Genitourinary safety aspects of SGLT2 inhibitor therapy in patients with type 2 diabetes

The introduction of sodium-glucose cotransporter 2 inhibitors (SGLT2i) into treatment algorithms for type 2 diabetes mellitus (T2DM) has initiated a shift from the traditional glucose-centric model to a strategy that considers multiple pathogenetic factors and clinical outcomes. Despite their proven efficacy in reducing cardiovascular mortality and chronic kidney disease progression, the actual clinical use of SGLT2i is often accompanied by patient complaints of dysuria, raising additional questions for clinicians regarding the urogenital safety of SGLT2i. This review summarizes current pathophysiological data, clinical trial results, and meta-analyses regarding the risk of urinary tract infections (UTIs) and genital mycotic infections (GMIs) associated with the use of various SGLT2i. The pathogenesis of these complications is diverse, with the primary component being pharmacological glucosuria, which transforms the urinary tract microenvironment into a breeding ground for pathogens, enhancing the expression of Escherichia coli virulence factors and stimulating the growth of Candida. The risk of infection is further exacerbated by the fact that patients with T2DM often exhibit signs of secondary immunodeficiency and neurogenic bladder dysfunction.

Currently, it is clear that the development of GMIs is a consistent adverse event associated with the use of SGLT2i, with a frequency more than three times higher than with placebo. However, significant heterogeneity is observed with respect to UTIs: a statistically significant risk has been confirmed primarily for dapagliflozin at a dose of 10 mg, while data for other members of the class are less clear. However, luseogliflozin and ipragliflozin demonstrate the most favorable safety profiles for urogenital infections. In 2015, the FDA expressed significant concern about the development of severe infections such as urosepsis and pyelonephritis. However, subsequent studies showed no association between SGLT2i use and the risk of these conditions. Furthermore, some studies found that inappropriate drug discontinuation after a UTI episode could lead to increased mortality and worse renal outcomes.

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