Sodium depletion is associated with the response to glepaglutide in short bowel syndrome with chronic intestinal failure.

Background

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Aims

Glepaglutide, a long-acting glucagon-like peptide 2 (GLP-2) analogue, reduces the need for parenteral support (PS) and increases nutrient absorption including sodium, in patients with short-bowel syndrome (SBS). We retrospectively studied the association between sodium homeostasis based on urine sodium levels and PS changes in response to glepaglutide for SBS chronic intestinal failure (SBS-CIF) patients.

Methods

The phase 3a EASE SBS-1 trial randomized 106 SBS patients with CIF (type III, according to the ESPEN classification) to receive glepaglutide 10 mg once (OW) or twice weekly (TW) vs. placebo for 24 weeks. We identified subgroups by sodium depletion, defined as a sodium concentration of <20 mmol/L or a sodium/potassium ratio of <1 in spot urine at baseline. Post-hoc subgroup analyses were performed using ANCOVA for the change in PS volume from baseline to week 24 (primary endpoint EASE SBS-1) and a logistic regression model for achieving the key secondary trial endpoint of clinical response (≥20 % reduction in PS volume from baseline to weeks 20 and 24). Groups receiving glepaglutide OW or TW were pooled in all analyses. We adjusted for sodium depletion, colon-in-continuity (CiC), treatment (active/placebo), and treatment-by-sodium depletion interaction.

Results

42 % (22/52) of patients without CiC vs. 9 % (5/54) with CiC were sodium-depleted at baseline (p<0.0001). The overall prevalence of sodium depletion increased from baseline (25 %) to week 24 (36 %). Patients without sodium depletion (n = 79) had a significantly greater PS reduction with glepaglutide vs. placebo (p = 0.02). The nondepleted patients receiving glepaglutide were numerically more likely to achieve a clinical response in PS reduction (p = 0.12). Patients with sodium depletion at baseline had nonsignificant differences in PS reduction or clinical response (n = 27) and were likely to remain depleted at week 24 (n = 24, OR 13.5; p<0.0001).

Conclusion

Sodium depletion is more common in SBS-CIF without CiC. This post-hoc analysis suggests that glepaglutide is more effective at reducing PS volume if sodium homeostasis is achieved before GLP-2 treatment begins.