Thiazolidinedione use and risk of bacterial enteric infection among adults with type 2 diabetes mellitus

Abstract Background Thiazolidinediones are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists commonly used to treat type 2 diabetes mellitus. In experimental models, epithelial PPAR-γ signaling contributes to colonization resistance against bacterial enteric pathogens by shaping oxygen and nitrate luminal bioavailability. Whether use of PPAR-γ agonists in humans is associate[ABS]d with reduced risk of bacterial enteric infection is unknown. Methods To investigate whether users of thiazolidinediones (PPAR-γ agonists) have decreased risk of bacterial enteric infection, we performed a retrospective nationwide analysis with the cloud-based TriNetX Analytics Platform which aggregates health records from 117 million patients across 66 US healthcare organizations, to assess the risk of bacterial enteric infection among diabetic patients prescribed thiazolidinediones, a class of PPAR-γ agonists, compared with other anti-diabetes medications. Results Among 85,916 thiazolidinedione users categorized as low-risk for bacterial enteric infection (no prior history of infection) and 1,974 persons identified as high-risk (prior history of bacterial enteric infection), the likelihood of bacterial enteric infection was reduced by 49% (RR 0.51, 95% CI 0.32-0.82) and 22% (RR 0.78, 95% CI 0.69-0.88) respectively, compared to users of other anti-diabetes medications. This reduction in risk was consistent across high-risk individuals, regardless of sex or age. Similar results were replicated in high-risk patients when thiazolidinedione users were directly compared to those on DPP-4 inhibitors. Conclusion These findings demonstrate an association between PPAR-γ agonist use and reduced risk of bacterial enteric infection and support further clinical investigation.