Tirzepatide was associated with lower all-cause mortality and fewer adverse gastrointestinal events than semaglutide in a large global cohort, researchers reported in a poster at Digestive Disease Week (DDW) 2026.

The real-world comparative effectiveness study was conducted to see whether the drugs’ side effects could help guide selection, principal investigator Aasma Shaukat, MD, NYU Langone Health, New York City, told Medscape Medical News.

“It was surprising that despite being a dual GLP inhibitor, tirzepatide was associated with fewer adverse events,” said Shaukat.

Using the TriNetX Global Collaborative Network, she and her team identified patients with overweight/obesity and type 2 diabetes and split them into two propensity-matched groups of 126,971 patients each initiating either tirzepatide or semaglutide from January 2018 to the present. Patients using both agents were excluded.

Outcomes were evaluated from 1 day to 5 years after the index date and included all-cause mortality, gastroparesis, paralytic ileus/intestinal obstruction, and aspiration pneumonitis. 

Tirzepatide was associated with significantly lower all-cause mortality, with 1182 vs 1998 events (0.9% vs 1.6%; relative risk [RR], 0.59). It was also associated with a lower risk for ileus/intestinal obstruction (0.9% vs 1.0%; RR, 0.84).

Aspiration pneumonitis was significantly less frequent with tirzepatide vs semaglutide (0.3% vs 0.4%; RR, 0.69), whereas gastroparesis risk was similar between the groups (1.0% vs 1.1%; RR, 0.95).

“By combining enhanced metabolic effects with preserved gastric motility and lower aspiration risk, tirzepatide demonstrates a more favorable benefit-risk profile than semaglutide in routine care,” the authors wrote in their poster. “These insights may help clinicians prioritize dual incretin therapy for appropriate patients.”

“The study has limitations of residual confounding but supports use of tirzepatide over semaglutide for fewer adverse events,” said Shaukat. “The findings need confirmation in other cohorts and prospective studies.”

The team’s next steps are to verify the findings in different cohorts and study dose-response relationships, she added.

Shaukat declared having no conflicts of interest. 

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.