UTI Risk by Type of SGLT2 Inhibitor

The risk of urinary tract infections (UTIs), but not necessarily genital infections, may vary by agent within the SGLT2 inhibitor class, according to a meta-analysis published in Diabetes, Obesity and Metabolism.¹

“Our meta-analysis results indicated that all doses of canagliflozin, dapagliflozin, and empagliflozin were associated with significantly higher risk of genital infections than placebo and other active treatments, but only dapagliflozin 10 mg could lead to higher risk of UTIs than placebo and other active treatments,” wrote lead author Huilin Tang, MSc, of Indiana University (Indianapolis, IN), along with colleagues in China.

“[D]apagliflozin appeared to have [a] dose-response relationship for risk of UTIs and genital infections. On the contrary, incidence of UTIs and genital infections remained similar or even decreased for empagliflozin and canagliflozin,” they added.

SGLT2 inhibitors have been linked to increased risk for UTIs and genital infections, most likely due to glucosuria induced by these drugs. In December 2015, the US Food and Drug Administration (USFDA) revised the labeling of SGLT2 inhibitors to include risk for serous UTIs, due to reports of urosepsis and pyelonephritis in 19 patients on SGLT2 inhibitors.²

Yet how risk for this well-known side effect may vary across members of this drug class and across dosages has been unclear. The current study updates past meta-analyses on this subject, and additionally includes an evaluation of dose effects. It is also the first study to quantitatively analyze risk factors associated with UTIs and genital infections, such as gender, baseline HbA1c, ethnicity, BMI, and T2DM duration.

In the study, researchers systematically searched PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to October 2016, for RCTs that reported on UTIs and genital infection in patients with T2D treated with SGLT2 inhibitors. They excluded trials with uncommonly used dosages. 

The analysis included 52 RCTs with a follow-up ranging from 24-160 weeks, and covering 36,689 patients: 11 on canagliflozin, 21 on dapagliflozin, 18 on empagliflozin, 1 on luseogliflozin, and 1 on ipragliflozin. Researchers excluded data from treatment arms that combined SGLT2 inhibitors with other active drugs. They did meta-regression analyses to evaluate possible effects of characteristics related to the study (study mode, follow-up periods, type of events, sample size) and participants (gender, race, baseline HbA1c, T2DM duration, BMI, age)

 Key results:

• UTIs and genital infections most commonly occurred during the first 24-26 weeks of therapy, and decreased over time

• Genital Infections:

♦ Significantly higher odds for canagliflozin, dapagliflozin, and empagliflozin vs placebo

♦ No significant differences across canagliflozin, dapagliflozin, and empagliflozin

♦ Dose: 55% increased risk with dapagliflozin 10 mg vs dapagliflozin 2.5 mg (OR 1.55, 95% CI 1.08-2.23)

• UTIs:

♦ Significantly higher risk only with dapagliflozin 10 mg vs placebo (OR 1.28, 95% CI 1.06-1.54) or other active drugs (OR 1.28, 95% CI 1.02-1.61)

♦ Significantly lower risk with empagliflozin vs dapagliflozin (OR 0.79, 95% CI 0.64-0.97)

♦ Dose: Significantly more UTIs with dapagliflozin 10 mg vs dapagliflozin 2.5 mg (OR 1.65, 95% CI 1.05-2.57)

• Only dapagliflozin appeared to have a dose-response relationship for UTIs and genital infections

• Gender:

♦ Genital infections: Significantly higher in women vs men for all SGLT2 inhibitors (OR 2.25, 95% CI 1.99-2.54) and placebo (OR 2.48, 95% CI 1.66-3.73)

♦ UTIs: Significantly higher UTI incidence in women vs men for empagliflozin (OR 4.92, 95% CI 4.22-5.74, P=0.082) and dapagliflozin (OR 3.08, 95% CI 2.08-4.55, P=0.664).

• Meta-regression suggested that follow-up period was the only factor that had a modifying effect on the strength of these findings

The authors noted that interpretation of gender differences in UTIs was complicated by the fact that women in placebo groups also experienced more UTIs than men. However, meta-regression results suggested that gender was not a significant modifying factor for these results.

“UTIs and genital infections should be monitored cautiously for all patients [on SGLT2 inhibitor therapy], even those who have never been deemed to be lower risk such as male patients,” they concluded.

Take-home Points

• A meta-analysis of RCTs found that all SGLT2 inhibitors are associated with an increased risk of genital infections.

• Only dapagliflozin 10 mg was associated with an increased risk of urinary tract infections (UTIs).

• Only dapagliflozin appeared to have a dose-response relationship for UTI and genital infections.

• Genital infections were significantly increased in women vs men for all SGLT2 inhibitors.

• UTIs were significantly increased in women vs men for empagliflozin and dapagliflozin.

• Patients on SGLT2 inhibitors should be closely monitored for genital infections and UTIs regardless of whether they are thought to be lower risk.

References:

1. Li D, et al. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016 Nov 12.

2. U. S. Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. 2015. Accessed December 13, 2016 at: http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm.