S1113 Long-Acting GLP-1 Receptor Agonists Are Associated With a Reduced Risk of Functional Lower Gastrointestinal Disorders in Obese Patients With or Without Diabetes

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used to treat type 2 diabetes mellitus (T2DM) and obesity, conditions commonly linked to functional lower gastrointestinal disorders (FLGDs). Prior studies found modest increases in gastrointestinal (GI) symptoms with GLP-1RAs compared to SGLT2 inhibitors, but only among T2DM patients. Our previous study (GUT, 2024) identified an increased Gastroesophageal Reflux Disease risk associated with short-acting but not long-acting GLP-1RAs in T2DM patients, suggesting effects may differ by medication duration, patient population, and comparator. We examined the associations between short- and long-acting GLP-1RAs and FLGDs in obese populations, both with and without T2DM. Methods: This retrospective cohort study utilized TriNetX database, identifying adults with outpatient visits from Jan 1, 2015, to Jan 1, 2025. Two populations were included: (1) patients with obesity and T2DM and (2) patients with obesity but without T2DM. Patients prescribed GLP-1RAs (short-acting [daily] or long-acting [weekly]) were propensity-score matched 1:1 to controls without GLP-1RA use based on demographics and relevant confounders. Exclusions included IBS-mimicking conditions, GI surgeries, malignancies, and concurrent GLP-1/GIP dual agonist or DPP-4 inhibitor use. Primary outcomes (constipation, IBS [IBS-D, -C, -M, -U], functional diarrhea, fecal incontinence) were assessed ≥6 months after initiation. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: Each matched cohorts comprised 156,883 obese patients with T2DM and 141,761 without T2DM. In both populations, long-acting GLP-1RAs were significantly associated with reduced risks of constipation (T2DM: OR 0.671, 95% CI 0.652–0.691; non-T2DM: OR 0.470, 95% CI 0.452–0.488), overall IBS (T2DM: OR 0.768, 95% CI 0.716–0.825; non-T2DM: OR 0.471, 95% CI 0.440–0.504), and fecal incontinence (T2DM: OR 0.597, 95% CI 0.538–0.662; non-T2DM: OR 0.336, 95% CI 0.292–0.386). Among patients without T2DM, long-acting GLP-1RAs also reduced risks for all IBS subtypes and functional diarrhea (OR 0.652, 95% CI 0.500–0.850). Short-acting GLP-1RAs showed no significant associations with FLGDs in either population. Conclusion: Long-acting GLP-1RAs reduce FLGD risks across obese populations regardless of T2DM status, while short-acting GLP-1RAs have neutral effects. These findings highlight the importance of GLP-1RA duration, patient population, and comparator selection in evaluating GI outcomes.