S427 Reduced Immunosuppression Requirements With GLP-1 Receptor Agonists Use in Patients Experiencing Immune-Mediated Diarrhea and Colitis

Introduction: Metformin, a common therapy for type 2 diabetes mellitus (T2DM), has been associated with worse outcomes in patients who develop immune-mediated diarrhea and colitis (IMDC) during immune checkpoint inhibitor (ICI) therapy, prompting interest in alternative agents. Glucagon-like peptide-1 receptor agonists (GLP-1RA), also used in T2DM, promote insulin secretion, delay gastric emptying, and promote satiety. Notably, GLP-1 receptors are expressed on immune cells, where activation promotes regulatory T cell responses and immune exhaustion gene expression. These immunomodulatory properties extend beyond glycemic control, with benefits in cardiovascular and renal disease. This study evaluated whether GLP-1RA use impacts IMDC severity or outcomes in ICI-treated patients. Methods: This retrospective single-center study included ICI-treated patients from 2015-2025. GLP-1RA users were compared with non-users and a historical metformin cohort. Chi-square and Fisher’s exact tests were used (SPSS v24; IBM Corp, Armonk, NY). Results: Among 1,128 patients, 58.6% were men and 89.8% White. Melanoma (34.9%) and genitourinary cancers (23.4%) were most common. ICI regimens included programmed cell death protein-1/ligand-1 inhibitors 553 (49%), cytotoxic T-lymphocyte-associated protein 4 inhibitors 192 (17%), and combined therapy 380 (33.6%). IMDC occurred in 5.3% of GLP-1RA (15) users vs 4.4% of non-users (1105). Despite similar biomarkers, GLP-1RA users more often had Common Terminology Criteria for Adverse Events (CTCAE) grade <2 colitis (85.7% vs 60.4%, P= 0.044), required fewer selective immunosuppressive therapy (SIT) doses (1 vs 3, P= 0.043), and trended toward fewer steroid tapers (1 vs 1, P= 0.082). ICI discontinuation was less common (86.7% vs 98.6%, P= 0.020), and resumption more frequent (60% vs 38.2%, P= 0.075). No significant mortality difference was observed. Compared to metformin users (IMDC incidence 7%, n = 105), GLP-1RA users had milder colitis (CTCAE grade <2: 85.7% vs 56.2%, P = 0.030), higher ICI resumption (60% vs 31.4%, P= 0.030), fewer SIT needs (1 vs 2, P= 0.075), and lower mortality (40% vs 65.7%, P= 0.054). Conclusion: This is the first study to explore GLP-1RA use during ICI therapy. GLP-1RA users demonstrated milder IMDC, reduced immunosuppression needs, higher rates of ICI resumption, and better survival compared to metformin users. While not all outcomes reached statistical significance, consistent trends suggest a possible immunomodulatory benefit. These findings support further investigation into GLP-1RA as a potentially favorable alternative in patients with T2DM receiving ICIs.