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 Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are increasingly used as first-line antidiabetics in Japan. This study assessed the risk of urinary tract infection (UTI) occurrence associated with SGLT2is relative to biguanides among diabetic patients 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 SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), or biguanides between April 2014 and March 2015. For computational ease, we randomly sampled 100% of SGLT2i users, 3% of DPP4i users, and 20% of biguanide users; new antidiabetic initiators were analyzed. We estimated the intention-to-treat hazard ratios (ITT-HRs) of UTI with inverse probability of treatment-weighted Cox's 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 HRs (PP-HRs) using inverse probability of treatment- and censoring-weighted Cox's models that adjusted for non-random treatment changes. Results We analyzed 11,364 SGLT2i initiators, 9035 DPP4i initiators, and 10,359 biguanide initiators. When compared with biguanide initiators, SGLT2i initiators had a crude HR of 1.14 (95% confidence interval: 1.05-1.24), ITT-HR of 0.94 (0.86-1.03), and PP-HR of 0.90 (0.78-1.03); and DPP4i initiators had a crude HR of 1.13 (1.04-1.23), ITT-HR of 0.85 (0.77-0.94), and PP-HR of 0.83 (0.71-0.95). Conclusion SGLT2i and DPP4i use did not increase the risk of UTI compared with biguanide use. Accounting for treatment changes did not substantially influence the estimated effects. This article is protected by copyright. All rights reserved.