CARDIOVASCULAR JOURNAL OF AFRICA • Volume 35, No 2, May – August 2024 106 AFRICA Empagliflozin significantly prevents QTc prolongation due to amitriptyline intoxication Veysel Özgür Barış, Esra Gedikli, Adnan Berk Dinçsoy, Ayşen Erdem Abstract Aim: Empagliflozin (EMPA) is a sodium-glucose transporter-2 inhibitor used in the treatment of type 2 diabetes and has positive effects on cardiovascular outcomes. Amitriptyline (AMT) can be used in many clinical indications but leads to cardiotoxicity by causing QT prolongation. Our aim in this study was to determine how the effects of the concomitant use of empagliflozin and amitriptyline, which have been shown to have effects on sodium and calcium metabolism in cardiomyocytes, would cause an effect on QT and QTc intervals in clinical practice. Methods: Twenty-four male Wistar albino rats were randomised into four groups. The control group received only physiological serum (1 ml) 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 (100 mg/kg) and empagliflozin (10 mg/kg). Under anaesthesia, QT and QTc intervals were measured at baseline, and in the first and second hours. Results: In the AMT group, QT intervals and QTc values were found to be statistically longer than in the control group (p ≤ 0.001). Empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. In the AMT+EMPA group, QT and QTc intervals were significantly lower compared to that in the AMT group (p < 0.01) Conclusion: In this study, we determined that empagliflozin significantly ameliorated amitriptyline-induced QT and QTc prolongation. This effect was probably due to the opposite effects of these two agents in the intracellular calcium balance. With more clinical trials, the routine use of empagliflozin may be suggested to prevent QT and QTc prolongation in diabetic patients receiving amitriptyline. Keywords: empagliflozin, amitriptyline, QTc prolongation Submitted 7/9/22; accepted 11/4/23 Published online 7/6/23 Cardiovasc J Afr 2024; 35: 106–110 www.cvja.co.za DOI: 10.5830/CVJA-2023-017 Empagliflozin (EMPA) is a selective sodium-glucose transporter-2 (SGLT-2) inhibitor used in patients with type 2 diabetes mellitus (DM).1 There are data showing that EMPA reduces cardiovascular mortality in patients with type 2 DM in addition to its antidiabetic effects.2 Although there is not yet a physiopathological explanation for these positive effects of EMPA, it has been shown that EMPA causes changes in the intracellular sodium (Na) and calcium (Ca) balance and in the duration of action potentials in cardiomyocytes, regardless of SGLT-2 inhibition.3,4 Tricyclic antidepressant (TCA) drugs can be used in many situations in clinical practice. However, TCA may cause cardiotoxicity that leads to high rates of mortality and morbidity, and AMT is the most common agent causing TCA toxicity.5,6 AMT may cause cardiotoxicity due to ventricular arrhythmias caused by its Na channel inhibition and changes in intracellular Ca metabolism.7,8 The toxicity caused by TCA is dose independent and this toxicity manifests itself with prolongation in PR, QT and QTc intervals, measured on the ECG.9 QT prolongation on ECG is a predictor for toxicity and indicates a poor prognosis.10 In this study, we aimed to determine how the effects of the concomitant use of EMPA and AMT, which are used in the treatment of type 2 DM and which have been shown to have effects on Na and Ca metabolism in cardiomyocytes, could cause an effect on QT and QTc intervals in clinical practice. Methods Twenty-four male Wistar albino rats (350–400 g) obtained from Kobay AŞ (local corporation) and housed in the Physiology Department of Hacateppe University was used for this study. All rats were kept under controlled conditions at 21 ± 2°C and 30–70% relative humidity with 12-h dark/12-h light illumination sequence (the lights were on between 07.00 and 19.00) with ad libitum access to tap water and standard rat chow. The study was approved by the Hacateppe University School of Medicine institutional ethics committee for animal experiments (dated 11/11/2019 and numbered 2019/12-02). All the study procedures were performed according to the Guiding Principles for the Care and Use of Laboratory Animals. The experimental animals were randomised into four groups. The first group was the control group (n = 6) and physiological serum (1 ml) was administered to the animals of this group via an orogastric tube. The second group was the EMPA group and EMPA (10 mg/kg, Jardiance, Boehringer Ingelheim) was administered to the animals of this group via an orogastric tube (based on a previous study11) (Fig. 1A). The third group was the AMT group and AMT (100 mg/kg; Laroxyl 25 mg, Roche) was administered to the animals of this group via an orogastric tube (based on a previous study12). The fourth group was the AMT+EMPA group and AMT (100 mg/ kg) and EMPA (10 mg/kg) were administered to the animals of this group via an orogastric tube. All drugs were suspended in physiological serum. Physiology Department, Hacettepe University, Gaziantep, Turkey Veysel Özgür Barış, MD, veyselozgurbaris@gmail.com Esra Gedikli, MD Adnan Berk Dinçsoy, MD Ayşen Erdem, MD
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