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Use of SGLT2 inhibitors and the incidence of urinary tract infections in patients with heart failure: a pooled analysis of four trials including 26.838 patients

Background: Sodium-glucose transport protein 2 (SGLT2) inhibitors are a novel class of drugs initially developed for the treatment of type II diabetes mellitus (T2DM) through the principal mechanism of glucose reabsorption inhibition at the proximal convoluted tubule. It was soon observed that SGLT2 inhibitors demonstrated potent cardioprotective effects beyond the hypoglycemic mechanism thus rendering their use in heart failure with reduced ejection fraction (HFrEF) to further reduce mortality and morbidity outcomes. In clinical trials, genital and urinary tract infection (UTI) and volume depletion associated with SGLT2 use have been commonly reported. Purpose: To determine the risk of UTI associated with SGLT2 use in patients with chronic or acutely worsened HF, compared to placebo. Methods: Three randomized clinical trials (RCTs) and a prespecified subanalysis of one major RCT were included in the analysis. Two included patients with HFrEF (DAPA-HF and EMPEROR-Reduced), one included patients with T2DM that were hospitalized for worsening HF (SOLOIST-WHF) while one was the subanalysis focused on a subgroup of patients that had HF and T2DM (DECLARE- TIMI 58). Two trials examined the use of dapagliflozin, one of empagliflozin and one of sotagliflozin. All trials reported on the incidence of urinary tract infections. Fixed-effects meta-analysis with Mantel Haenszel algorithm was performed with a relative risk (RR) and 95% confidence intervals (95% CI) reported as main outcome measures. Heterogeneity across studies was inspected by I2 statistic. Results: A total of four trials encompassing 26.838 patients with HF with pooled 569 UTI events were recorded. Of these, 285 UTI events were recorded in the SGLT2 group (2.12%) and 284 in the placebo group (2.11%). The observed heterogeneity across studies was low and non- significant (I2=11%) in the random- effects model, therefore, the main analysis was carried out by using a fixed-effects model. We found that the use of SGLT2 inhibitor was similar to placebo concerning the risk of UTI among patients with HF (RR 1.005, 95% CI 0.855-1.181 ; Figure 1) and this was based on the evidence of no significant heterogeneity across included studies (P=0.336). The leave- one-out fixed-effects analysis confirmed this finding (Figure 2). Conclusion: In patients with heart failure, treatment with SGLT2 inhibitors was not associated with an increased risk of urinary tract infections compared to placebo.

Heart Failure ; HF ; HFrEF ; Heart failure with reduced ejection fraction ; SGLT2 ; sodium-glucose cotransporter 2 ; urinary tract infections ; UTI ; diabetes mellitus ; T2DM ; dapagliflozin ; empagliflozin ; sotagliflozin

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