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

Abstract

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.

Primary funding source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

Figure 1:

Propensity-score matched Kaplan-Meier curves for cumulative incidence of severe UTI events in the pooled cohort of patients DPP4: Dipeptidyl peptidase-4 inhibitors; GLP1: Glucagon-like peptide agonists; SGLT2: Sodium Glucose Cotransporter-2 inhibitors

Figure 1:

Propensity-score matched Kaplan-Meier curves for cumulative incidence of severe UTI events in the pooled cohort of patients DPP4: Dipeptidyl peptidase-4 inhibitors; GLP1: Glucagon-like peptide agonists; SGLT2: Sodium Glucose Cotransporter-2 inhibitors