Sodium–glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy

Abstract

Background: 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 recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. Methods: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. Results: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. Conclusion: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

Bibliometric Study of Sodium Glucose Cotransporter 2 Inhibitors in Cardiovascular Research

“…SGLT2 inhibitors were shown to significantly improve diastolic function in the human heart, as confirmed in the myocardium of mice with or without DM and further in HFpEF models ( Habibi et al., 2017 ; Pabel et al., 2018 ; Zhang et al., 2019 ). Substantial evidence has suggested that SGLT2 inhibitors ameliorate worsening cardiac dysfunction by reducing cardiac inflammation and oxidative stress ( Ye et al., 2017 ; Li et al., 2019 ; Arow et al., 2020 ; Byrne et al., 2020 ). Although an increasing number of studies on HFpEF have been conducted ( Anker et al., 2019 ), more in-depth research on SGLT2 inhibitors in HFpEF is expected to be conducted in the future.…”

Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy

“…Some of these commonly-used models of diabetes, e.g. streptozotocin-treatment (STZ) and the db/db genetic mouse model, have previously been combined with angiotensin II or uninephrectomy to mimic and accelerate DbCM or DN, respectively 21 – 23 .…”

Comparison of the Effect of Dapagliflozin on Contrast to Standard Therapy of the Patients With Type 2 Diabetes Mellitus and Concomitant Obesity, Their Effect on Laboratory and Anthropometric Parameters

“…Dapagliflozin is a selective and inverse inhibitor of type 2 glucose cotransporter (SGLT2) [8]. Dapagliflozin lowers glucose levels both after ingestion and on an empty stomach by reducing renal glucose absorption and as a consequence of its excretion in the urine [8]. However, this medicine does not interfere with the normal production of endogenous glucose in response to hypoglycemia and acts independently of insulin secretion and action.…”

“…Urinary glucose excretion induced by dapagliflozin is associated with calorie loss and weight loss [9]. Suppression of the co-transport of glucose and sodium by dapagliflozin may be accompanied by minor urine output and temporary excretion of sodium by urine [8].…”