Dysplastic urothelial changes accompany empagliflozin administration in urinary bladder of experimental diabetes

Abstract

Summary Empagliflozin (EMPA) is a promising novel antidiabetic drug; however, doubts have been raised regarding its use and the increased risk of urinary bladder carcinoma. In this study, we evaluated urothelium expression of cytokeratins (CKs) and Ki‐67 proliferative activity in the urinary bladder of diabetic (DM + EMPA) and non‐diabetic rats after EMPA administration. By routine histology, dysplastic changes were detected in the urothelium of diabetic as well as non‐diabetic animals after EMPA administration. Moreover, the expression of CK‐7 and CK‐8 was significantly decreased (P < .05) while that of CK‐20 as well as Ki‐67 was significantly increased (P < .05) in EMPA per se and DM + EMPA urothelium groups compared to that of control and diabetics. The dysplastic changes together with the increased proliferative activity in urothelium after EMPA administration provide a cellular evidence that supports the former clinical concerns.

Insights into the impact of sodium‐glucose cotransporter 2 inhibition on urinary tract malignancy: A two‐sample Mendelian randomization

“…However, the mechanisms by which SGLT2 analogues may be associated with prostate and bladder cancer are not well understood. Empagliflozin may interfere with caspase 3 and Bcl2 at the genetic level resulting in an imbalance in the apoptotic/anti‐apoptotic pathway, allowing for aberrant changes in the urinary tract epithelium 16 . SGLT2 inhibitors have led to an increase in the levels of glycosuria produced, which may cause chronic irritation of the urinary tract epithelium.…”

“…Despite the controversy, the meta‐analysis by Tang et al also observed that empagliflozin might increase the risk of bladder cancer 15 . Notably, a recent basic study discovered that the use of empagliflozin in rats induced uroepithelial dysplasia, suggesting that this SGLT2 inhibitor may elevate the incidence of premalignant proliferative lesions and carcinomas of the bladder 16 . However, the mechanisms by which SGLT2 analogues may be associated with prostate and bladder cancer are not well understood.…”

Deciphering the Causal Relationship between Sodium-glucose Cotransporter 2 Inhibition and Cancer Risks: A Comprehensive Mendelian Randomization Study

“…Upon reviewing the literature, we found that current evidence regarding the impact of SGLT2 inhibition on prostate cancer remains limited. A study examining the effect of empagliflozin on the urothelium of diabetic and non-diabetic animals observed abnormal dysplastic urothelial changes, such as increased proliferative activity 52 .…”

Pioglitazone Induces Dysplastic Urothelial Changes in Urinary Bladder of Experimental Diabetes

“…Together with Ki67, CK20 may be helpful in differential consideration for urothelial dysplasia from reactive atypia. [ 32 33 ] Ki67 is well known marker for epithelial proliferation in vascular, 34 metabolic[35-40] as well as pre-neopalstic lesions. [41-43] CK20 expression is restricted to the umbrella cells in normal urothelium.…”