Are SGLT2 inhibitors really associated with increased urinary tract infection risk? A trial-level meta-analysis across type 2 diabetes, heart failure, and chronic kidney disease.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are established therapies across the cardiovascular-renal continuum. Although the excess risk of external genital infection is well recognized, the association between SGLT2 inhibition and urinary tract infection (UTI), particularly serious/complicated urinary infection, remains uncertain. METHODS: We conducted a systematic review and meta-analysis of randomized placebo-controlled trials of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and bexagliflozin in adults with type 2 diabetes, chronic kidney disease, or heart failure. Co-primary urinary safety outcomes were any UTI and serious/complicated urinary infection, the latter defined using directly reported serious UTI endpoints or the closest reported severe urinary phenotype. Sensitivity analysis, subgroup analyses by drug and population, leave-one-out analyses, and exploratory meta-regression were performed. RESULTS: A total of 14 studies were included. For the primary any-UTI analysis, 11 studies contributed data, comprising 62,542 participants and 4,685 events. SGLT2 inhibitors were associated with a pooled RR of 1.14 (95% CI 0.99-1.32; P = 0.073), with substantial heterogeneity (I²=76.0%). In the prespecified sensitivity analysis excluding reconstructed CANVAS estimates, 10 studies comprising 52,400 participants and 4,019 events yielded a pooled RR of 1.08 (95% CI 1.00-1.18; P = 0.060), with lower heterogeneity (I²=23.3%). For the serious/complicated urinary infection analysis, 7 studies comprising 34,396 participants and 339 events were available. The pooled RR was 0.99 (95% CI 0.78-1.27; P = 0.960), with no detectable heterogeneity (I²=0.0%). No significant subgroup differences were observed by individual SGLT2 inhibitor or by clinical population. CONCLUSIONS: SGLT2 inhibitors were not associated with a statistically significant increase in any UTI or serious/complicated UTI. These findings support a distinction between lower-grade urinary events and clinically severe urinary infection, and suggest that urinary safety concerns should not be considered equivalent to the established excess risk of external genital infection.