Patients with stable inflammatory bowel disease (IBD) and comorbid obesity or diabetes who initiated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) did not have lower rates of disease relapse over one year than similar patients who did not receive the medications, according to a large target trial emulation published in Clinical Gastroenterology and Hepatology. The findings suggest that while semaglutide and tirzepatide appear safe for this population, current evidence does not support their use as disease-modifying therapy for IBD.
Relapse rates after one year were virtually identical among patients with milder disease, occurring in 7.9% of both GLP-1 RA initiators and noninitiators. Among patients receiving advanced therapies or immunomodulators, relapse occurred in 12.4% of GLP-1 RA users compared with 15.6% of nonusers — a difference the authors reported was not statistically significant.
“Despite real enthusiasm that GLP-1 receptor agonists might modify IBD, we found no benefit with adjunctive GLP-1 receptor agonists in patients with stable IBD on background IBD-directed therapy in this large target trial emulation,” said Siddharth Singh, MD, an author of the study.
The study evaluated adults with stable Crohn's disease or ulcerative colitis who also had obesity and/or diabetes using data from the OptumLabs Data Warehouse between 2018 and 2023. To emulate a randomized clinical trial, the investigators compared patients who initiated semaglutide or tirzepatide with propensity score-matched patients who did not receive a GLP-1 RA. The authors analyzed patients with milder disease receiving either 5-aminosalicylates (5-ASAs) or no IBD-directed therapy separately from those receiving immunomodulators or advanced therapies, reflecting differences in baseline disease severity.
The study found no significant differences in major safety outcomes between treatment groups in either cohort; GLP-1 RA initiation was not associated with an increased risk of IBD relapse or major adverse safety events.
Although GLP-1 RAs have attracted attention because of their anti-inflammatory properties and benefits in obesity and type 2 diabetes, the investigators wrote that evidence supporting a disease-modifying effect in IBD has remained limited. They noted that previous observational studies suggested potential benefits but included primarily patients with diabetes and older-generation GLP-1 RAs, whereas the current analysis focused specifically on semaglutide and tirzepatide and used a target trial emulation framework designed to better approximate a randomized trial.
The authors also noted a high rate of treatment discontinuation. According to the study, nearly half of patients receiving 5-ASAs or no IBD therapy and about four in 10 patients receiving advanced therapies discontinued their GLP-1 RA within one year, with approximately one-quarter of all initiators stopping treatment within the first three months. The authors noted that these rates were consistent with real-world experience in patients with obesity and diabetes.
Dr. Singh said the discontinuation pattern carries implications for future clinical trials.
“GLP-1 RA discontinuation was striking: nearly half stopped within a year, about a quarter within three months,” Dr. Singh said. “Any trial banking on a disease-modifying effect must plan for this dropout. Otherwise, high discontinuation will dilute the very benefit these studies are designed to detect.”
For practicing gastroenterologists and hepatologists, the findings offer reassurance about safety while underscoring the current limits of the evidence. Dr. Singh said he would prescribe GLP-1 RAs for obesity or diabetes while awaiting randomized trials before expecting any disease-modifying effect in IBD.
“For now, I would prescribe GLP-1 RAs for obesity or diabetes with confidence, counsel patients that many stop within a year, and wait for the randomized trials before expecting any disease-modifying effect in IBD,” Dr. Singh said.
The investigators acknowledged several limitations. Because the analysis relied on administrative claims data, it lacked endoscopic findings, biomarkers, detailed measures of disease activity and information on the degree of weight loss achieved. The authors also cited the possibility of residual confounding inherent to observational research, potential misclassification of patients obtaining GLP-1 RAs outside insurance claims and limited generalizability, because the database included commercially insured and Medicare Advantage beneficiaries but not uninsured patients or those covered by Medicaid or Medicare fee-for-service. Relatively infrequent cardiovascular events also limited the precision of some safety estimates.
The authors concluded that randomized controlled trials will be needed to determine whether GLP-1 RAs have any disease-modifying role in active IBD, and recommended that future studies account for the high rates of treatment discontinuation observed in routine practice.
Dr. Singh reported no relevant conflicts of interest. The study was funded by an International Organization for the Study of Inflammatory Bowel Diseases operating grant and a National Institute of Diabetes and Digestive and Kidney Diseases grant, both supporting Dr. Singh. Several coauthors disclosed consulting, advisory board or speaker relationships with pharmaceutical companies including AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer and Takeda.