Tirzepatide boasts lower risk of GI side effects vs other GLP1-RAs

The use of tirzepatide delivers a better safety profile when compared to other glucagon-like peptide-1 receptor agonists (GLP-1RAs), as shown by the lower risk of gastrointestinal (GI) side effects associated with its use, reports a real-world study presented at DDW 2025.

Overall, 81,738 patients were treated with tirzepatide and 851,379 with other GLP-1RAs. The two cohorts had similar demographic and clinical characteristics following propensity score matching, reported lead author Dr Fouad Jaber of Baylor College of Medicine in Houston, Texas, US.

At 6 months, treatment with tirzepatide resulted in a significantly decreased odds of gastroparesis (adjusted odds ratio, 0.280, 95 percent confidence interval [CI], 0.239‒0.328), gastro-oesophageal reflux disease (GERD; aOR, 0.473, 95 percent CI, 0.459‒0.487), and Barrett’s oesophagus (aOR, 0.431, 95 percent CI, 0.370‒0.502). [DDW 2025, abstract Su2055]

Patients who received tirzepatide also showed a significantly lower risk of acute pancreatitis (aOR, 0.314, 95 percent CI, 0.293‒0.336), irritable bowel syndrome (aOR, 0.414, 95 percent CI, 0.379‒0.453), and bowel obstruction (aOR, 0.353, 95 percent CI, 0.280‒0.445) than those treated with other GLP-1RAs.

Similarly, the tirzepatide cohort were less likely to experience nausea and vomiting (aOR, 0.291, 95 percent CI, 0.258‒0.328), as well as constipation (aOR, 0.380, 95 percent CI, 0.370‒0.391) and dyspepsia (aOR, 0.421, 95 percent CI, 0.385‒0.461).

These findings persisted at 1- and 2-year follow-up. Additionally, the use of tirzepatide significantly correlated with reduced risks of biliary diseases, including cholecystitis, cholelithiasis, choledocholithiasis, and cholecystectomy at 6 months, but not a 1- and 2-year follow-up.

GI side effects

“Our study provides real-world evidence that tirzepatide has a significantly lower risk of GI side effects compared to GLP-1 RAs, suggesting a favourable GI safety profile for patients with obesity or type 2 diabetes (T2D),” Jaber said. “However, long-term studies are needed to confirm these findings.”

In another study, Jaber also reported the protective benefits of GLP-1RAs against the development of GI-related cancers, such as oesophageal, colorectal, gallbladder, stomach, small intestine, pancreatic, liver, and cholangiocarcinoma cancers, among others. [DDW 2025, abstract Mo2067]

The current retrospective cohort study used the TriNetX US Collaborative Network, which holds data from 69 healthcare institutions. Using ICD-10 and CPT codes, Jaber and colleagues identified adults prescribed tirzepatide or single-agent GLP-1RAs for T2D or obesity. They excluded patients with pregnancy, liver cirrhosis, inflammatory bowel disease, heart failure, chronic pancreatitis, or cancer.

The research team used one-to-one propensity score matching to balance cohorts for demographics and clinical factors. Adjusted ORs with 95 percent CIs were calculated to analyse outcomes, including gastroparesis, Barrett’s oesophagus, and GERD at 6 months, 1 year, and 2 years. Other outcomes were constipation, dyspepsia, nausea/vomiting, biliary disease, acute pancreatitis, and bowel obstruction.

“Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, has shown superior efficacy in glycaemic control and weight loss compared to other GLP-1 RAs,” according to Jaber and colleagues.