Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication via intracellular calcium regulation
Authors: Baris V , Gedikli E , Dincsoy A B , Erdem A 
Published: October 2021

Abstract

Background
Empagliflozin is a SGLT-2 inhibitor used in the treatment of Type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation.

Aim
Our aim in the present study is to observe the effect of the concomitant use of amitriptyline and empagliflozin together, which have an effect on sodium and calcium balance in myocytes, on QTc by using ECG.

Materials and methods
Twenty-four male Wistar-Albino rats were randomized into four groups. The control group received only serum physiologic (1ml) via orogastric gavage (OG). The EMPA group received empagliflozin (10 mg/kg) via OG. The AMT group received amitriptyline (100 mg/kg) via OG. The AMT+EMPA group (n: 6) received amitriptyline and empagliflozin at same dose. Under anesthesia; QT and QTC intervals were measured at baseline, first, and second hours.

Results
The differences in QT and QTc values between the AMT group and control group were observed from the 1nd hour (Table 1, Figure 1). It was detected that the measurements of the control group were within normal limits. In the control group, QT was 77.33±9.02 ms at the basal, 73.50±2.26 ms at the 1st hour, 78.17±6.18 ms at the 2nd hour. QTc calculation was 165.42±18.34±10.5 ms at the basal, 166.63±17.92 msat the 1st hour, 184.65±12.86 ms at the 2nd hour. ECG findings of the EMPA group were within normal limits and similar to the control group (Table 1). The durations of QT interval and QTc calculations were found to be statistically longer in the AMT group than the control group at the 1st and 2nd hour (p≤0.001). Empagliflozin significantly ameliorated AMT-induced QT and QTc prolongation. The durations of QT interval were significantly lower at first (p&lt;0,001) and 2nd hours (p&lt;0.01) in the AMT+EMPA group compared to the AMT group. Moreover, QTc calculation was significantly lower in the AMT+EMP group than the AMT group at 1st and 2nd hour (P&lt;0.01) (Table 1). Electrocardiographic comparisons of all groups for one second within the second hour can be seen in Figure 2.

Conclusion
In the present study, we have detected that empagliflozin significantly ameliorates amitriptyline induced QT prolongation. This effect is probably due to the opposite effects of these two agents in the intracellular calcium balance. It's known that; toxic dose of amitriptyline increases the amount of Sarcoplasmic Ca and the calcium permeability of Ryanodine channels, decreases SERCA-mediated Ca-reuptake by decreasing the calcium binding capacity of calsequestrin, and these leads QTc prolongation. It has been shown that empagliflozin increases Ca reuptake by causing a significant increase in SERCA activity, and decreases Ca sparks by causing inhibition of Ryanodine activity. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QTc prolongation in the diabetic patients receiving amitriptyline.

Funding Acknowledgement
Type of funding sources: None. Table 1. QT, QTc durations and HR for groupsFigure 1. ECG traces – a: CON, b: EMPA, c: AMT, d: AMT+EMP