Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections A Population-Based Cohort Study

Background: Prior studies evaluating risk for severe urinary tract infections ( UTIs) with sodium-glucose cotransporter-2 ( SGLT-2) inhibitors have reported conflicting findings. Objective: To assess whether patients initiating use of SGLT-2 inhibitors were at increased risk for severe UTI events compared with those initiating use of dipeptidyl peptidase-4 ( DPP-4) inhibitors or glucagon-like peptide-1 receptor ( GLP-1) agonists. Design: Population-based cohort study. Setting: 2 large, U. S.-based databases of commercial claims ( March 2013 to September 2015). Participants: Within each database, 2 cohorts were created and matched 1: 1 on propensity score. Patients were aged 18 years or older, had type 2 diabetes mellitus, and were initiating use of SGLT-2 inhibitors versus DPP-4 inhibitors ( cohort 1) or GLP-1 agonists ( cohort 2). Measurements: The primary outcome was a severe UTI event, defined as a hospitalization for primary UTI, sepsis with UTI, or pyelonephritis; the secondary outcome was outpatient UTI treated with antibiotics. Hazard ratios ( HRs) were estimated in each propensity score-matched cohort, with adjustment for more than 90 baseline characteristics. Results: After 1: 1 matching on propensity score, 123 752 patients were identified in cohort 1 and 111 978 in cohort 2 in the 2 databases. In cohort 1, persons newly receiving SGLT-2 inhibitors had 61 severe UTI events ( incidence rate [ IR] per 1000 person-years, 1.76), compared with 57 events in the DPP-4 inhibitor group ( IR, 1.77) ( HR, 0.98 [ 95% CI, 0.68 to 1.41]). In cohort 2, those receiving SGLT-2 inhibitors had 73 events ( IR, 2.15), compared with 87 events in the GLP-1 agonist group ( IR, 2.96) ( HR, 0.72 [ CI, 0.53 to 0.99]). Findings were robust across sensitivity analyses; within several subgroups of age, sex, and frailty; and for canagliflozin and dapagliflozin individually. In addition, SGLT-2 inhibitors were not associated with increased risk for outpatient UTIs ( cohort 1: HR, 0.96 [ CI, 0.89 to 1.04]; cohort 2: HR, 0.91 [ CI, 0.84 to 0.99]). Limitation: Generalizability of the study findings may be limited to patients with commercial insurance. Conclusion: In a large cohort of patients seen in routine clinical practice, risk for severe and nonsevere UTI events among those initiating SGLT-2 inhibitor therapy was similar to that among patients initiating treatment with other second-line antidiabetic medications.