DAPAGLIFLOZIN ATTENUATES DIABETIC CARDIOMYOPATHY AND THE ACTIVATION OF THE NLRP3/ASC INFLAMMASOME IN MICE WITH TYPE-2 DIABETES: A GLUCOSE-LOWERING AND SGLT-2 INDEPENDENT EFFECT



Yochai Birnbaum, M.D., UTMB, Galveston, Texas, USA

Purpose: We assessed whether 1) Dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function and inflammasome activation in diabetic mice. 2) the effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. 3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in-vitro.

Methods: Type-2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS.

Results: Left ventricular ejection fraction (LVEF) was 81±1% in the WT and 53±1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68±1% and 74.6±1% in the BTBR mice (p<0.001). The mRNA levels of NALP3, ASC, IL-1â, IL-6, Caspase-1 and TNFá were significantly higher in the BTBR compared to the WT hearts; and Dapa and Dapa+Saxa significantly attenuated these levels. Collagen-1 and -3 mRNA levels significantly increased in the BTBR mice and these increases were attenuated by Dapa and Dapa+Saxa. The in-vitro study showed that NALP3, ASC, IL-1â and Caspase-1 mRNA levels were higher in the BTBR cardiofibroblasts and attenuated with Dapa. The effect was AMPK-dependent and SGLT1-independent.

Conclusions: Dapa attenuated the activation of the inflammasome, fibrosis and deterioration of LVEF in BTBR mice. The anti-inflammatory, anti-fibrotic effects are likely SGLT2- and glucose-lowering-independent, as they were replicated in the in-vitro model. The effects on remodeling were augmented when Saxa was added to Dapa. Yet, adding Saxa to Dapa did not result in a greater effect on myocardial fibrosis and collagen levels.