The Risk of Bladder Cancer in Type 2 Diabetes Mellitus with Combination Therapy of SGLT-2 Inhibitors and Pioglitazone

Abstract

Background: Either sodium-glucose cotransporter-2 (SGLT-2) inhibitors or pioglitazone (Pio) has doubtful issues of bladder cancer, especially for the combination therapy with these two drugs. Our study aimed to investigate the risk of bladder cancer under combination therapy of SGLT-2 inhibitors and Pio. Materials and Methods: We included 97,024 patients with type 2 diabetes mellitus (T2DM) in the Chang Gung Research Database in Taiwan from 1 January 2016 to 31 December 2019. The primary outcome was newly diagnosed bladder cancer after combination therapy with SGLT-2 inhibitors and Pio. Group 1 received both study drugs, group 2 received SGLT-2 inhibitors, group 3 received Pio, and group 4 received non-study drugs (the reference group). The secondary outcome in each group was all-cause mortality. Results: In group 1, no newly diagnosed bladder cancer was detected after a mean 2.8-year follow-up and all-cause mortality decreased significantly (adjusted hazard ratio (AHR), 0.70; 95% confidence interval (CI), 0.54–0.92) in comparison to the reference group (group 4). In group 2 and group 3, no trend of increased bladder cancer was observed (group 2: AHR 0.49, 95% CI 0.05–4.94; group 3: AHR 0.48, 95% CI 0.15–1.58) and it still reduced all-cause mortality (group 2: AHR 0.83, 95% CI 0.70–0.99; group 3: AHR 0.90, 95% CI 0.83–0.99). Conclusions: In T2DM patients without previous or active bladder cancer, the combination therapy of SGLT-2 inhibitors and Pio was not associated with newly diagnosed bladder cancer and had lower all-cause mortality.

Comparison between sodium‐glucose cotransporter 2 inhibitors and dipeptidyl peptidase 4 inhibitors on the risk of incident cancer in patients with diabetes mellitus: A real‐world evidence study

“…33 However, several recent studies have reported the absence of any significant association between SGLT-2i use and the risk of bladder cancer. 29,49,50 This finding indicates that evidence on the relationship between SGLT-2i use and the risk of bladder cancer remains inconclusive, possibly because of differences in studies' design, such as differences in follow-up periods, control group settings, and ethnicities of participants. Additionally, the side effects of SGLT-2is, such as an increased risk of urinary tract infection, could have increased the likelihood of urinary tract cancer being detected early in randomised trials.…”

“…A meta‐analysis conducted on 46 randomised controlled trials revealed that the risk of bladder cancer was nearly four times higher in patients who took an SGLT‐2i than in those who did not 33 . However, several recent studies have reported the absence of any significant association between SGLT‐2i use and the risk of bladder cancer 29,49,50 . This finding indicates that evidence on the relationship between SGLT‐2i use and the risk of bladder cancer remains inconclusive, possibly because of differences in studies' design, such as differences in follow‐up periods, control group settings, and ethnicities of participants.…”

SGLT2 inhibition and three urological cancers: Up‐to‐date results

“…4,[22][23][24] However, numerous studies have reported the incidence of cancer, especially bladder cancer, after treatment initiation. 13,[25][26][27] Those studies generated confusing results and we could not confirm the causal association between SGLT2 inhibition and cancer incidence. Recently, three original studies explored the same topic.…”

“…Recently, three original studies explored the same topic. 13,25,26 One extracted data from European pharmacovigilance database 26 and concluded that SGLT2 inhibitors could increase the risk of bladder cancer in sensitive analysis (OR: 6.84, 95%CI: 5.41-8.65). While the other two did not report the risk of bladder cancer incidence compared with placebo or positive controls, 13,25 the follow-up year was relatively short (<3 years).…”

“…13,25,26 One extracted data from European pharmacovigilance database 26 and concluded that SGLT2 inhibitors could increase the risk of bladder cancer in sensitive analysis (OR: 6.84, 95%CI: 5.41-8.65). While the other two did not report the risk of bladder cancer incidence compared with placebo or positive controls, 13,25 the follow-up year was relatively short (<3 years). MR analysis was able to overcome the shortcomings of conventional cohort studies and establish a causal relationship from the genetic level.…”