Comparative Gastrointestinal Safety of Dulaglutide, Semaglutide and Tirzepatide in Adults With Type 2 Diabetes

Glucagon-like peptide-1 (GLP-1) receptor agonists and tirzepatide, a dual agonist for the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, are widely used to treat type 2 diabetes and obesity because of their benefits for these conditions and the associated reduced risks of cardiovascular, renal and other diseases. However, drugs in these classes are associated with an increased risk of gastrointestinal adverse events, including nausea, diarrhea, vomiting, constipation and, in some cases, more serious conditions such as pancreatitis or biliary disease.[1]

A cohort study published in the Annals of Internal Medicine in November 2025 compared the gastrointestinal safety of two GLP-1 drugs (dulaglutide [TRULICITY[2]] and subcutaneous semaglutide [OZEMPIC[3], WEGOVY[4]]) and tirzepatide (MOUNJARO[5], ZEPBOUND[6]), a GLP-1/GIP drug, in adults with type 2 diabetes.[7] The study found that dulaglutide, subcutaneous semaglutide, and tirzepatide have similar gastrointestinal safety profiles.[8]

The new study[9]

Using deidentified patient data from a large database of commercial health insurance claims, the study compared patients aged 18 years or older with type 2 diabetes who initiated one of the three injectable therapies — dulaglutide, subcutaneous semaglutide, and tirzepatide — between Jan. 1, 2019, and Aug. 30, 2024. Three pairwise comparisons were evaluated: subcutaneous semaglutide versus dulaglutide (65,238 matched pairs), tirzepatide versus dulaglutide (20,893 matched pairs), and tirzepatide versus subcutaneous semaglutide (46,620 matched pairs).

To minimize bias and ensure comparable baseline risk, patients were required to have continuous health plan enrollment for 365 days before the start of treatment, no prior exposure to GLP-1 medications, and no history of severe gastrointestinal conditions such as bowel obstruction or biliary disease. Additional exclusion criteria included type 1 diabetes, end-stage renal disease, multiple endocrine neoplasia type 2, and certain prior surgical procedures.

Patients were followed from the day after treatment initiation until the occurrence of a study outcome, treatment discontinuation or switching, loss of enrollment, death, or the end of the study period.

The primary outcome of the study was a composite of severe gastrointestinal adverse events resulting in an inpatient and/or emergency department encounter, including acute pancreatitis (inflammation of the pancreas), biliary disease, bowel obstruction, gastroparesis (delayed gastric emptying) and severe constipation. Secondary outcomes grouped the primary outcomes into two categories: pancreaticobiliary events (acute pancreatitis and biliary disease) and gastrointestinal motility-related events (bowel obstruction, gastroparesis and severe constipation).

The study findings

For each cohort, the number of incident gastrointestinal adverse events and incidence rates per 1,000 person-years were calculated and compared. Overall, the results showed no meaningful differences in the risk of severe gastrointestinal adverse events among the three injectable GLP-1-based therapies.

In the subcutaneous semaglutide versus dulaglutide cohort, the primary outcome occurred in 695 patients in the subcutaneous semaglutide group (12.07% incidence rate) and 754 patients in the dulaglutide group (12.49% incidence rate), indicating similar risk between the two drugs.

In the tirzepatide versus dulaglutide cohort, severe gastrointestinal adverse events occurred in 169 patients receiving tirzepatide (12.01% incidence rate) and 156 patients receiving dulaglutide (12.66% incidence rate).

In the tirzepatide versus subcutaneous semaglutide cohort, the primary outcome was observed in 298 patients receiving tirzepatide (10.56% incidence rate) and 260 patients receiving subcutaneous semaglutide (9.96% incidence rate).

For secondary outcomes, the findings were consistent across all three types of GLP-1 receptor agonists in the three cohorts, with no difference in the risk of pancreaticobiliary events or gastrointestinal motility-related events.

Notably, although relative risks were similar, the study found higher overall incidence rates of serious gastrointestinal adverse events among patients using insulin or those with recent opioid use. In addition, compared with sodium-glucose cotransporter-2 inhibitors (a different class of diabetes drugs), dulaglutide, semaglutide and tirzepatide were associated with a higher risk of serious gastrointestinal adverse events, particularly those related to impaired gastrointestinal motility.

The study evaluated patients with type 2 diabetes and did not include individuals using these medications only for weight management.

Another recent cohort study comparing tirzepatide and semaglutide for weight loss in patients with overweight or obesity found similar rates of gastrointestinal adverse events with either drug.[10]

What You Can Do

If you are currently being treated with dulaglutide, injectable semaglutide, or tirzepatide, or you are considering starting treatment, be aware that these three drugs have similar gastrointestinal safety profiles. For type 2 diabetes, these drugs are associated with higher risks of serious gastrointestinal adverse events than some other diabetes drugs. For type 2 diabetes or chronic weight management, discuss with your clinician which treatment is best for you.
 

References

[1] Crisafulli S, Alkabbani W, Paik JM, et al. Comparative gastrointestinal safety of dulaglutide, semaglutide, and tirzepatide in adults with type 2 diabetes. Ann Intern Med. November 4, 2025. doi:10.7326/ANNALS-25-01724.

[2] Eli Lilly and Co. Label: dulaglutide (Trulicity). May 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/125469s063lbl.pdf. Accessed December 15, 2025.

[3] Novo Nordisk. Label: semaglutide (Ozempic). January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209637s035,209637s037lbl.pdf. Accessed December 15, 2025.

[4] Novo Nordisk. Label: semaglutide (Wegovy). August 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/215256s024lbl.pdf. Accessed December 15, 2025.

[5] Eli Lilly and Co. Label: tirzepatide (Mounjaro). September 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/215866s034lbl.pdf. Accessed December 15, 2025.

[6] Eli Lilly and Co. Label: tirzepatide (Zepbound). September 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/215866s034lbl.pdf. Accessed December 15, 2025.

[7] Crisafulli S, Alkabbani W, Paik JM, et al. Comparative gastrointestinal safety of dulaglutide, semaglutide, and tirzepatide in adults with type 2 diabetes. Ann Intern Med. November 4, 2025. doi:10.7326/ANNALS-25-01724

[8] Ibid.

[9] Ibid.

[10] Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, et al. Semaglutide vs tirzepatide for weight loss in adults with overweight or obesity. JAMA Intern Med. July 8, 2024. 2024;184:1056-1064. doi:10.1001/jamainternmed.2024.2525.