Dave CV, Schneeweiss S, Kim D, et al. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections: A Population-Based Cohort Study. Ann Intern Med. 2019 Jul 30. pii: 2739786. doi: 10.7326/M18-3136. (Original 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.

Primary Funding Source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Endocrine 6 / 7
Internal Medicine 6 / 7
Comments from MORE raters

Endocrine rater

These results are reassuring regarding risk for UTIs with SGLT2-inhibitors, but generalizability of the findings are limited to younger patients with insurance.

Endocrine rater

Important information as it refutes real-world data from some UTI RCT studies. A possible reason is that in RCTs, the patients were treated for RUA findings that were asymptomatic in real-world patients.

Endocrine rater

This is new reassuring news about a potential complication of SGLT-2's.

General Internal Medicine-Primary Care(US) rater

Previous studies suggest that SGLT2i may be associated with UTI, so although this study is a secondary data analysis of claims data, it provides some reassurance that SGLT2i do not appear to be associated with increased risk. Additional trials examining the safety of SGLT2i are still needed.

Internal Medicine rater

The study has severe limitations. This study will not change my practice. We are obligated to inform the patients the possibility of UTIs when SGLT2 inhibitors are being started.

Internal Medicine rater

This goes against what many might have assumed. Good to know there is no increased risk for UTI.

Internal Medicine rater

This is good news. This study reduces the concern about the risk for UTIs in patients taking SGLT-2 inhibitors.
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