Impact of sodium glucose cotransporter 2 inhibitors on bladder cancer and breast cancer: a pharmacovigilance analysis and Mendelian randomization study

There is conflicting real-world evidence regarding the risk of breast and bladder cancer associated with sodium glucose cotransporter 2 (SGLT2) inhibitors. We conducted a pharmacovigilance study on SGLT2 inhibitors and breast and bladder cancer using the US FDA Adverse Event Reporting System (FAERS) and a Mendelian randomization (MR) study. We used AERSMine to mine adverse events from FAERS. We provided proportional reporting ratio (PRR) with 95% confidence interval (CI), and the lower limit of the 95% credible interval of the information component (IC₀₂₅). A two-sample MR approach was used to investigate the causal relationship between SGLT2 inhibition and breast and bladder cancer. We did not find a disproportionate association between SGLT2 inhibitors (PRR = 1.26; 95%CI 1.05–1.51; p = 0.014; IC₀₂₅ = 0.01) and their molecules with breast cancer. SGLT2 inhibitors were associated with a disproportionately higher reporting frequency of bladder cancer events compared to metformin, dipeptidyl peptidase 4 inhibitors, or glucagon-like peptide-1 receptor agonists. MR analysis results showed that SGLT2 inhibition was associated with a higher risk of bladder cancer (odds ratio 1.01; 95%CI 1.00–1.01; p = 0.004). Our results suggest that the use of SGLT2 inhibitors is associated with a higher reporting frequency/risk of bladder cancer, rather than breast cancer.