The association between sodium glucose cotransporter-2 (SGLT2) inhibitors and the risk of urothelial carcinoma (UC) remains controversial. This study aimed to investigate this relationship in Asian populations where upper tract urothelial carcinoma (UTUC) is prevalent.

Using Taiwan's National Health Insurance Database from 2016 to 2021, we conducted a nationwide cohort study comparing SGLT2 (n = 150,278) and dipeptidyl peptidase-4 (DPP4) inhibitor users (n = 363,178). Inverse probability of treatment weighting was applied to balance baseline characteristics, including demographics, comorbidities, and concurrent medications. Cumulative drug days were used to evaluate medication exposure. The primary outcome was the incidence of UC, including bladder cancer and UTUC. To avoid reverse causation and consider cancer latency, outcomes were assessed starting one year after treatment initiation.

During a mean follow-up of 2.62 years, we found no significant association between the use of SGLT2 inhibitors as a class and the risk of UC compared to DPP4 inhibitors (adjusted hazard ratio = 0.99, 95 % confidence interval: 0.77–1.27). This null association was consistent for both bladder cancer and UTUC. Furthermore, no significant associations were observed when analyses were stratified by individual drug type or cumulative drug days. Although some trends were noted in exploratory sensitivity analyses, no findings remained robustly significant after accounting for multiple comparisons.

SGLT2 inhibitor use was not associated with an increased risk of UC, with potential protective associations in specific subgroups requiring further investigation.