Effect of SGLT2 Blockade with Dapagliflozin on the Development of Cardiomyopathy in Diabetes

Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are new diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential use of these drugs to prevent cardiovascular deterioration. However, the mechanism of protection remains unclear. In our study, we investigated the effect of Dapagliflozin (SGLT2I) on diabetic cardiomyopathy in angiotensin II (AT) stressed db/db mice.

Methods: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of AT for 30 days using an osmotic pump at a rate of 1000ng·kg⁻¹·min⁻¹. Dapagliflozin (1.5mg/kg/day) was administered concomitant with AT in drinking water. Intracellular calcium level was measured using fluorescent indicator indo-1-AM. In addition, isolated cardiomyocytes exposed to different levels of glucose (7.5-33 mM) were treated with Dapagliflozin in vitro.

Results: In vitro, Dapagliflozin decreased intracellular calcium, inflammatory markers and ROS production in AT- treated cardiomyocytes exposed to different levels of glucose (7.5 and 33 mM).

In vivo studies: AT infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis, inflammation (TNFα, TLR4) and down regulation of anti-oxidative defense (HO-1). Treatment by Dapagliflozin ameliorated these markers in both control db/db and AT treated db/db mice. It significantly decreased blood glucose (874±111 to 556±57 mg/dl) and blood pressure (147±4 to 134±2 mmHg). The left ventricular fractional shortening improved in AT treated db/db mice (34.9±2.6% vs 46±6.5% p<0.05).

Conclusion: A direct cardioprotective effect of Dapagliflozin was observed in the diabetic heart. Dapagliflozin suppression of intracellular calcium level is associated with attenuation of inflammation and oxidative stress thereby reducing the detrimental AT effects in the diabetic heart. Our in vitro studies suggest that the protective effect is independent of glycemic control.