Annals of Internal Medicine study finds tirzepatide and semaglutide have similar gastrointestinal safety

A new study published in Annals of Internal Medicine compared three widely used injectable diabetes drugs — dulaglutide, subcutaneous semaglutide (sold as Ozempic for type 2 diabetes and Wegovy for weight management) and tirzepatide (Mounjaro and Zepbound) — and found their rates of serious gastrointestinal problems were similar ^[1].

The researchers used a "new-user, active-comparator" design, meaning they followed people who were starting one of these drugs for the first time and compared them directly against people starting a different one, rather than against no treatment. The study included adults with type 2 diabetes who began treatment between January 1, 2019, and August 30, 2024 ^[1].

What the study measured

The main outcome was a composite — a single tally that counted any of five serious events: acute pancreatitis, biliary disease (gallbladder and bile duct problems), bowel obstruction, gastroparesis (delayed stomach emptying) and severe constipation ^[1]. Each of those conditions was also examined individually as a secondary outcome ^[1].

To make the groups comparable, the authors used 1:1 propensity score matching, pairing each person on one drug with a similar person on the comparison drug. That produced 65,238 matched pairs for semaglutide versus dulaglutide, 20,893 pairs for tirzepatide versus dulaglutide, and 46,620 pairs for tirzepatide versus semaglutide ^[1].

The results showed no statistically meaningful differences. The hazard ratio for gastrointestinal events was 0.96 (95% CI, 0.87 to 1.06) for semaglutide versus dulaglutide, 0.96 (CI, 0.77 to 1.20) for tirzepatide versus dulaglutide, and 1.07 (CI, 0.90 to 1.26) for tirzepatide versus semaglutide ^[1]. A hazard ratio of 1.00 would mean identical risk; in all three comparisons, the confidence intervals crossed 1.00, which means the data are consistent with no difference between the drugs.

The authors concluded that "dulaglutide, semaglutide, and tirzepatide have similar gastrointestinal safety profiles in adults with T2D" and said the study "provides clinicians with evidence to weigh the benefits and risks of these medications" ^[1]. The work was primarily funded by the National Institute of Diabetes and Digestive and Kidney Diseases ^[1].

Limits of the findings

The researchers flagged "possible residual confounding by glycemic control and body mass index" as a limitation ^[1]. In plain terms: even after matching, people prescribed one drug may have differed from people prescribed another in ways the data could not fully capture, such as their A1c levels or their weight. Observational studies like this one can show associations but cannot prove cause and effect the way a randomized trial can.

Several other things are not established by this study. It enrolled only adults with type 2 diabetes, so it does not directly address people taking these medicines for obesity without diabetes. It looked at subcutaneous (injected) semaglutide, not the oral form (Rybelsus). The published abstract does not report the absolute number of events, the incidence rates, or the results for each individual condition, so the size of the underlying risk for any one problem is not available from the abstract text ^[1].

Why it matters for patients

Gastrointestinal side effects are the most common reason people stop GLP-1 and dual-agonist medicines, and the rarer but more serious events — pancreatitis, gallbladder disease, bowel obstruction, gastroparesis — are the ones that show up in warning labels and lawsuits. Until now, the abstract notes, "the comparative gastrointestinal safety across glucagon-like peptide-1 receptor agonists and tirzepatide is still unclear" ^[1].

For someone weighing a switch between drugs, this study suggests serious GI risk is unlikely to be the deciding factor, at least among adults with type 2 diabetes taking these three medicines. It does not say these events do not happen — only that they appeared to happen at roughly similar rates across the three drugs ^[1]. Everyday nausea, vomiting and diarrhea, which are far more common than the five conditions studied, were not part of the primary composite outcome ^[1].

What happens next

The study period ended August 30, 2024, so it does not cover the most recent prescribing patterns ^[1]. Longer follow-up, data on people using these drugs for weight management rather than diabetes, and results for each individual GI condition would help fill in the picture. Whether such analyses are planned is not stated in the published abstract.

Anyone with questions about digestive symptoms on these medications should raise them with the clinician managing their care.