Thiazolidinediones increase bladder cancer risk while SGLT2 inhibitors show potential protective effects in Type 2 DiabetesDiabetes medications show different links to bladder cancer risk

Bladder cancer (BC) is the most common malignancy of the urinary system worldwide. Type 2 diabetes mellitus (T2DM) and its treatments may influence BC risk, but existing evidence is conflicting. This study aimed to systematically evaluate the association between various classes of antidiabetic medications (ADMs) and BC risk in patients with T2DM. We conducted a systematic review and meta-analysis following PRISMA guidelines, searching multiple databases up to September 30, 2025. Cohort studies, case-control studies, and randomized controlled trials (RCTs) reporting on ADM use and BC risk were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. Heterogeneity, subgroup analyses, and publication bias were assessed. A total of 85 studies were included. The meta-analysis showed that thiazolidinediones (TZDs) use was associated with an increased risk of BC (OR = 1.10, 95% CI: 1.04-1.18), while sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) showed a potential protective effect (OR = 0.81, 95% CI: 0.68-0.97). No significant association was found between BC risk and the use of metformin, sulfonylureas (SUs), insulin, or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors). Analysis of RCTs for glucagon-like peptide-1 receptor agonists (GLP-1 RAs) also showed no significant effect. Among patients with T2DM, TZDs use may be associated with an increased risk of BC, while SGLT2 inhibitors may be protective. Other major ADM classes showed no significant association. Given that the evidence primarily comes from observational studies with heterogeneity, clinical decisions should still be based on comprehensive benefit-risk assessment. However, given that the existing evidence primarily comes from observational studies with considerable heterogeneity and RCTs show no significant associations, these conclusions should be viewed with caution, and clinical decisions should be based on comprehensive benefit-risk assessment. REGISTRATION NUMBER: CRD420251149266.