Durability of Linear Small‐Intestinal Growth Following Treatment Discontinuation of Long‐Acting Glucagon‐Like Peptide 2 (GLP‐2) Analogues

Abstract

Background: Short-bowel syndrome is the leading cause of pediatric intestinal failure, resulting in dependency on long-term parenteral nutrition (PN). To promote enteral autonomy in neonates, a key outcome may be intestinal growth in length. The purpose of this study was to determine if intestinal lengthening persists following discontinuation of treatment with 1 of 2 GLP-2 analogues with different pharmacokinetic profiles. Methods: Neonatal short-bowel piglets were assigned to saline control (S), 7-day treatment with teduglutide (T) (0.05 mg/kg twice daily), or 7-day treatment with apraglutide (A) (5 mg/kg twice weekly). Comparisons were made between day 7 and day 14 endpoints using analysis of variance. Data included small-intestine length, weight, histology, and quantitative polymerase chain reaction analysis of mucosal transcripts for peptide growth factors and their receptors, nutrient transporters, and tight-junction proteins. Results: Compared with control, 7 days of GLP-2 analogue treatment induced mucosal adaptation based on villus hyperplasia (P = .003), which was not durable 7 days after treatment cessation (day 14; P = .081). Treatment increased intestinal growth in length by day 7 (P = .005), which was maintained (by T) or further increased (by A) at day 14 (P < .001). No significant differences in mucosal transcripts were detected. Conclusion: Unlike mucosal adaptation, intestinal growth appears to be a lasting outcome of treatment with long-acting GLP-2 analogues in a neonatal piglet short-bowel model. This has significant clinical implications for neonates, given their potential for intestinal growth. Intestinal lengthening varies between analogues with different half-lives; however, molecular mechanisms require further elucidation.

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“…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 . It has been hypothesized that producing additional length may be a more durable effect and allow for discontinuation of the medication once enteral autonomy has been achieved.…”

“…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 It has been hypothesized that producing additional length may be a more durable effect and allow for discontinuation of the medication once enteral autonomy has been achieved. This is contrary to teduglutide, which has traditionally been considered lifelong therapy in those who respond.…”

Glucagon-like peptide-2 analogues for Crohn’s disease patients with short bowel syndrome and intestinal failure

“…These two molecules apparently showed similar results in this case: Intestinal growth appeared to be a lasting outcome of treatment with long-acting GLP-2 and persisted for at least 7 d after discontinuation. In contrast, mucosal hypertrophy appeared to regress 7 d after the end of treatment with both agents[ 80 ]. However, these results must be interpreted with caution and need further confirmation.…”