• Chintan V Dave, Sebastian Schneeweiss, Dae Kim, Michael Fralick, Angela Tong, and Elisabetta Patorno.
• Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (C.V.D., S.S., D.K., M.F., A.T., E.P.).
• Ann. Intern. Med. 2019 Aug 20; 171 (4): 248-256.

BackgroundPrior studies evaluating risk for severe urinary tract infections (UTIs) with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have reported conflicting findings.ObjectiveTo 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.DesignPopulation-based cohort study.Setting2 large, U.S.-based databases of commercial claims (March 2013 to September 2015).ParticipantsWithin 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).MeasurementsThe 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.ResultsAfter 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]).LimitationGeneralizability of the study findings may be limited to patients with commercial insurance.ConclusionIn 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.Primary Funding SourceBrigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

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