Comparative effectiveness of tirzepatide versus GLP-1 receptor agonists on the risk of incident infection and severe infection–related outcomes in type 2 diabetes

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of infection-related morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may exert immunomodulatory effects beyond glycemic control. Tirzepatide, a dual glucose-dependent insulinotropic peptide and GLP-1 receptor agonist, has demonstrated superior metabolic efficacy, but its association with infection-related outcomes remains unclear. We conducted a retrospective cohort study using the TriNetX research network including adults with T2DM between January 2022 and November 2025. New users of tirzepatide were compared with new users of GLP-1RAs. Propensity score matching (1:1) balanced demographic characteristics, comorbidities, medications, and laboratory variables. The primary endpoint was a composite of infection-related events within 1 year. Secondary outcomes included pneumonia, skin infection, and all-cause mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs). After matching, 143,288 patients were included in each group. Tirzepatide initiation was associated with a modestly lower risk of composite infection-related events compared with GLP-1RAs (HR 0.97, 95% CI 0.95–0.99). Lower risks were observed for pneumonia (HR 0.95, 95% CI 0.92–0.98), skin infection (HR 0.96, 95% CI 0.93–0.99), and all-cause mortality (HR 0.89, 95% CI 0.82–0.98). Results were consistent across most prespecified subgroups and sensitivity analyses, including landmark analyses and a negative control outcome. No significant differences were observed for acute pyelonephritis or gastrointestinal infection. In this large real-world cohort of patients with T2DM, tirzepatide use was associated with a modestly lower risk of infection-related outcomes compared with GLP-1RAs. These findings suggest that dual GIP/GLP-1 receptor agonism may be associated with differences in infection-related outcomes, although prospective studies are needed to confirm causality.