Effects of glepaglutide, a long‐acting glucagon‐like peptide‐2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial

BACKGROUND: The proadaptive 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 end points, 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, crossover, dose‐finding, phase 2 trial before and after three weeks of treatment with glepaglutide: plasma citrulline and 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‐ 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 toward an 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.