Sodium-Glucose Co-Transporter 2 inhibitors and the Short-term Risk of Bladder Cancer: An International Multi-Site Cohort Study

Objective: To determine whether sodium-glucose co-transporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide-receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP4) inhibitors are associated with an increased risk of early bladder cancer events.

Research Design & Methods: We conducted a multi-site, population-based, new-user active comparator cohort study using the United Kingdom Clinical Practice Research Datalink, Medicare fee-for-service, Optum© Clinformatics® Data Mart, and MarketScan Health from January 2013 through December 2020. We assembled two cohorts of adults with type 2 diabetes initiating (1) SGLT2 inhibitors or GLP-1RAs, and (2) SGLT2 inhibitors or DPP4 inhibitors. Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident bladder cancer. The models were weighted using propensity score fine stratification. Site-specific HRs were pooled using random-effects models.

Results: SGLT2 inhibitor (n=453,560) and GLP-1RA (n=375,997) users had a median follow-up ranging from 1.5-2.2 years. Overall, SGLT2 inhibitors were not associated with an increased risk of bladder cancer, compared with GLP-1RAs (HR=0.90; 95% CI: 0.81-1.00). Similarly, when compared with DPP-4 inhibitors (n=853,186), SGLT2 inhibitors (n=347,059) were not associated with an increased risk of bladder cancer (HR: 0.99, 95% CI: 0.91-1.09) over a median follow-up ranging from 1.6-2.6 years. Results were consistent across sensitivity analyses.

Conclusions: Contrary to previous randomized controlled trials, these findings indicate that the use of SGLT2 inhibitors is not associated with an increased risk of bladder cancer when compared with GLP-1RAs or DPP4 inhibitors. This should provide reassurance on the short-term effects of SGLT2 inhibitors on bladder cancer incidence.