There has been a consistent increase in the global occurrence of type 2 diabetes mellitus (T2DM). It is predicted that there will be 500 million people with diabetes by 2035, and that one in three people could have T2DM by 2050 [1, 2]. T2DM is a significant cause of cardiovascular disease [3]. T2DM also damages the heart’s conduction system, leading to cardiac neuropathy, which affects around a third of people with T2DM [1]. This damage can increase sympathetic nervous system activity, potentially affecting cardiac repolarization and causing fatal ventricular arrhythmias, independent of disorders like hypertension, coronary artery disease (CAD), or heart failure [2].

Metabolic and mechanical abnormalities in CAD can lead to a greater degree of repolarization dispersion, which in some cases may be the basis for ventricular arrhythmias. The QT interval, as seen in electrocardiography, represents the repolarization of the heart. Numerous studies have shown that the QT interval represents potentially fatal ventricular arrhythmias [4, 5]. In addition to the QT interval, changes in the QT dispersion and T wave are also used to assess arrhythmias [6]. Research suggests that the difference between the highest and lowest points of the T wave (Tp-e) on the electrocardiogram (ECG) is more sensitive than the QT interval in predicting fatal ventricular arrhythmias [7, 8, 9]. In addition, it has been determined that the Tp-e/QT ratio is an important indicator of ventricular arrhythmias [6].

Compelling evidence has been offered in recent studies regarding the efficacy of sodium-glucose co-transporter 2 (SGLT-2) inhibitors in preventing cardiovascular complications [10, 11, 12]. In particular, the EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) study demonstrated how empagliflozin was effective in reducing hospitalizations related to both glycemic control as well as heart failure in people with T2DM [13]. SGLT2 inhibitors significantly reduce mortality, major adverse cardiac events, nonfatal heart attacks and heart failure in T2DM patients, according to a meta-analysis. Interestingly, different SGLT-2 inhibitor subtypes appear similarly beneficial [11]. However, the effect of SGLT-2 inhibitors on cardiac electrical activity and the risk of ventricular arrhythmias is unclear.

The objective of this study is to investigate the way empagliflozin affects ECG parameters in T2DM patients associated with ventricular arrhythmias.

Of the 177 patients who were part of the study, 95 were diagnosed with T2DM and their clinical and demographic attributes are depicted in Table 1. Of the 95 T2DM patients, 40 were male (42%), whereas in the control group of 82 patients, 40 were male (48%) (p = 0.152). The average age of the T2DM patients was 60.2 $\pm$ 9.0 years, while the average age of the control group was 58.2 $\pm$ 9.2 years (p = 0.374). No statistically significant differences existed between the groups with regard to BMI, systolic arterial pressure (SAP), diastolic arterial pressure diastolic arterial pressure (DAP), smoking status, hypertension (HT), hyperlipidemia (HPL) and incidence of CAD. No significant differences were observed between the two groups in terms of hemogram, white blood cell count, creatinine, sodium, potassium, calcium and magnesium. As expected, there were significantly greater levels of HbA1c in the T2DM group. In addition, when comparing the medical treatments received by the patients between the groups, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB), calcium channel blockers (CCB) and beta-blockers (BB) was similar, whereas the use of acetylsalicylic acid (ASA) and statins was considerably greater in the T2DM group. Finally, when the doses of empagliflozin treatment were determined, it was found that in the T2DM group, a dose of 10 mg was given to 68 patients (72%) and a dose of 20 mg was given to 27 patients (28%).

Table 2 demonstrates the conventional echocardiographic and electrocardiographic properties of the patients taking part in the study. In the conventional echocardiographic assessment, the left ventricular ejection fraction (LVEF) was statistically significantly less in the T2DM patients in comparison to the control group (LVEF 58.6 $\pm$ 8.0/60.9 $\pm$ 5.7, p = 0.029). While there was no between-group difference in left ventricular end-diastolic dimension (LVEDD), in the empagliflozin group with T2DM (LVESD 30.7 $\pm$ 2.2/28.8 $\pm$ 2.9, p 0.001), left ventricular end-systolic dimension (LVESD) was considerably higher. Similarly, no significant variations existed between groups in left ventricular wall thickness and left atrial diameter. Regarding the parameters of left ventricular diastolic function, E wave, A wave and E/A ratio did not show statistically significant variations among the groups. When comparing the electrocardiographic properties among the groups, the heart rate (HR) did not differ, but the baseline values of QT, QTc, QTd, Tp-e and Tp-e/QTc were statistically significantly larger in the group of patients with T2DM (QT 408. 5 $\pm$ 22.9/370.9 $\pm$ 20.2, p 0.001; QTc 427.0 $\pm$ 20.5/385.8 $\pm$ 16.0, p 0.001; QTd 52.1 $\pm$ 1.2/46.2 $\pm$ 2.1, p 0.001; Tp-e 82.3 $\pm$ 8.7/61.2 $\pm$ 5.8, p 0.001; Tp-e/QTc 0.19 $\pm$ 0.01/0.16 $\pm$ 0.01, p 0.001).

The blood pressure and laboratory results of the patient group before and following treatment are summarised in Table 3. There was no significant variation in blood pressure before and following treatment. Although no significant difference was observed in haemogram, white blood cell count, creatinine, sodium, potassium, calcium and magnesium results, a significant difference was noted in the levels of HbA1c (HbA1c 9.1 $\pm$ 1.4/8.0 $\pm$ 1.0; p 0.001).

Table 4 depicts the conventional echocardiographic and electrocardiographic characteristics of patients with T2DM prior to and following empagliflozin treatment. Regarding echocardiographic parameters, there were no significant changes in LVEF, LVEDD, LVESD, IVS, PW, LA, E wave, A wave and E/A ratio values between the pre- and post-treatment assessments. However, when examining the electrocardiographic parameters, no differences in heart rate (HR) were observed between the pre-treatment and post-treatment phases. In particular, the values of QT, QTc, QTd, Tp-e and Tp-e/QTc showed statistically significant reductions after empagliflozin treatment compared to pre-treatment values (QT 408.5 $\pm$ 22.9/378.8 $\pm$ 14. 1, p 0.001; QTc 427.0 $\pm$ 20.5/404.7 $\pm$ 13.8, p 0.001; QTd 52.1 $\pm$ 1.2/47.8 $\pm$ 1.7, p 0.001; Tp-e 82.3 $\pm$ 8.7/67.1 $\pm$ 5.1, p 0.001; Tp-e/QTc 0.19 $\pm$ 0.01/0.17 $\pm$ 0.01, p 0.001) (Figs. 3,4,5).

Fig. 3.

Changes in the pre-treatment and post-treatment QT and QTc values. QTc, corrected QT interval.

Fig. 4.

Changes in the pre-treatment and post-treatment Tp-e and QTd values. Tp-e, Tpeak-to-Tend interval; QTd, QT dispersion.

Fig. 5.

Changes in the pre-treatment and post-treatment Tp-e/QTc ratio. Tp-e, Tpeak-to-Tend interval; QTc, corrected QT interval.

The mean difference values for conventional echocardiographic and electrocardiographic characteristics before and after empagliflozin treatment, grouped by treatment dose in patients with T2DM, are shown in Table 5. In this analysis, no significant differences in LVEF, LVEDD, LVESD and E/A wave values were observed between treatment doses. However, in the group receiving the 20 mg dose of empagliflozin, changes in left atrium (LA) values were increasingly prominent, showing a statistically significant difference (Delta-LA –0.02/0.55, p = 0.026). When electrocardiographic parameters were similarly examined, changes in HR, QT, QTd, Tp-e and Tp-e/QTc were not influenced by empagliflozin dose. However, the QTc showed a more pronounced decrease in the 20 mg empagliflozin group, with a statistically significant reduction (QTc 19.4/29.6, p = 0.038).

A stepwise method of linear regression assessment was used to assess the parameters affecting post-treatment QTc values, as shown in Table 6. First, statistically significant parameters and those likely to influence the QTc parameter were included in the model. In this context, the relationship between HbA1c, empagliflozin dose, beta-blocker (BB) use, age, BMI, LVEF, sex, CAD, SAP, Haemoglobin, Creatinine, Potassium, Calcium, Magnesium, ACE-I/ARB use, HT and smoking status with post-treatment QTc was evaluated. HbA1c and empagliflozin dose were identified as independent predictors of post-treatment QTc.

We investigated the impact of empagliflozin on ECG ventricular repolarisation factors in patients with T2DM in this research. Our findings can be summarised as follows: (i) We observed that the QT, QTc, QTd, Tp-e and Tp-e/QTc values significantly varied among the patient group and the control group. (ii) We observed a significant variation in QT, QTc, QTd, Tp-e and Tp-e/QTc values within the patient group when comparing measurements taken before empagliflozin treatment and those obtained six months after the start of treatment. (iii) We analysed the difference in ventricular repolarisation factors on the ECG based on the treatment dose and found a statistically significant dose-related reduction in the QTc parameter. (iv) Using linear regression analysis, we identified HbA1c levels and empagliflozin treatment dose as independent factors affecting QTc.

Empagliflozin, a potent SGLT-2 inhibitor, is the first glucose-lowering medicine shown to reduce cardiovascular events [16]. Despite several studies suggesting potential effects on atherosclerosis, cardiac remodelling or inflammatory processes, the precise pathophysiology underlying its cardiac effects remains unclear. There is consensus that the drug acts through a complex mechanism of action [17, 18, 19].

The effect of this drug on heart rhythm is also unclear. Some studies have shown that therapeutic doses of the drug do not prolong the QT interval [20], others have reported longer QT intervals in people with T2DM and CAD in comparison to the general population [18, 20]. We also noticed in our research that ventricular repolarisation parameters (QT, QTc, QTd, Tp-e and Tp-e/QTc) were all considerably prolonged in the patient group in contrast to the control group. However, at the six-month follow-up after the addition of empagliflozin to glucose control, a significant shortening of these ventricular repolarisation parameters (QT, QTc, QTd, Tp-e and Tp-e/QTc) was observed.

Although QTd has historically been considered a marker of increased repolarization dispersion and a useful indicator of arrhythmogenic events, contemporary preferences have shifted to more sensitive parameters for predicting arrhythmogenic events on ECGs [21]. Nonetheless, several studies have pointed to impaired QT intervals and QTd in individuals with T2DM and CAD [22]. It is worth noting that increased QT and QTd values in the presence of autonomic neuropathy and arrhythmias are significant contributors to the possibility of death due to sudden cardiac arrest [8, 23]. In our study, we also observed that in comparison to the control group, both QT and QTd were substantially greater in the patient group and that QTd decreased in the patient group after treatment with empagliflozin. These findings suggest that empagliflozin may be linked to decreasing the possibility of death due to sudden cardiac arrest.

The Tp-e interval and the Tp-e/QT ratio are key markers of ventricular repolarisation and greater dispersion [24]. The findings of recent studies have emphasised that the Tp-e/QT ratio provides a more precise assessment of ventricular repolarisation dispersion compared to QT dispersion, QTc dispersion and Tp-e intervals, independent of heart rate variations. In addition, an elevated Tp-e/QT ratio has been linked to a greater risk of arrhythmogenic events [7, 8, 25]. The primary mechanism of Tp-e interval prolongation is the disruption of ion transfer during ventricular repolarization [26]. The Tp-e interval reflects epicardial and myocardial repolarisation, but subendothelial M-cells are vulnerable to early depolarisation. This vulnerability can lead to arrhythmias, and inappropriate stimulation of M-cells can result in lethal cardiac rhythms such as ventricular fibrillation or ventricular tachycardia [8, 27, 28, 29]. A substantial difference in Tp-e interval and Tp-e/QTc ratio among the patient and control groups was observed in this research. When these parameters were remeasured six months after the start of treatment with empagliflozin, we observed significant improvements compared with baseline values. Therefore, it is reasonable to conclude that empagliflozin may reduce the risk of arrhythmias by decreasing the Tp-e interval as well as the Tp-e/QTc ratio. According to the information available, our study seems to be one of the first to examine the link between empagliflozin and the Tp-e interval, as we could not identify any previous studies investigating this aspect.

In the study carried out by Taha et al. [30], a significant association was found between left ventricular diastolic dysfunction (LVDD) and the length of QTc duration. In our study, we found that the values of E and A waves decreased with treatment, but this change was not statistically significant and in this context, we concluded that LVDD does not independently show a significant effect on QTc duration. Of course, we are aware that the hypothesis of our study is not relevant to this issue and in this context, the number of LVDD patients in the patient group is not sufficient to reach such a conclusion [30].

Studies investigating the relationship between empagliflozin dose and QTc in the literature are limited and there is no comprehensive study with long-term results. A study by Ring et al. [20] investigated empagliflozin doses of 25 and 200 mg, but found no significant relationship with QTc. It is worth noting that this study was based on data from a 24-hour monitoring period [20]. Treatment of chronic diseases often requires longer-term studies, and our study with a 6-month follow-up suggests that empagliflozin dosing leads to significant changes in QTc, in contrast to the findings of that study. There is one study in the literature suggesting that empagliflozin may prevent QTc prolongation induced by amitriptyline. However, this study only used a 10 mg dose [31]. Our study supports the idea that higher doses may produce more favourable results. Another study did not find a direct relationship between empagliflozin dose and cardiovascular effects, but suggested that increasing the dose of empagliflozin because of metabolic disorders associated with glycaemic control would not change cardiovascular effects. In other words, it argues that there is no need to increase the dose for cardiovascular effects and that if dose escalation is needed for metabolic reasons, it should be done accordingly [32]. Our study contributes to these considerations in the literature by emphasising that dose may be independently effective in preventing arrhythmias and by suggesting a new perspective on the need for dose adjustment.

Although the cardiovascular effects of SGLT-2 inhibitors were initially thought to be due to an increase in the amount of fasting ketones in the body, this was not clinically supported [33]. On the other hand, there are articles in the literature investigating how sodium-hydrogen exchanger-1 is inhibited, which is a potent receptor in the renal proximal tubule and myocyte membrane, thus keeping calcium, which causes myocardial toxicity, inside the cell [34, 35]. Another hypothesis is that renal medullary hypoxia is caused by SGLT-2 inhibitors due to increased active sodium reabsorption in the distal convoluted tubule, which leads to the formation of hypoxia-inducible factors, and this brings about the release of erythropoietin. The mass of erythrocytes increases, characterized by an increase in haematocrit, which enhances the provision of oxygen to the myocardium and decreases the mass of the left ventricle [36, 37]. In a review by Talha et al. [38], it was noted that many hypotheses have been put forward for the cardiovascular effects of SGLT-2 inhibitors, but it was argued that the exact mechanism of action is not yet clear. Unfortunately, we could not prove the results that would reveal the cardiac effects of SGLT-2 inhibitors, but we hope that it will be useful in future studies on this topic.

The QT, QTc, QTd, Tp-e and Tp-e/QTc values in our research were impaired in CAD and T2DM, as shown in similar studies. However, unlike previous studies, we investigated the response of these parameters to empagliflozin and found that the drug reduced them all. Although the mechanism of empagliflozin’s beneficial effects on the heart has not yet been elucidated, we hope that the results of our study will help to explain this mechanism. In particular, our finding that empagliflozin has a beneficial effect on the cardiac conduction system is a new contribution to the literature.

Very limited cases are studied in this research and there is a need for further publications with more cases. The observation period of the patients in this study was relatively limited. Therefore, multicenter studies with a longer follow-up are needed. In addition, because we did not include T2DM patients without CAD, we could not clarify whether the changes we observed in the ECG occurred in relation to T2DM or CAD, or only when both diseases coexisted. Finally, our study was not sufficient to clarify the mechanism of action of empagliflozin on the cardiovascular system.

In conclusion, our study sheds light on the possible advantages of empagliflozin in enhancing ventricular repolarisation factors in patients suffering from T2DM. We observed significant reductions in QTc, QTd, Tp-e and Tp-e/QTc after six months of empagliflozin treatment. These findings suggest that the use of empagliflozin is potentially linked to reduced incidence of ventricular arrhythmias. Further long-term studies need to be carried out to validate these effects and to investigate the underlying mechanisms. In addition to providing glycaemic control, empagliflozin may also have cardiovascular benefits, making it a valuable addition to the treatment options for people with T2DM who are at risk of cardiac complications.

The datasets used in the current study are available from the corresponding author upon reasonable request.

FO, HT and AA designed the research study. HT, AA and HAB performed the research. FO, HT and HAB conducted data collection. FO and HAB provided help and advice on language. AA analyzed the data. FO and HAB wrote the manuscript. AA and HT conducted writing review. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was conducted in accordance with the Declaration of Helsinki. This study received ethics approval from Yuzuncu Yıl Universty Hospital Faculty of Medicine University Ethics Committee. The ethics approval number is 2019-09. All individuals have signed informed consent.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.