Antidiabetic drug exposure and risk of bladder cancer: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of bladder cancer, but the impact of specific antidiabetic drug classes remains uncertain. METHODS: We conducted a systematic review and meta-analysis following PRISMA guidelines. PubMed/MEDLINE, Embase, Scopus and CENTRAL were searched through 2024 for observational studies assessing the association between antidiabetic drug exposure and incident bladder cancer. Adjusted effect estimates (HRs, RRs, ORs) were pooled using random-effects models. Analyses were performed separately for pioglitazone, metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors. Heterogeneity was assessed using the I2 statistic. RESULTS: Fourteen observational studies including approximately 6.3 million individuals with T2DM were included. Pioglitazone use was not significantly associated with bladder cancer risk (pooled RR ≈ 1.05, 95% CI 0.52-2.09), although substantial heterogeneity was observed (I2 = 99%). Several studies suggested a duration and dose-dependent association, particularly with prolonged exposure. Metformin use was associated with a lower risk of bladder cancer (pooled RR = 0.67, 95% CI 0.46-0.98), although substantial heterogeneity was observed. SGLT2 inhibitor use was not associated with an increased risk of bladder cancer (pooled RR = 0.98, 95% CI 0.70-1.37), with moderate heterogeneity across studies (I2 = 63%). CONCLUSIONS: We did not demonstrate a statistically significant association between pioglitazone use and bladder cancer risk. However, several individual studies suggested a possible duration-dependent effect with prolonged exposure. Metformin use was associated with a lower risk of bladder cancer (pooled RR = 0.67, 95% CI 0.46-0.98), although substantial heterogeneity was observed. SGLT2 inhibitors appear oncologically safe with respect to bladder cancer.