Sodium-glucose cotransporter-2 inhibitors and the risk of urinary tract infection among diabetic patients in Japan: Target trial emulation using a nationwide administrative claims database

Aim: To assess the risk of urinary tract infection (UTI) occurrence associated with sodium-glucose cotransporter-2 (SGLT2) inhibitor use relative to biguanide use in diabetes in a population-based cohort study using a target trial emulation framework. Methods: Using a Japanese nationwide administrative claims database, we constructed a cohort of patients aged ≥40 years who were dispensed SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors or biguanides between April 2014 and March 2015. For computational ease, we randomly sampled 100% of SGLT2 inhibitor users, 3% of DPP-4 inhibitor users, and 20% of biguanide users; new antidiabetic drug initiators were analysed. We estimated the intention-to-treat (ITT) hazard ratios (HRs) of UTI with inverse probability of treatment (IPT)-weighted Coxʼs proportional hazards models that ignored subsequent treatment changes. Treatment weights were computed using patient sex, age, medications, medical history and hospitalization history. We also estimated per-protocol (PP) HRs using IPT- and inverse probability of censoring-weighted Coxʼs models that adjusted for nonrandom treatment changes. Results: We analysed 11 364 SGLT2 inhibitor initiators, 9035 DPP-4 inhibitor initiators, and 10 359 biguanide initiators. When compared with biguanide initiators, SGLT2 inhibitor initiators had a crude HR of 1.14 (95% confidence interval [CI] 1.05-1.24), an ITT HR of 0.94 (95% CI 0.86-1.03), and a PP HR of 0.90 (95% CI 0.78-1.03); and DPP-4 inhibitor initiators had a crude HR of 1.13 (95% CI 1.04-1.23), an ITT HR of 0.85 (95% CI 0.77-0.94), and a PP HR of 0.83 (95% CI 0.71-0.95). Conclusion: Use of SGLT2 inhibitors or DPP-4 inhibitors did not increase the risk of UTI compared with biguanide use. Accounting for treatment changes did not substantially influence the estimated effects.