Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are new generation oral antidiabetics, acting through inhibition of sodium and glucose absorption in proximal renal tubules, thus increasing urinary glucose excretion. The resulting osmotic diuresis has raised the concern that SGLT2i might be associated with increased lower urinary tract symptoms (LUTS), which is still not clear in the literature. Up to the present date, there is only one study reporting increased LUTS in patients taking SGLT2i up to 1 year [1]. There is still no data on the long-term effect of SGLT2i in LUTS and data from cardiovascular research advance that the diuretic effect is transitory [2]. The aim of this study was to assess the prevalence of LUTS in patients with type 2 diabetes mellitus (T2D) chronically treated (≥ 1 year) with SGLT2i. This is the first report of LUTS in patients taking SGLT2i for this period of time.

This is a cross-sectional study, which included patients with T2D chronically treated with SGLT2i, followed by Endocrinology between 2010 and 2020. Inclusion criteria were: age 45-80 years old; T2D diagnosis 3 years ago or more; taking SGLT2i for 1 year or more. Exclusion criteria were: presence of prostate or bladder cancer, urinary lithiasis, pelvic radiotherapy, neurogenic bladder, or known lower urinary tract dysfunction. This study was approved by local ethical committee and informed consent was obtained from all participants.
A urine dipstick analysis was performed to exclude urinary infection and confirm high urinary glucose concentration. The following questionnaires were then applied: IPSS, OABSS and PPBC. Uroflowmetry, prostate volume and post-void residual (PVR) measurement were also performed.

A total of 34 patients were enrolled in the study (n=23 male and n=11 female). Mean age was 62 years. We found mild storage and voiding LUTS and good functional parameters with a mean bladder voiding efficiency (BVE) of 81,19% and a mean Qmax of 19.4 mL/s. Correspondingly, patients reported a very good quality of life and in PPBC assessment 79% of patients reported no symptoms or very minor symptoms. Demographic, questionnaires scores and morpho-functional parameters are summarized in table 1. No significant differences were found between genders in all parameters.

In our study, diabetic patients of both genders chronically treated with SGLT2i presented mild LUTS and showed good BVE. Contrariwise to previous data on SGTL2i treatment for <1 year [1], we found that SGLT2i treatment for ≥ 1 year is not associated with increased LUTS neither worse functional outcomes. These results could represent an adaptation to SGLT2i osmotic diuretic effect. Moreover, we hypnotize that SGLT2i long-term use can also be valuable to bladder remodeling and thus counteract diabetic cistopathy. Our hypothesis is based on recent cardiovascular data of SGLT2i pleiotropic effects in heart failure [3]. Further studies are needed to better define the impact of SGLT2i on LUTS and bladder function.

SGLT2i long-term use in diabetic patients is not associated with bothersome LUTS or impaired functional parameters. The SGLT2i therapy should not be discouraged, although a possible increase in LUTS in the beginning of the treatment.

Chilelli NC, Bax G, Bonaldo G, Ragazzi E, Iafrate M, Zattoni F, et al. Lower urinary tract symptoms (LUTS) in males with type 2 diabetes recently treated with SGLT2 inhibitors-overlooked and overwhelming? A retrospective case series. Endocrine. 2018;59:690-3.
Ansary TM, Nakano D, Nishiyama A. Diuretic Effects of Sodium Glucose Cotransporter 2 Inhibitors and Their Influence on the Renin-Angiotensin System. Int J Mol Sci. 2019;20.
Kaplan A, Abidi E, El-Yazbi A, Eid A, Booz GW, Zouein FA. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev. 2018;23:419-37.