Sodium–Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections

Abstract

Background: Prior data evaluating risk of severe UTI infections with Sodium-Glucose Co-Transporter 2 inhibitors (SGLT2i) have reported conflicting findings.Objective: To assess whether patients initiating SGLT2i were at an increased risk of developing severe UTI events compared to those initiating Dipeptidyl peptidase-4 inhibitors (DPP-4i) and Glucagon-like Peptide 1 receptor agonists (GLP1a). Design-Population-based cohort study Setting-Two large US-based commercial claims databases (March 2013 -September 2015)Participants-Within each database, two cohorts of 1:1 propensity score-matched patients 18 years and older with type 2 diabetes mellitus, initiating SGLT2 inhibitors vs DPP-4 inhibitors (cohort 1) or GLP1 agonists (cohort 2) Measurements: The primary outcome was a severe UTI event, defined as a hospitalization for either primary UTI, sepsis with UTI or pyelonephritis; secondary outcome was outpatient UTI treated with antibiotics. Hazard ratios [HRs] were estimated in each propensity-score matched cohort adjusting for more than 90 baseline characteristics.Results-After 1:1 PS matching, we identified 123,752 patients in cohort 1 and 111,978 patients in cohort 2 in the two databases. In cohort 1, there were 61 severe UTI events among initiators of SGLT2 inhibitors (incidence rate [IR] per 1,000 person-years=1.76) v 57 in the DPP-4 inhibitor group (IR =1.77), corresponding to a HR of 0.98 (95% CI, 0.68, 1.41). In cohort 2, there were 73 events in the SGLT2 inhibitor group (IR=2.15) vs 87 in the GLP1 agonist group (IR=2.

Incidence of severe urinary tract infections not increased by initiating sodium–glucose cotransporter 2 inhibitors

“…The incidence rates of genital infection and severe UTI in patients with the use of SGLT‐2 inhibitors are absolutely different (Table ). The incidence of severe UTI in the present study was approximately 2.0 per 1,000 person‐years, which is markedly lower than that of genital infection (50–900 per 1,000 person‐years, depending on whether it is symptomatic and on the studies). The present study is valuable in that it explored the very rare incidence rate of severe UTI through a large number of patients by adjustment for confounding factors using the propensity‐match scoring method.…”

“…After the Food and Drug Administration’s advice, Dave et al. carried out a population‐based cohort study to examine whether patients initiating SGLT‐2 inhibitors had an increased risk for severe UTI events. The study included a large number of patients with type 2 diabetes who initiated SGLT‐2 inhibitors: 123,752 in cohort 1 and 111,978 patients in cohort 2.…”

A hypothesis for why sodium glucose co‐transporter 2 inhibitors have been found to cause genital infection, but not urinary tract infection

“…Because clinical trials are often underpowered to detect adverse events, and often exclude patients at highest risk, observational studies using real‐world data with much larger sample sizes than is possible in clinical trials have been conducted to confirm that there is truly no increased risk. Three observational studies, including nearly 100 000 patients who received an SGLT2 inhibitor, have been completed, and none have detected an increased risk of UTI relative to a comparator diabetes medication (Table ) …”

Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials

“…However, in 2015, the FDA added a warning to sodium glucose cotransporter 2 inhibitors (SGLT2is) regarding their risk of causing severe UTIs, sepsis, and pyelonephritis . Recently, a population‐based cohort study examined the risk of severe UTI with initiation of SGLT2i compared to glucagon‐like peptide 1 (GLP‐1) agonists or dipeptidyl peptidase IV (DPP‐IV) inhibitors . They derived their patient data from two large, US‐based databases, comprising 235 730 patients.…”

“…94 Recently, a population-based cohort study examined the risk of severe UTI with initiation of SGLT2i compared to glucagon-like peptide 1 (GLP-1) agonists or dipeptidyl peptidase IV (DPP-IV) inhibitors. 95 They derived their patient data from two large, US-based databases, comprising 235 730 patients. To be included in the study, patients had to be older than 18 years of age and diagnosed with T2DM prior to receiving study pharmacotherapy.…”