Dapagliflozin Pretreatment Prevents Cardiac Electrophysiological Changes in a Diet and Streptozotocin Induction of Type 2 Diabetes in Rats: A Potential New First-Line?

Abstract

Purpose: Dapagliflozin exerts cardioprotective effects in Type 2 Diabetes Mellitus (T2DM). However, whether these effects prevent electrocardiographic changes associated with T2DM altogether remain unknown. Our aim was to investigate the prophylactic effect of dapagliflozin pretreatment on the rat ECG using a high-fat, high-fructose (HFHf) diet and a low dose streptozotocin (STZ) model of T2DM.

Methods: Twenty-five (25) rats were randomized into five (5) groups: normal control receiving a normal diet while the other groups received an 8-week HFHf and 40mg/kg STZ on day 42, and either: saline for the diabetic control (1 mg/kg/d), low dose (1.0 mg/kg/d) and high dose dapagliflozin (1.6 mg/kg/d), or metformin (250 mg/kg/d). Oral glucose tolerance (OGT), electrocardiograms (ECGs), paracardial adipose mass, and left ventricular fibrosis were determined. Data were analyzed using GraphPad version 9.0.0.121, with the level of significance at p < 0.05.

Results: Compared to the diabetic control group, a high dose of dapagliflozin preserved the OGT (p = 0.0001), QRS-duration (p = 0.0263), QT-interval (p = 0.0399), and QTc intervals (p = 0.0463). Furthermore, the high dose dapagliflozin group had the lowest paracardial adipose mass (p = 0.0104) and fibrotic area (p = 0.0001). In contrast, while metformin showed favorable effects on OGT (p = 0.0025), paracardial adiposity (p = 0.0153) and ventricular fibrosis (p = 0.0291), it did not demonstrate significant antiarrhythmic effects.

Conclusion: Pretreatment with higher doses of Dapagliflozin exhibits prophylactic cardioprotective characteristics against diabetic cardiomyopathy that include antifibrotic and antiarrhythmic qualities. This suggests that higher doses of dapagliflozin could be a more effective initial therapeutic option in T2DM.

Keywords: animal model; diabetic cardiomyopathy; electrocardiogram; prophylaxis; sodium glucose co-transporter inhibitors.

Figure 1

(A) Body mass: The weekly body mass measurements during the experimental period. (B) Fasting plasma glucose: The weekly fasting plasma glucose measurements during the experimental period. i.p 40mg/kg of streptozotocin injected on day 42 for all groups except the normal control (NC). (C) Oral glucose tolerance: The area under the curve (AUC, measured in mmol/l×min) calculated values from the oral glucose tolerance curves after an oral bolus of 2g/kg of glucose solution.

Figure 2

Typical electrocardiogram tracings obtained at the end of the experimental period of the (A) NC group, (B) DC group, (C) LD group, (D) HD group and (E) MET group. Dotted lines indicate where measurements were taken by the LabChart™ software.

Figure 3

(A) QT interval duration at the end of the experiment. (B) QTc duration at the end of the experiment. (C) QRS interval at the end of the experiment. Values are expressed as mean ± SEM. n = 5 rats in each group (*p < 0.05, **p < 0.01).

Figure 4

Paracardial adipose mass between experimental groups. Values are expressed as mean ± SEM. n = 5 rats in each group, (*p < 0.05, **p < 0.01, one-way ANOVA).

Figure 5

The percentage fibrotic area of the experimental groups calculated using longitudinal sections of the left ventricle, (*p < 0.05, ***p < 0.001, **** p < 0.0001, one-way ANOVA).