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

Abstract

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

The indications and results of the use of teduglutide in patients with short bowel

“…Apraglutide, a long-acting GLP-2 analog, is safe and effective in enhancing intestinal absorption of fluid, electrolytes, and energy, as manifested by increased urinary output [32 ▪ ,33]. Glepaglutide, another novel long-acting GLP-2 analog with fast and long duration of intestinotrophic action in animal model [34], can induce an increase in citrulline level and morphological intestinal modification, which may be potentially associated with enhanced intestinal absorption [35]. It may have the advantage of not warranting dosage adjustment in patients with renal failure [36 ▪ ].…”

From intestinal failure to transplantation: Review on the current need for transplant indications under multidisciplinary transplant programs worldwide

“…Intestinal rehabilitation continues to evolve as novel therapies emerge to support the adaptation process. Newer GLP‐2 analogs in longer acting forms will allow for more sporadic dosing 84,85 . Interestingly, these longer acting analogs have shown a different pharmacodynamic profile in animal studies, producing similar results in terms of villous height and crypt depth but also causing intestinal lengthening 86 .…”

Treatment of short bowel syndrome: Breaking the therapeutic ceiling?

“…53 These effects were explained by a prolonged GI transit and increased plasma citrulline, with increased epithelium height and crypt depth for the 10-mg dose. 54,55 Phase 3 trials to study the clinical efficacy and safety are ongoing with glepaglutide 10 mg once or twice per week vs placebo for 24 weeks and a long-term follow-up for 2 years. 56,57 Finally, substitution by four amino acids increased the half-life of apraglutide to 72 h, allowing once-weekly dosing.…”

“…Besides a reduced fecal output, increased intestinal absorption and body weight were found for the highest doses (1 and 10 mg) 53 . These effects were explained by a prolonged GI transit and increased plasma citrulline, with increased epithelium height and crypt depth for the 10‐mg dose 54,55 . Phase 3 trials to study the clinical efficacy and safety are ongoing with glepaglutide 10 mg once or twice per week vs placebo for 24 weeks and a long‐term follow‐up for 2 years 56,57 .…”