Association of pharmacotherapy with all-cause mortality among patients with irritable bowel syndrome

Abstract Background Irritable bowel syndrome (IBS) is a common disorder associated with high healthcare costs and reduced quality of life. The long-term safety of its pharmacotherapies remains unclear. This study aims to assess the association between long-term pharmacotherapies and all-cause mortality in this population. Method We performed a retrospective cohort study using a nationwide U.S. electronic health record database (January 1, 2005, to January 1, 2023). A 1:1 propensity score-matched cohort included 669,083 adults (aged 18–65) with IBS. Patients were grouped by pharmacotherapy use, with subgroup analyses for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). Follow-up started at the time of medication prescription after diagnosis. Exposures included guideline-recommended therapies for IBS, IBS-D, or IBS-C. The primary outcome was all-cause mortality, assessed using Cox proportional hazards models and target trial emulation. Results Antidepressant use is associated with an increased risk of all-cause mortality (hazard ratio HR, 1.35; 95% CI, 1.26–1.45; mortality rate, 1.6% vs. 1.0%). This association remains consistent across antidepressant subclasses and demographic subgroups. Antispasmodic use is not linked to increased mortality (HR, 0.95; 95% CI, 0.89–1.00). For IBS-D, cholestyramine/colestipol, eluxadoline, and rifaximin are not associated with mortality. However, diphenoxylate (HR, 1.89; 95% CI, 1.02–3.51) and loperamide (HR, 2.39; 95% CI, 1.48–3.90) show increased mortality risk. For IBS-C, polyethylene glycol-3350 and secretagogues have no significant association with mortality. Conclusions These findings raise concerns regarding the safety of antidepressants and mu receptor agonists in IBS treatment and underscore the need for cautious prescribing and further research.