Beyond intestinal failure: Expanding therapeutic frontiers of glucagon-like peptide-2 in gastrointestinal disease

Table 1 Summary of clinical and experimental studies on glepaglutide in short bowel syndrome

Ref.	Design/population	Intervention and dose	Duration	Key findings	Main outcomes/notes
Hvistendahl et al[22]	Randomized, double-blind, phase 2 crossover trial (n = 18 SBS patients with distal resections)	Daily glepaglutide 0.1 mg, 1 mg, or 10 mg	3 weeks per dose (with washout)	Dose-dependent delay in gastric emptying and small-bowel transit (scintigraphy)	Prolonged nutrient exposure; improved absorption potential; scintigraphy most sensitive to gastrointestinal transit changes
Agersnap et al[23]	Phase 1 study in healthy volunteers	SC 5 or 10 mg weekly × 6 weeks; single IV 1 mg dose	6 weeks	Sustained plasma exposure via active metabolites (M1, M2); half-life 88-124 hours	Supports once- or twice-weekly dosing; increased plasma citrulline (increased enterocyte mass); mild injection-site reactions only
Naimi et al[24]	Randomized, cross-over phase 2 trial (n = 18 SBS patients)	Daily glepaglutide 0.1 mg, 1 mg, or 10 mg	3 weeks	10 mg improved hepatic excretory function (increased ICG clearance, decreased retention)	Suggests benefit in IFALD; mild macrophage activation (increased soluble CD163); no major safety issues
Vanuytsel et al[25]	International real-world survey (19 intestinal failure centers)	Clinical use of GLP-2 analogues (mainly teduglutide, some glepaglutide)	Cross-sectional	Approximately 30% eligible; approximately 10% treated due to cost barriers; early initiation common	Mean PS reduction ≥ 20%; improved urine output; mild AEs (abdominal pain, stoma hypertrophy)
Naimi et al[26]	Randomized, phase 2 crossover study (n = 18 SBS patients)	Daily glepaglutide 0.1-10 mg	3 weeks	Increased plasma citrulline (1 and 10 mg); increased crypt depth and epithelial height	Reduced fecal output; structural mucosal adaptation without perfusion changes
Pinar et al[27]	Open-label phase 3b study (n = 10 SBS patients; SBS-IF and SBS-II)	Glepaglutide (dose not specified, long-term use)	52 weeks	Increased intestinal energy absorption (+1038 kJ/day, +23%); decreased PS volume by 800 mL/day (-30%)	Improved carbohydrate absorption and electrolyte balance; well tolerated long term

SC: Subcutaneous; IV: Intravenous; SBS: Short bowel syndrome; IFALD: Intestinal failure-associated liver disease; GLP-2: Glucagon-like peptide-2; PS: Parenteral support; AEs: Adverse events; SBS-IF: Short bowel syndrome-intestinal failure; SBS-II: Short bowel syndrome-intestinal inflammation.