OBJECTIVES: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have received an expanded indication for heart failure with preserved ejection fraction (HFpEF) by the Food and Drug Administration, but little is known about their real-world in-class comparative safety in patients with HFpEF. We aimed to compare in-class safety of SGLT2i for the risk of genitourinary infections, a composite of urinary tract infections (UTI) or genital infections, among patients with HFpEF.

METHODS: We conducted a cohort study using MarketScan® Commercial and Medicare Supplemental databases (2012–2020). Patients aged ³18 years diagnosed with HFpEF who initiated an SGLT2i were included. The index date was the first prescription fill date of SGLT2i. We established three pairwise comparisons of patients including cohort 1 (dapagliflozin vs. canagliflozin), cohort 2 (empagliflozin vs. canagliflozin), and cohort 3 (dapagliflozin vs. empagliflozin). After stabilized inverse probability treatment weighting, Cox proportional hazards regression was used to compare the composite outcome and each individual component outcome in each cohort.

RESULTS: We identified 1,776 patients with HFpEF who initiated SGLT2i (415 dapagliflozin, 513 canagliflozin, and 848 empagliflozin users). Among these, 27 canagliflozin, 24 dapagliflozin, and 66 empagliflozin users had the composite outcome during follow-up. No significant difference was observed between dapagliflozin and canagliflozin on the composite outcome (adjusted hazard ratio [aHR], 0.64; 95% confidence interval [CI], 0.36 - 1.14). Similarly, no difference was observed between empagliflozin and canagliflozin (aHR, 1.25; 95% CI, 0.77 – 2.05), nor between dapagliflozin and empagliflozin (aHR, 0.76; 95% CI, 0.48–1.21). These results were consistent in separate analyses of the individual component (UTI and genital infections) outcomes.

CONCLUSIONS: We observed no evidence of difference in the risk of genitourinary infections among users of canagliflozin, dapagliflozin, and empagliflozin.