'Reassuring': New Type 2 Diabetes Drugs Not Linked to UTIs

Miriam E. Tucker

July 29, 2019

Use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of type 2 diabetes does not appear to increase the risk for urinary tract infections (UTIs) compared with two other new classes of type 2 diabetes agents, results from of a large population-based study indicate.

While SGLT-2 inhibitors have consistently been shown to increase the risk for genital infections (predominantly fungal ones as well as the rare but serious complication Fournier gangrene), their link to UTIs is less clear and prior data have been conflicting. However, in 2015, the US Food and Drug Administration added a warning about severe UTIs to the labels of all SGLT2 inhibitors following reports of sepsis with UTIs and pyelonephritis in users of the agents.

In the current study of two large US-based commercial claims databases, comparisons of more than 100,000 individuals with type 2 diabetes initiating SGLT-2 inhibitors with matched patients initiating either dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor (GLP-1) agonists revealed no differences in the rates of either serious or nonserious UTIs over about a 2-year period.

"On the basis of our findings, other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 therapy for patients with diabetes in routine care settings," Chintan V. Dave, PharmD, PhD, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Boston, Massachusetts, and colleagues note.

Their finding were published online today in Annals of Internal Medicine.

"Reassuring Real-World Data"

This new study is "reassuring…[and] has several important implications and represents a key addition to the literature," say Kristian B. Filion, PhD, and Oriana H. Yu, MD, of McGill University and Lady Davis Institute of the Jewish General Hospital, Montreal, Canada, in an accompanying editorial.

It has several strengths, Filion and Yu continue. "Through its propensity score-matched design, use of active comparators at similar points in the management of type 2 diabetes, and rigorous statistical adjustment…it reduced confounding by indication and by other variables. With more than 100,000 patients per cohort, the authors could restrict the analysis to severe UTIs, a clinically important end point among patients with type 2 diabetes. Results were consistent across several analyses, suggesting that the findings are robust to study assumptions."

However, Filion and Yu caution that the work does have some limitations, most notably that patients at high risk for UTIs (eg, those with hydronephrosis, vesicoureteral reflux, spinal cord injuries, or catheter use) were excluded.

"Although such exclusions may have increased validity, they may also have adversely affected generalizability. They also prevented subgroup analyses among patients at greatest risk for the outcome of interest."

Nonetheless, the editorialists conclude: "Ultimately, although some uncertainty remains, the study by Dave and colleagues provides encouraging evidence of the real-world safety of SGLT-2 inhibitors, allowing patients to benefit from their use with greater confidence in their safety with respect to severe UTIs." 

No Differences in Severe or Nonsevere UTIs

The study population came from IBM MarketScan ("MarketScan") and Optum Clinformatics Data Mart ("Optum"), both US databases of patients with employer-based insurance.

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.

Comparing 61,876 SLGT-2 inhibitor users who were propensity-score matched 1:1 (on more than 90 characteristics) with DPP-4 inhibitor users, severe UTI events occurred in 61 patients in the SGLT-2 inhibitor group and 57 in the DPP-4 inhibitor group, giving incidence rates of 1.76 vs 1.77 cases per 1000 person-years respectively, a nonsignificant difference (P = .93).

In a second cohort, after propensity score-matching 55,989 pairs of new SGLT-2 inhibitor users compared with the same number of GLP-1 agonist users, events occurred in 73 vs 87 patients, respectively, giving incidence rates of 2.15 vs 2.96 cases per 1000 person-years, respectively (hazard ratio 0.72, P = .040). 

While that finding seems to suggest a lower UTI risk for SGLT-2 inhibitors compared with GLP-1 agonists, the authors "caution against overinterpreting these results, because additional sources of uncertainty — possibly including chance findings, bias due to differential surveillance, and residual confounding caused by differences in access policies — may have affected our final point estimates and corresponding confidence bounds."

The results were consistent for secondary outcomes, including less severe UTIs. There was also no variation across a range of sensitivity and subgroup analyses, including by sex, age, baseline frailty, or individual SGLT-2 inhibitors. 

In 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," Dave and colleagues reiterate.

The study was supported by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School. Dave has disclosed no relevant financial relationships. Filion holds a Chercheur-Boursier Junior II award from the Fonds de Recherche du Québec – Santé (Quebec Foundation for Health Research) and a William Dawson Scholar award from McGill University. Yu holds a Chercheur-Boursier Clinicien Junior 1 award from the Fonds de Recherche du Québec – Santé.  

Ann Intern Med. Published online July 29, 2019. Abstract, Editorial

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