Sodium‐glucose cotransporter 2 inhibitor ameliorates thiazolidinedione‐induced fluid retention through vascular leakage reduction in white adipose tissue

Abstract Aim Thiazolidinediones (TZDs) are effective insulin sensitisers; however, their use is restricted owing to adverse effects such as fluid retention. Previous research has linked increased vascular permeability in white adipose tissue (WAT) to TZD‐induced fluid retention. We explore the potential of sodium‐glucose cotransporter 2 inhibitors (SGLT2is) to counteract this side effect and elucidate the underlying mechanisms. Materials and Methods High‐fat‐diet‐induced obese mice (C57BL/6) were assigned to three groups: (1) lobeglitazone 0.5 mg/kg (TZD monotherapy); (2) a combination of lobeglitazone 0.5 mg/kg plus empagliflozin 10 mg/kg with 0.16 mg/mL in drinking water (TZD + SGLT2i combination therapy); and (3) distilled water (control). After 6 weeks of treatment, body composition and water content in multiple tissues were measured. The expression of proteins and mRNA related to vascular permeability, renal sodium and water channels was investigated. Additionally, in vivo and in vitro experiments (the latter in human umbilical vein endothelial cells) using anti‐VEGF agents were conducted. Results TZD treatment escalated vascular leakage and fluid retention in WAT, which was associated with diminished VE‐cadherin expression and compromised vascular integrity. Co‐treatment with the SGLT2i mitigated these adverse effects, reinstating VE‐cadherin expression, reducing vascular permeability and normalizing tissue water content. Empagliflozin was found to inhibit the VEGF‐A/VEGFR2 signalling pathway, thereby reducing VE‐cadherin internalisation and degradation. In vitro studies reinforced these findings, emphasizing the interplay between VEGF and VE‐cadherin in maintaining endothelial junction stability. Conclusions Our results suggest that SGLT2is protect against TZD‐induced fluid retention by preserving vascular integrity in WAT, providing a viable therapeutic strategy to minimise TZD‐associated side effects.