Progressive Inflammatory Cystitis (PIC) has recently been defined as an idiopathic cause end stage bladder (ESB) characterized by lower urinary tract symptoms, reduced capacity and compliance, upper tract abnormalities, and diffuse inflammatory changes on cystoscopy [1]. This retrospective case series was conducted in response to two index cases of PIC diagnosed by the senior author. Based on their presentation, we hypothesized that sodium-glucose cotransporter 2 inhibitors (SGLT2i), a class of diabetic medications, are associated with development of PIC/ESB.

We performed a retrospective chart review to identify patients with history of diabetes treated with a SGLT2i who subsequently developed PIC/ESB. To do so, we queried TriNetX, a cloud-based database platform with access to our single academic center’s electronic medical record (EMR) data recorded on or after 9/2010. Because PIC/ESB does not have an International Classification of Diseases (ICD) code, we employed multiple search strategies to identify potential cases, including symptoms such as urgency urinary incontinence and low bladder capacity, as well as codes for diagnostic and/or therapeutic procedures that would be used for PIC/ESB (e.g., urodynamics). Patients with clear confounders like pelvic radiation therapy, bladder outlet obstruction, or spinal cord injury were excluded. Potential case charts were reviewed for pertinent information from urology encounters, cystoscopy, urodynamics, pathology, and SGLT2i prescription history. Patients were included if chart review was consistent with PIC/ESB, defined as two of three categories: (1) small bladder capacity (≤150 mL), (2) ≥3 months urinary storage symptoms, (3) reduced bladder compliance (≤30 mmH20/mL) , vesicoureteral reflux, hydronephrosis, or chronic diffuse inflammatory cystitis changes on cystoscopy.

The initial query returned 357 patients. Two patients met inclusion criteria following chart review. The two index cases were also included, for a total of 4 patients. All patients were white and non-Hispanic, and half (n = 2) were female. Median age at presentation was 58.5 years (range, 35 – 72 years). Symptoms at presentation included urinary urgency/frequency (n = 3), hydronephrosis (n = 3), incontinence (n = 2), urinary retention (n = 2), and fungal UTIs (n = 1). Median duration of SGLT2i exposure was 21.5 months (range, 5 – 36 months). Half the cohort (n = 2) had pre-existing urinary symptoms that were exacerbated with SGTL2i, and the other half (n = 2) developed symptoms 5 – 26 months after initiating SGLT2i. Cystoscopy results were variable and two patients had no findings. Significant urodynamics findings included low compliance (median, 5 mL/cmH2O), low/borderline capacity (median, 154 mL), and vesicoureteral reflux. One patient progressed to suprapubic catheter and two are undergoing urinary diversion.

These cases may represent early stages of PIC/ESB that were triggered or exacerbated by SGLT2i. SGLT2i are commonly used for glycemic control in type 2 diabetes mellitus and work by blocking renal resorption of glucose. In 2015, the U. S. Food and Drug Administration (FDA) issued a warning about life-threatening ascending UTIs associated with SGLT2i [2]. Notably, two patients in this cohort had recurrent bacterial or fungal UTIs. Little data are available on fungal UTIs associated with SGLT2i, but one trial found that SGLT2i duration and dosage was positively associated with the number of Candidal colony forming units found in mice kidneys [3]. Based on our cohort findings, we hypothesize that in a subset of UTI-susceptible patients, glucosuria from SGLT2i leads to funguria/bacteruria, promoting inflammation and oxidative stress, resulting in structural bladder changes with compromised compliance and capacity. A causal relationship has not been documented in the literature, and the FDA Adverse Event Reporting System database (FAERS) was queried for cases of PIC/ESB associated with SGLT2i and no reports were found.

PIC/ESB is a poorly defined and heterogenous diagnosis with poor prognosis [1]. This case series aims to explore a potential relationship between SGLT2i exposure and PIC/ESB. We propose a potential underlying mechanism of infection, inflammation, and resultant structural bladder changes. Future prospective study should focus on refining diagnostic criteria of PIC/ESB and large population-based case-cohort studies to compare risk of PIC/ESB in patients with versus without SGLT2i exposure.

Faris, A. et al. Destroyed bladders: Characterization of progressive inflammatory cystitis. Neurourol. Urodyn. 42, 1194–1202 (2023).
U.S. Food and Drug Administration. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. (2015).
Rodrigues, C. F., Rodrigues, M. E. & Henriques, M. Candida sp. Infections in Patients with Diabetes Mellitus. J. Clin. Med. 8, 76 (2019).