Urothelial carcinoma (UC) is consistently ranked among the ten most common cancers worldwide, with Taiwan showing one of the highest incidence rates of UC. In Taiwan, bladder cancer remained one of the top ten cancers among males in 2018 and was ranked seventh in 2022. Bladder urothelial carcinoma (UCB) constitutes 90 %–95 % of all urothelial carcinomas, whereas upper tract urothelial carcinoma (UTUC) is rare, representing only 5 %–10 % of all urothelial carcinomas. However, in endemic areas such as Taiwan, the incidence of UTUC can be as high as 30 % [[1], [2], [3]].

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic agents that function independently of insulin resistance or deficiency [4]. Compared to other antidiabetic agents, such as dipeptidyl peptidase-4 inhibitors (DPP4 inhibitors), SGLT2 inhibitors confer additional therapeutic advantages, including renal protection and a reduction in cardiovascular risk [5]. Recent studies have reported that SGLT2 inhibitors exhibit anticancer properties in various in vitro and in vivo models [6,7]. An increase in genital infections and a potential rise in urinary tract infections have been reported; however, these adverse events frequently necessitate the discontinuation of therapy [[8], [9], [10], [11], [12]].

The potential association between SGLT2 inhibitors and an elevated risk of bladder cancer remains a topic of concern [13]. In the EMPA-REG OUTCOME trial, an increased incidence of bladder cancer was observed among patients receiving empagliflozin compared with those receiving placebo [14]. To address this concern, the U.S. Food and Drug Administration (FDA) has underscored the importance of post-marketing surveillance studies, as chronic glycosuria induced by SGLT2 inhibitors may expose the urinary tract to potential harm [11]. In addition, a recent case-control study using a European database reported a significantly higher incidence of bladder cancer in patients treated with SGLT2 inhibitors [15]. Conversely, a previous meta-analysis of large randomized controlled trials found no significant association between SGLT2 inhibitors and bladder cancer risk [16]. Consequently, the potential association between SGLT2 inhibitor therapy and bladder cancer remains inconclusive; however, it continues to represent a critical safety concern that warrants further investigation.

Given the uniquely high prevalence of UTUC in Taiwan compared to Western countries, coupled with the possibility that diabetes-related risk factors may differentially affect upper and lower urinary tract cancers, there is a compelling need for region-specific research. This study uniquely leveraged the comprehensive Taiwan National Health Insurance database to examine the association between SGLT2 inhibitor use and urothelial carcinoma, with a distinctive focus on analyzing risk patterns across different anatomical sites of the urinary tract.