GLP-1 RAs Carry Higher Risk of Serious GI Side Effects Than SGLT-2 Inhibitors: Daily Dose

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On November 4, 2025, we reported on a study published in Annals of Internal Medicine that was designed to compare the risk for severe gastrointestinal (GI) adverse events across dulaglutide, subcutaneous semaglutide, and tirzepatide in adults with type 2 diabetes (T2D).

The study

For the new-user, active-comparator cohort study, researchers analyzed data from Optum's Clinformatics Data Mart database, identifying adults with T2D who initiated 1 of the 3 GLP-1 drugs between January 2019 and August 2024. After 1:1 propensity-score matching, they established 3 comparison cohorts: 65 238 semaglutide-dulaglutide pairs, 20 893 tirzepatide-dulaglutide pairs, and 46 620 tirzepatide-semaglutide pairs. The primary composite outcome included acute pancreatitis, biliary disease, bowel obstruction, gastroparesis, and severe constipation requiring emergency department visits or hospitalization.

The findings

Results showed no meaningful differences in risk for serious pancreatitis, gastroparesis, or bowel obstruction that required emergency department visits or hospitalization:

• semaglutide vs dulaglutide (HR 0.96, 95% CI 0.87-1.06)

• tirzepatide vs dulaglutide (HR 0.96, 95% CI 0.77-1.20)

• tirzepatide vs semaglutide (HR 1.07, 95% CI 0.90-1.26)

However, all 3 agents demonstrated significantly elevated GI risk compared with SGLT-2 inhibitors, with hazard ratios ranging from 1.22 to 1.53.

Authors' comments

"These findings suggest that dulaglutide, semaglutide, and tirzepatide have similar gastrointestinal safety profiles in adults with T2D. This study provides clinicians with evidence to weigh the benefits and risks of these medications."

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