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

Background: SGLT2 inhibition with empagliflozin reduced the primary composite outcome (cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke) in patients with type-2 diabetes (T2D).
Purpose: To assess whether Dapagliflozin (Dapa) attenuates the deterioration of left ventricular (LV) function and the activation of the inflammasome in T2D mice.
Methods: Male BTBR ob/ob and wild type (WT) mice received vehicle or Dapa for 8W. I.P. glucose tolerance test and echocardiogram were performed. Hearts were harvested. Cardiofibroblasts from WT and T2D hearts and incubated with Dapa (0 to 0.5μM) for 16h and exposed to LPS for 3h. The components of the inflammasome were assessed by rt-PCR.
Results: Dapa improved glucose tolerance in the T2D mice. Left LV ejection fraction (LVEF) was 81±1% in the WT mice and 53±1% in the T2D-cont mice. Dapa improved LVEF to 68±1% in the T2D mice (p<0.001). Likewise, left ventricular end-diastolic and end-systolic volume were increased in the T2D-cont compared to the WT mice. Dapa significantly attenuated the increase in the T2D mice. SGLT-2 was not expressed in the hearts of the WT and T2D mice. The mRNA levels of NALP3, ASC, IL-1β, IL-6, Caspase-1 and TNFα were significantly higher in the T2D compared to the WT hearts. Dapa significantly attenuated the mRNA levels of NALP3 (5.1±0.4 vs. 11.9±1.5), ASC (4.3±0.4 vs. 13.0±2.1), IL-1β (2.6±0.2 vs. 7.8±1.0), IL-6 (2.3±0.2 vs. 7.1±0.9), Caspase-1 (3.0±0.2 vs. 0.4±1.0) and TNFα (4.0±0.3 vs. 7.7±0.4)(pConclusions: Dapa attenuates T2D-induced activation of the inflammasome, increased expression of collagen and the adverse cardiac remodeling. As SGLT-2 is not expressed in the heart and similar effects were seen in vitro, a direct SGLT-2 and glucose lowering independent effect is present.