Are We Overlooking Long-Term Risks in IBS Management? New 20-Year Safety Data, With Ali Rezaie, MD

Management of irritable bowel syndrome (IBS) has undergone a notable evolution in recent decades, shifting from largely empirical, symptom-based treatment toward a more nuanced, mechanism-driven approach. However, as clinicians increasingly rely on long-term pharmacotherapy for a condition often diagnosed in early adulthood, questions around the durability and safety of these treatments have come into sharper focus.

A recent large-scale study led by Ali Rezaie, MD, medical director of the GI Motility Program at Cedars-Sinai, sought to address a critical gap in the literature surrounding the long-term mortality risk associated with commonly used IBS medications. His research utilized nearly 2 decades of electronic health records from > 650,000 US adults with IBS, making it the largest real-world study to examine the long-term safety of IBS treatments.

“One important thing about the irritable bowel syndrome is that a lot of patients are diagnosed in their 20s, 30s, or 40s. If you start them on a medication, this is not necessarily a curable disease, so they will be on that medication for years and decades,” Rezaie explained. “The issue is that when we do clinical trials using medications, they have a limited timeframe and they're generally small, so a rare side effect or long-term side effects will not pop up in those types of research. It's very important when we are treating patients with a specific medication to know whether there are risks associated with it.”

He and colleagues performed a retrospective cohort study using a nationwide US electronic health record database from January 2005 to January 2023. Their 1:1 propensity score-matched cohort included 669,083 adults with IBS. Patients were grouped by pharmacotherapy use, with subgroup analyses for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). Rezaie noted the analysis accounted for more than 50 variables—including comorbidities, concomitant medications, demographics, and lifestyle factors—to minimize confounding.

Results showed antidepressant use was 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%) and remained consistent across antidepressant subclasses and demographic subgroups.

While the relative increase was approximately 30%, the absolute risk difference remained modest. However, given that IBS affects a substantial portion of the US population, Rezaie noted that even small absolute increases could translate into meaningful population-level impact.

“Individually, the risk is not that high, but if you think about the fact that more than 10% of the US population has irritable bowel syndrome, that 0.6% potentially can translate into a significant number of deaths that we can potentially induce by starting patients on antidepressants in an IBS, which is not a fatal disease by itself,” he explained.

Further analyses reinforced the robustness of these findings. Comparisons with active comparator groups, stratification by age, and evaluation of negative control conditions all supported the observed association. Additionally, a dose-response relationship emerged, with higher numbers of prescription refills correlating with greater mortality risk. Mechanistically, the study identified increased rates of known antidepressant-related adverse events, including falls, arrhythmias, heart failure, bleeding, and suicidal ideation, which may mediate this risk.

Of note, results additionally showed antispasmodic use was not linked to increased mortality (HR, 0.95; 95% CI, 0.89–1.00).

Subgroup analyses provided additional clinical insight. For IBS-D, cholestyramine/colestipol, eluxadoline, and rifaximin were 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 showed no significant association with mortality.

Rezaie emphasized the implications for clinical practice. Because IBS is a chronic, non-fatal condition often requiring decades of management, long-term safety data are essential for informed decision-making. He noted that current guidelines largely lack such data and continue to emphasize symptom control without fully addressing potential long-term harms. These findings, he suggested, should prompt more transparent discussions with patients and may ultimately inform future guideline updates.

“I guess the bottom line is that when we are starting patients on medications for irritable bowel syndrome, along with the safety data that we have from clinical trials, I think it's fair to describe the long term side effects of these medications with the patients for more informed decision making,” he said “Also, I think right now, societal guidelines are are not incorporating long term side effects because there's no data, and hopefully this [research] will guide some of those recommendations and societal guidelines.”

Editors’ note: Rezaie reports relevant disclosures with Bausch Health, Ardelyx, and others.

References

1. Mehravar, S., Yeo, Y.H., Pimentel, M. et al. Association of pharmacotherapy with all-cause mortality among patients with irritable bowel syndrome. Commun Med 6, 176 (2026). https://doi.org/10.1038/s43856-026-01498-6

2. Cedars-Sinai Medical Center. Some common IBS treatments linked to higher risk of death. EurekAlert! April 8, 2026. Accessed April 9, 2026. https://www.eurekalert.org/news-releases/1122913