Semaglutide, tirzepatide, and dulaglutide have similar gastrointestinal safety profiles among patients with type 2 diabetes (T2D), an active-comparator cohort study showed.

“We were somewhat surprised by the fact that despite differences in receptor activity and potency, dulaglutide, semaglutide, and tirzepatide showed a remarkably similar risk of serious gastrointestinal events,” Elisabetta Patorno, MD, DrPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston; Salvatore Crisafulli, PhD, of Brigham, Harvard, and University of Verona in Verona, Italy; and Wajd Alkabbani, PhD, of Brigham, Harvard, and University of Waterloo in Waterloo, Ontario, Canada, told Medscape Medical News by email.

“However,” they added, “clinicians should note that while the risk is comparable within this class, it remains higher than that observed with other classes of diabetes medications.”

The study was published online in the Annals of Internal Medicine.

Reassurance Provided

Researchers used data from Optum’s de-identified database to emulate three clinical trials of adults with T2D who were new users of dulaglutide, subcutaneous semaglutide, or tirzepatide from January 2019 through August 2024.

They assessed 65,238 matched pairs in the semaglutide vs dulaglutide cohort; 20,893 in the tirzepatide vs dulaglutide cohort; and 46,620 in the tirzepatide vs semaglutide cohort. Participants’ mean age was about 62, and about half were women.

Baseline characteristics in the three cohorts were well balanced except for A1c levels, which were imbalanced in the cohorts comparing subcutaneous semaglutide vs dulaglutide (mean, 8.2% vs 8.5%) and tirzepatide vs dulaglutide (mean, 7.8% vs 8.3%).

The primary outcome was a composite of severe adverse events resulting in an inpatient and/or emergency department encounter, including acute pancreatitis, biliary disease, bowel obstruction, gastroparesis, or severe constipation.

Secondary outcomes were the individual components of the primary outcome. Patients were 1:1 propensity score matched within each comparison.

The hazard ratio of gastrointestinal events was 0.96 in the semaglutide vs dulaglutide cohort; 0.96 in the tirzepatide vs dulaglutide cohort; and 1.07 in the tirzepatide vs semaglutide cohort.

The findings were consistent across subgroups, including older adults, patients with BMI > 30, and patients with recent opioid use.

A sensitivity analysis confirmed an increased risk for severe gastrointestinal adverse events, particularly gastrointestinal motility-related outcomes, when comparing individual GLP-1s and the dual glucose-dependent insulinotropic polypeptide/GLP-1 tirzepatide with a different medication class, namely, SGLT2 inhibitor.

The authors acknowledged possible residual confounding by glycemic control and BMI.

Nevertheless, Patorno, Crisafulli, and Alkabbani said, “These findings should provide reassurance that gastrointestinal safety is broadly similar across commonly used GLP-1 receptor agonists and tirzepatide. The results suggest that clinicians could base their choice among these agents on factors such as metabolic benefit, dosing preferences, and patient experience, rather than on concerns about differences in serious gastrointestinal safety.”

“At the same time,” they noted, “further research is warranted to identify which patients may be more susceptible to gastrointestinal intolerance and to understand how dose escalation and prior gastrointestinal history may influence risk.”

Some Patients at Higher Risk

Mohammed Ali, MD, co-director of the Emory Global Diabetes Research Center in Atlanta, commented on the study for Medscape Medical News.

“I wasn’t totally surprised by the findings,” he said. “What was nice about the study is that the real-world database they used does give us more confidence that the results weren’t just the result of selection bias.”

In primary care, Ali said, he sees many patients who don’t have access to all three drugs because of lack of insurance. “Knowing that there is benefit for all three and no worse severe side effects means that potentially, even if insurance covers the least expensive of the three, it’s still not harmful for my patient.”

Ali also noted that even though side effects were comparable across the three medication types, the heterogeneity of effect findings showed that the risk of ending up in the emergency room or at a doctor’s office with a severe adverse event was higher in people who were older, female, frail, and insulin users and those with high opioid use.

“Clinicians should be aware that if they have a high-risk patient with multiple comorbidities, and possibly chronic pain or other reasons that they’re using opioids, the adverse event risk may be double or triple the 1% found in the study. That’s a message we can all take home,” he concluded.

This study was supported by a research grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Patorno reported being supported by research grants from the Patient-Centered Outcomes Research Institute and the FDA not related to the topic of this work. She also reported being the principal investigator of a research grant to the Brigham and Women’s Hospital from Boehringer Ingelheim, not related to the topic of this work, and she reported receiving royalties from UpToDate. Alkabbani, Crisafulli, and Ali reported 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.