SGLT2 Inhibitors and Bladder Cancer: Analysis of Cases Reported in the European Pharmacovigilance Database.

The association between sodium-glucose cotransporter 2 inhibitors (SGLT2is) and cancer risk is unclear. The objective of this study was to analyze whether a disproportionate number of cases of bladder cancer are reported for SGLT2is in EudraVigilance. A case/noncase study was conducted to assess the association between bladder cancer and SGLT2is, calculating reporting odds ratios (RORs) from November 11, 2012 (approval date for the first SGLT2i, dapagliflozin) to May 19, 2020. First, cases involving SGLT2is were compared with those involving all other drugs; and similar analysis was performed for each SGLT2i. Second, to reduce the risk of confounding by indication, the RORs for SGLT2is compared with other antidiabetics were obtained. Besides, 2 measures were taken to evaluate a possible notoriety bias: a sensitivity analysis excluding pioglitazone was performed and the evolution of the ROR over time for SGLT2is was measured. There were 6602 cases of bladder cancer in the 4,213,637 reports during the study period. SGLT2is were involved in 155 cases. The ROR for pooled SGLT2is was 3.97 (95% confidence interval [CI], 3.39-4.66), disproportionality also being observed for each SGLT2i separately. The association was strongest for dapagliflozin (ROR, 7.02; 95%CI, 5.69-8.66). Nonetheless, this association disappeared when comparing SGLT2is with other antidiabetic drugs (ROR, 0.20; 95%CI, 0.17-0.24). But when excluding pioglitazone from the analysis, a safety signal for SGLT2is compared with other antidiabetics emerged (ROR, 6.84; 95%CI 5.41-8.65). Our study found a disproportionately high number of cases of bladder cancer among users of SGLT2is. However, observational analytical studies will be needed to confirm these results.