GLP-1 Receptor Agonist GI Safety Comparable Within the Class, But Exceeds SGLT-2 Inhibitor Risk

Three widely prescribed GLP-1-based therapies for type 2 diabetes (T2D), subcutaneous semaglutide (Ozempic), dulaglutide (Trulicity), and tirzepatide (Mounjaro), carry similar risks for serious gastrointestinal (GI) adverse events, with rates of approximately 10 to 12 events per 1,000 person-years, according to a large real-world cohort study published in Annals of Internal Medicine.1

Specfically, head-to-head comparisons among the GLP-1-based medications revealed no meaningful differences in risk for serious pancreatitis, gastroparesis, or bowel obstruction that required emergency department visits or hospitalization:

• semaglutide versus dulaglutide (HR 0.96, 95% CI 0.87-1.06)
• tirzepatide versus dulaglutide (HR 0.96, 95% CI 0.77-1.20)
• tirzepatide versus semaglutide (HR 1.07, 95% CI 0.90-1.26)

However, all 3 agents demonstrated significantly elevated GI risk compared with SGLT-2 inhibitors, with hazard ratios ranging from 1.22 to 1.53, according to study authors led by Elisabetta Patorno, MD, DrPH, of Brigham and Women's Hospital and Harvard Medical School in Boston.1

Mechanistic Similarities and Differences

Semaglutide and dulaglutide are GLP-1 receptor agonists that enhance insulin secretion and slow gastric emptying, while tirzepatide is a dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist. Despite tirzepatide's dual mechanism, its GI safety profile did not differ substantially from the GLP-1-only agents. The findings provide reassurance that GI safety should not be a differentiating factor when selecting among these 3 agents for patients with T2D, Patorno and colleagues wrote.

When investigators compared the 3 GLP-1 drugs with SGLT-2 in hibitors, each of them carried a significantly higher risk for adverse GI events: semaglutide (HR 1.22, 95% CI 1.09-1.37), dulaglutide (HR 1.36, 95% CI 1.21-1.53), and tirzepatide (HR 1.53, 95% CI 1.21-1.93). The excess risk versus SGLT-2 inhibitors was driven mainly by motility-related problems, such as gastroparesis and bowel obstruction, effects consistent with the known pharmacologic action of GLP-1-based therapies,2 they wrote. SGLT-2 inhibitors work through an entirely different mechanism, promoting glucose excretion through the kidneys without directly affecting GI function.

Study Design and Population. For the new-user, active-comparator cohort study, Patorno and fellow researchers analyzed data from Optum's Clinformatics Data Mart database, identifying adults with T2D who initiated 1 of the 3 GLP-1 drugs between January 2019 and August 2024. After 1:1 propensity-score matching, they established 3 comparison cohorts: 65,238 semaglutide-dulaglutide pairs, 20,893 tirzepatide-dulaglutide pairs, and 46,620 tirzepatide-semaglutide pairs.

Mean age across groups ranged from 60.2 to 62.8 years, with women comprising 49.3% to 53.2% of participants. Median follow-up duration was 163 to 183 days (approximately 5 to 6 months).

Primary and Secondary Outcomes. The primary composite outcome included acute pancreatitis, biliary disease, bowel obstruction, gastroparesis, and severe constipation requiring emergency department visits or hospitalization. Secondary outcomes examined each component individually.

Study Limitations, Research Opportunities

Among the study's limitations the authors acknowledged potential diagnostic code misclassification and residual confounding from incomplete data on body mass index and HbA1c levels. Also, the analysis focused exclusively on severe GI outcomes requiring medical attention, excluding milder symptoms such as nausea and vomiting that are difficult to capture reliably in administrative claims data.

The study did not directly evaluate dose-response relationships, which the authors identified as an important area for future investigation. While higher doses or rapid titration may increase mild GI intolerance early in treatment, whether these factors contribute to more severe events remains unclear. The short median follow-up time lays groundwork for longer-term studies, authors emphasized, to assess whether GI risks persist, attenuate, or evolve with continued use of these medications.

Bottom Line

The outcomes' strong support for the therapeutic equivalnce among the 3 medications in terms of GI saftey allows treatment decisions to focus on other factors such as efficacy, dosing convenience, cost, and patient preference, Patorno et al concluded. However, the class-wide elevation in GI risk compared with SGLT-2 inhibitors warrants consideration when selecting initial or add-on therapy, particularly in patients with pre-existing GI conditions or concerns about motility disorders.

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. Published online November 4, 2025. doi:10.7326/ANNALS-25-01724
2. Sodhi M, Rezeaeianzadeh R, Kezouh A, Etminan M. Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss. JAMA. 2023;330;(18):1795-1797. doi:10.1001/jama.2023.19574