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:

• electrocardiogram
• diabetic cardiomyopathy
• sodium glucose co-transporter inhibitors
• prophylaxis
• animal model

Abbreviations

NC, normal control; DC, diabetic control; LD, low dose dapagliflozin; HD, high dose dapagliflozin; MET, metformin; STZ, streptozotocin.

Acknowledgments

We thank Mr. F. Ungaya Mmbaya and Mr. Mwaniki from the Department of Biochemistry, University of Nairobi for assistance with lab reagents and procedures pertaining to the handling of the animals respectively.

Author Contributions

All four authors (PKJ, BMC, PWM and FB) meet the criteria for authorship. PKJ and PWM conceptualized and designed the study. PKJ and BMC executed the study, collected and analyzed the data. PKJ, PWM and FB interpreted the results. PKJ drafted the initial manuscript, and all four authors critically reviewed the article. All four authors reached an agreement on the journal to which the article will be submitted, approved all versions of the article before and during revision, accepted the final version for publication, and managed any significant changes introduced during the proofing stage. Furthermore, all authors agree to take responsibility and be accountable for the contents of the article.

Disclosure

The authors report no conflicts of interest in this work.