyanine green.RESULTS: In the 1 mg and 10 mg dose groups, glepaglutide significantly increased plasma citrulline by 15.3 µmol/L (p=0.001) and 15.6 µmol/L (p=0.001), respectively. Trends towards increase in villus height, crypt depth, and epithelium height were seen in the same groups. No significant changes were seen in gene expressions or intestinal perfusion.CONCLUSION: The increase in plasma citrulline and the morphological improvements may partly account for improvement in the intestinal absorptive function. However, the finding of a stability in perfusion after three weeks of treatment with glepaglutide may have been preceded by a more profound acute-phase increase in intestinal perfusion at treatment initiation.CLINICAL RELEVANCY STATEMENT: Our findings in the present article showed that three weeks of treatment with glepaglutide, a novel long-acting glucagon-like peptide-2 analog, was associated with increased concentration of plasma citrulline, reflecting increased enterocyte mass, and morphological improvements in the remaining intestine. Glepaglutide did not significantly affect intestinal perfusion evaluated at the end of week three by quantitative fluorescence angiography with indocyanine green and Laser Speckle Contrast Imaging. Thus, glepaglutide plays a role in the restoration of intestinal structure and function which may partly account for the improvement in the intestinal absorptive function as reported previously. This article is protected by copyright. All rights reserved.

AB - BACKGROUND: The pro-adaptive effects of glucagon-like peptide-2 (GLP-2) include stimulation of intestinal mucosal growth as well as intestinal blood flow and angiogenesis. We have recently reported that daily subcutaneous injections of glepaglutide, a long-acting GLP-2 analog, improved intestinal absorptive function in patients with short bowel syndrome (SBS). As secondary and exploratory endpoints, the effects of glepaglutide on intestinal morphology and perfusion are reported.METHODS: The following assessments were done in 18 patients with SBS in a randomized, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide: Plasma citrulline; Mucosa biopsies to assess changes in 1) intestinal morphology by immunohistochemistry, and 2) gene expressions associated with absorption, proliferation, and markers of tight junction integrity by quantitative polymerase chain reaction. Intestinal perfusion was assessed in stoma nipples by laser speckle contrast imaging and quantitative fluorescence angiography with indocyanine green.RESULTS: In the 1 mg and 10 mg dose groups, glepaglutide significantly increased plasma citrulline by 15.3 µmol/L (p=0.001) and 15.6 µmol/L (p=0.001), respectively. Trends towards increase in villus height, crypt depth, and epithelium height were seen in the same groups. No significant changes were seen in gene expressions or intestinal perfusion.CONCLUSION: The increase in plasma citrulline and the morphological improvements may partly account for improvement in the intestinal absorptive function. However, the finding of a stability in perfusion after three weeks of treatment with glepaglutide may have been preceded by a more profound acute-phase increase in intestinal perfusion at treatment initiation.CLINICAL RELEVANCY STATEMENT: Our findings in the present article showed that three weeks of treatment with glepaglutide, a novel long-acting glucagon-like peptide-2 analog, was associated with increased concentration of plasma citrulline, reflecting increased enterocyte mass, and morphological improvements in the remaining intestine. Glepaglutide did not significantly affect intestinal perfusion evaluated at the end of week three by quantitative fluorescence angiography with indocyanine green and Laser Speckle Contrast Imaging. Thus, glepaglutide plays a role in the restoration of intestinal structure and function which may partly account for the improvement in the intestinal absorptive function as reported previously. This article is protected by copyright. All rights reserved.

U2 - 10.1002/jpen.2389

DO - 10.1002/jpen.2389

M3 - Journal article

C2 - 35511704

VL - 47

SP - 140

EP - 150

JO - Journal of Parenteral and Enteral Nutrition

JF - Journal of Parenteral and Enteral Nutrition

SN - 0148-6071

IS - 1

ER -