What is Known and Objective: Empagliflozin treatment is significantly associated with lower risk of cardiovascular events in patients with diabetes mellitus (DM) independent of its antihyperglycemic effect. However, little is known regarding the impact of empagliflozin on electrocardiography (ECG) parameters. This study aimed to investigate whether empagliflozin has favourable effect on frontal plane QRS‐T (fQRST) angle, which is an ECG sign of ventricular repolarization heterogeneity, in patients with type 2 DM. Methods: We prospectively enrolled 111 patients with known diagnosis of type 2 DM who newly prescribed empagliflozin on top of their standard anti‐diabetic therapy. Patients were divided into two groups according to presence or absence of cardiovascular disease (CVD) at baseline and followed‐up for 6 months. The impact of empagliflozin treatment on fQRST angle was investigated and patient groups were compared regarding the pre‐ and post‐treatment fQRST angle. Results and Discussion: Among 111 patients, 32 (28.8%) had CVD and 79 (71.2%) had no CVD. Empagliflozin treatment lead a significant decrease in the mean fQRST angle throughout the study period and mean fQRST angle was significantly lower at 3‐ and 6‐month follow‐up visits compared to baseline values (62° ± 17.4° vs. 57.2° ± 14.8° vs. 50.5° ± 13.6°, p < 0.001 for all dual comparisons). However, despite similar antihyperglycemic effect with empagliflozin treatment in patients with and without CVD, the significant decrease in the mean fQRST angle was observed only in patients with CVD and no significant decrease was observed in the mean fQRST angle in patients without CVD. What is New and Conclusion: Empagliflozin leads a significant narrowing in the fQRST angle in type 2 DM patients with known CVD.
Keywords: cardiovascular disease; diabetes mellitus; electrocardiography; empagliflozin; frontal plane QRS‐T angle
Empagliflozin treatment is associated with a significant decrease in the frontal plane QRS‐T angle (fQRST) in patients with diabetes mellitus (DM). However, despite similar antihyperglycemic effect with empagliflozin treatment in patients with and without cardiovascular disease (CVD), the significant decrease in fQRST angle was observed only in patients with CVD and no significant decrease was observed in fQRST angle in patients without CVD. Therefore, as a sign of ventricular repolarization heterogeneity that can be easily measured from a standard 12‐lead electrocardiography (ECG), fQRST angle may be a useful ECG parameter in the monitoring of cardiovascular effects of empagliflozin in type 2 DM patients with CVD.
There is a close link between diabetes mellitus (DM) and cardiovascular disease (CVD) and CVD is the leading cause of morbidity and mortality in patients with DM.1 Glycemic control is the key point to prevent future cardiovascular events in patient with DM, and as a sodium–glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin is a useful anti‐diabetic drug in the management of hyperglycemia.2 Empagliflozin treatment is also associated with reduced risk of cardiovascular events independent of its antihyperglycemic effect, and hence it is recommended as a first‐line drug in the anti‐diabetic therapy to improve prognosis.2,3 Importantly, although electrocardiography (ECG) has an important role in the monitoring of cardiovascular complications of DM, limited data is available regarding the effects of anti‐diabetic drugs on ECG parameters.
Frontal plane QRS‐T (fQRST) angle defines the angular difference between depolarization (QRS axis) and repolarization (T axis) vectors, it is an ECG sign of ventricular repolarization heterogeneity, and increased fQRST angle is significantly associated with adverse cardiovascular events in patients with and without CVD.4–6 Moreover, increased fQRST angle seems to be an independent predictor of future cardiovascular events in patients with DM.7,8 However, little is known regarding the effect of empagliflozin on fQRST angle. Therefore, the present study aimed to investigate whether empagliflozin treatment has favourable effect on fQRST angle in patients with type 2 DM.
From January 2021 to June 2021, a total of 121 consecutive patients with known diagnosis of type 2 DM who newly prescribed empagliflozin treatment on top of their standard anti‐diabetic therapy were prospectively enrolled for the study. Empagliflozin was administered to all patients at the standard dose of 10 mg once daily without dose titration. The patients who were already receiving empagliflozin treatment were excluded at baseline and not screened for the study. Among patients enrolled, 10 patients were excluded from the study (4 patients for requirement of additional anti‐diabetic or cardiovascular drug during follow‐up period, 3 patients for discontinuation of empagliflozin treatment, and 3 patients due to loss to follow‐up). As a result, the remaining 111 patients were included into the study. Patients were divided into two groups according to presence or absence of CVD at baseline and all patients were followed for 6 months. The impact of empagliflozin treatment on fQRST angle was investigated and patient groups were compared regarding the pre‐ and post‐treatment fQRST angle values.
Demographic characteristics of patients were recorded on admission. Biochemical analyses were made from venous blood samples obtained after an overnight fasting. All study participants underwent an echocardiographic examination to assess the cardiac functions. Hypertension was defined as systolic blood pressure levels of ≥140 mmHg and/or diastolic blood pressure levels of ≥90 mmHg and/or known treatment with antihypertensive drugs. DM was defined as at least two fasting plasma glucose levels of ≥126 mg/dl, or 2‐h plasma glucose levels of ≥200 mg/dl during oral glucose tolerance test, or glycated haemoglobin (HbA1c) levels of ≥6.5% or known treatment with antidiabetic medications.9 Smoking was defined as the regular use of cigarettes. The study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee. A detailed informed consent was obtained from all study participants.
A standard 12‐lead surface ECG (Nihon Kohden, Tokyo, Japan) using a 0.16–100 Hz filter range, 25 mm/s speed, and 10 mm/mV amplitude was obtained from all patients at baseline, and at 3‐ and 6‐month follow‐up visits. fQRST angle was calculated as the absolute difference between QRS axis and T wave axis obtained from automated ECG reports. If the angle exceeds 180°, it was calculated by subtracting from 360°.6,10 Figure 1 demonstrates an example of measurement of fQRST angle from a standard 12‐lead ECG. fQRST angle was measured for all study participants at baseline and at 3‐ and 6‐month follow‐up visits. fQRST angles measured after 3 and 6 months of empagliflozin treatment were compared to baseline values. Also, patients with and without CVD were compared regarding the changes in the fQRST angle during follow‐up period.
Descriptive statistics of the data were expressed as mean, standard deviation and frequency. The normality distribution of continuous variables was assessed with Kolmogorov–Smirnov or Shapiro–Wilk tests. Continuous variables were compared using independent samples or pairwise Student's t‐tests where appropriate. Categorical variables were compared with the chi‐square test or Fisher's exact test. A p value of <0.05 was considered to indicate statistical significance.
The mean age of the study population was 51.2 ± 7.35 years with %49.5 being males, and average fQRST angle was 62° ± 17.4°. Among 111 patients, 32 (28.8%) had CVD and 79 (71.2%) had no CVD. There was no significant difference between patients with and without CVD regarding baseline medications including insulin, oral anti‐diabetic drugs, statins and renin‐angiotensin‐aldosterone system blockers. Patients with CVD were older and had reduced left ventricular ejection fraction (LVEF) compared to those without CVD, however, no significant difference was observed for fasting glucose and HbA1c levels between patient groups. Table 1 demonstrates the baseline clinical characteristics of study participants and patient groups. After initiation of empagliflozin treatment, fasting glucose and HbA1c levels were significantly decreased for both patient groups with and without CVD at 3‐ and 6‐month follow‐up visits compared to baseline values. Table 2 shows the glycemic parameters of study participants and patient groups at baseline and during follow‐up period. Importantly, the mean fQRST angle was decreased in the study population throughout the study period and was significantly lower at 3‐ and 6‐month follow‐up visits compared to baseline values (62° ± 17.4° vs. 57.2° ± 14.8° vs. 50.5° ± 13.6°, p < 0.001 for all dual comparisons). However, while there was a significant decrease in the mean fQRST angle at 3‐ and 6‐month follow‐up visits in patients with CVD, no significant decrease was observed in the mean fQRST angle in patients without CVD during follow‐up period. Table 3 demonstrates the mean fQRST angle of the study population and patient groups at baseline and during follow‐up period. Although baseline mean fQRST angle was significantly higher in patients with CVD compared to those without CVD (79.5° ± 16.3° vs. 54.9° ± 11.9°, p < 0.001), there was a significant narrowing in the mean fQRST angle in patients with CVD after 6 months of empagliflozin treatment, and no significant difference was observed in the mean fQRST angle of patient groups at 6‐month follow‐up visit (47.4° ± 16.3° vs. 51.7° ± 12.3°, p = 0.128). Table 4 shows the comparison of fQRST angle of patients with and without CVD at baseline and at 3‐ and 6‐month follow‐up visits.
1 TABLEBaseline clinical characteristics of study participants and patient groups
All patients ( CVD ( No CVD ( Age (years) 51.2 ± 7.35 59.2 ± 5.19 48 ± 5.40 <0.001 Male gender n, (%) 55 (49.5%) 20 (62.5%) 35 (44.3%) 0.082 BMI, kg/m2 27.3 ± 2.88 27.5 ± 3.52 27.2 ± 2.59 0.588 Hypertension n, (%) 49 (44.1%) 15 (46.9%) 34 (43.0%) 0.712 Smoking n, (%) 29 (26.1%) 9 (28.1%) 20 (25.3%) 0.760 LVEF (%) 56.6 ± 9.37 47.7 ± 9.42 60.3 ± 6.50 <0.001 Fasting glucose, (mg/dl) 148 ± 13.1 149.1 ± 12.43 147.4 ± 13.45 0.536 HbA1c (%) 7.27 ± 0.48 7.30 ± 0.42 7.26 ± 0.50 0.709 fQRST angle, (°) 62 ± 17.4 79.5 ± 16.3 54.9 ± 11.9 <0.001 Creatinine, (mg/dl) 0.97 ± 0.22 1.0 ± 0.28 0.96 ± 0.19 0.395 AST (U/L) 21.4 ± 4.23 21.8 ± 4.97 21.2 ± 3.91 0.481 TSH, (μIU/ml) 2.55 ± 0.57 2.58 ± 0.54 2.53 ± 0.59 0.683 Haemoglobin (g/dl) 13.3 ± 1.32 13.3 ± 1.54 13.2 ± 1.23 0.861 WBC count (×103/μl) 7.60 ± 0.76 7.45 ± 0.53 7.66 ± 0.83 0.192 Platelet count (×103/μl) 271 ± 53.3 269 ± 63.9 272 ± 48.7 0.805 Triglyceride, (mg/dl) 134 ± 17.9 139 ± 10.1 132 ± 20 0.076 LDL‐cholesterol (mg/dl) 105 ± 22.4 103 ± 22 106 ± 22.7 0.651 HDL‐cholesterol (mg/dl) 39 ± 4.58 38.7 ± 3.6 39 ± 4.9 0.697
1 Abbreviations: CVD, cardiovascular disease; BMI: Body mass index; LVEF, left ventricular ejection fraction; HbA1c, haemoglobin A1c; fQRST angle, frontal plane QRS‐T angle; AST, aspartate aminotransferase; TSH, thyroid‐stimulating hormone; WBC, white blood cell; LDL, low‐density lipoprotein; HDL, high‐density lipoprotein.
2 TABLEGlycemic parameters of study participants and patient groups at baseline and during follow‐up period
All patients ( Fasting glucose at baseline (mg/dl) Fasting glucose at 3 months (mg/dl) Fasting glucose at 6 months (mg/dl) 148 ± 13.1 142 ± 10.9 137 ± 9.03 <0.001 HbA1c at baseline (%) HbA1c at 3 months (%) HbA1c at 6 months (%) 7.27 ± 0.48 7.13 ± 0.45 6.95 ± 0.38 <0.001
2 TABLEGlycemic parameters of study participants and patient groups at baseline and during follow‐up period
Patients with cardiovascular disease ( Fasting glucose at baseline (mg/dl) Fasting glucose at 3 months (mg/dl) Fasting glucose at 6 months (mg/dl) 149.1 ± 12.43 143 ± 13.3 137 ± 11.8 <0.001 HbA1c at baseline (%) HbA1c at 3 months (%) HbA1c at 6 months (%) 7.30 ± 0.42 7.13 ± 0.39 6.92 ± 0.33 <0.001
2 TABLEGlycemic parameters of study participants and patient groups at baseline and during follow‐up period
Patients without cardiovascular disease ( Fasting glucose at baseline (mg/dl) Fasting glucose at 3 months (mg/dl) Fasting glucose at 6 months (mg/dl) 147.4 ± 13.45 142 ± 9.78 137 ± 7.75 <0.001 HbA1c at baseline (%) HbA1c at 3 months (%) HbA1c at 6 months (%) 7.26 ± 0.50 7.12 ± 0.47 6.96 ± 0.40 <0.001
- 2 Abbreviation: HbA1c, Haemoglobin A1c.
- 3 * Statistical significance for both comparisons versus baseline.
- 3 TABLEFrontal plane QRS‐T angle of study population and patient groups at baseline and during follow‐up period
fQRST angle at baseline (°) fQRST angle at 3 months (°) fQRST angle at 6 months (°) All patients (n = 111) 62 ± 17.4 57.2 ± 14.8 50.5 ± 13.6 <0.001 Patients with cardiovascular disease (n = 32) 79.5 ± 16.3 67.7 ± 15.9 47.4 ± 16.3 <0.001 Patients without cardiovascular disease (n = 79) 54.9 ± 11.9 52.9 ± 12 51.7 ± 12.3 NS+
- 4 Abbreviation: fQRST angle, frontal plane QRS‐T angle.
- 5 * Statistical significance for both comparisons versus baseline, NS: non‐significant (
+ p = 0.312 for baseline vs. 3 months and p = 0.061 for baseline vs. 6 months). - 4 TABLEComparison of frontal plane QRS‐T angle of patients with and without cardiovascular disease during follow‐up period
fQRST angle at baseline (°) fQRST angle at 3 months (°) fQRS‐T angle at 6 months (°) Patients with CVD (n = 32) 79.5 ± 16.3 <0.001 67.7 ± 15.9 <0.001 47.4 ± 16.3 0.128 Patients without CVD (n = 79) 54.9 ± 11.9 52.9 ± 12 51.7 ± 12.3
6 Abbreviations: CVD, cardiovascular disease; fQRST angle, frontal plane QRS‐T angle.
The main finding of the present study was that empagliflozin treatment lead a significant decrease in the mean fQRST angle in patients with type 2 DM throughout the study period. Importantly, the effect of empagliflozin in the narrowing the fQRST angle was observed only in patients with established CVD and no significant decrease in the fQRST angle was observed for patients without CVD. Moreover, this different effect of empagliflozin on fQRTS angle in patients with and without CVD was observed in the presence of similar antiglycemic effect in both patient groups. To the best of our knowledge, this is the first study to report the effect of empagliflozin treatment on fQRST angle in patient with type 2 DM.
DM is a major risk factor for atherosclerotic coronary artery disease, causes myocardial fibrosis and CVD is the leading cause of morbidity and mortality in patients with DM.1,11,12 ECG has an important role in the detecting cardiovascular complications of DM and in the monitoring of diabetic cardiomyopathy, and presence of abnormal ECG findings in patients with DM is significantly associated with clinical and subclinical CVD and independently predicts adverse cardiovascular events.13–15 fQRST angle is an important ECG sign of ventricular repolarization heterogeneity, and an increased fQRST angle, as a sign of electrical instability in the cardiac conduction system, is significantly associated with increased morbidity and mortality in patients with CVD.5,6,16,17 Increased fQRST angle is also considered as a sign of early‐stage subclinical myocardial damage even before the emergence of clinically evident CVD.18–20 Moreover, increased fQRST angle seems to be also associated with diabetic cardiomyopathy and may predict adverse cardiovascular events and mortality independently in patients with DM.7,8 However, little is known regarding the usefulness of fQRST angle in the monitoring of anti‐diabetic treatment and whether anti‐diabetic drugs have favourable effects on fQRST angle.
SGLT2 inhibitors are newer antihyperglycemic drugs that have been demonstrated to have cardiovascular benefits independent of their glucose lowering effect and are recommended as first line antihyperglycemic drugs for many patients with type 2 DM.2,21 As a SGLT2 inhibitor, empagliflozin is significantly associated with lower rates of cardiovascular events in patient with DM.22,23 Moreover, treatment with empagliflozin seems to be associated with lower risk of cardiovascular death or hospitalization for heart failure in patients with reduced LVEF regardless of the presence or absence of DM.2,24 Therefore, cardiovascular benefits of empagliflozin seem to be more evident in patients with deteriorated cardiac functions. Importantly, SGLT2 inhibitors seem to have favourable effects on ventricular repolarization heterogeneity and may reduce the risk of arrhythmias.25–27 However, their effect on fQRST angle is not well described. In our study, the favourable effect of empagliflozin treatment on fQRST angle was observed only for patients with CVD who had depressed LVEF. This finding may be explained by the increased cardiovascular benefit of empagliflozin in patients with CVD and reduced LVEF. The potential mechanisms underlying the cardiovascular benefits of empagliflozin may be its favourable effects on blood pressure lowering, increasing diuresis/natriuresis, improving cardiac energy metabolism, preventing inflammation and adverse cardiac remodelling, decreasing oxidative stress, and improving the vascular function.28,29 Hence, in our study, empagliflozin induced decreased cardiac pressures and its positive effects on cardiovascular hemodynamics and cardiac physiology may be the main contributing factors in the narrowing the fQRST angle in type 2 DM patients with CVD and depressed LVEF. In this sense, fQRST angle may be a useful ECG parameter to monitor the favourable effects of empagliflozin on cardiac functions in type 2 DM patients with established CVD.
The present study has some limitations. Small number of patients and low statistical power are the main limitations. Also, although increased fQRST angle is a strong predictor of cardiovascular events, the prognostic value of the narrowing in the fQRST angle remains unclear. Further studies are necessary to demonstrate the prognostic value of our findings.
The present study demonstrated that addition of empagliflozin on top of the standard anti‐diabetic treatment lead a significant decrease in the fQRST angle in type 2 DM patients with established CVD. Importantly, despite the similar antiglycemic effect compared to patients with CVD, empagliflozin treatment was not associated with a significant decrease in the fQRST angle in type 2 DM patients without known CVD. Therefore, as a sign of ventricular repolarization heterogeneity that can be easily measured from a standard 12‐lead ECG, fQRST angle may be a useful ECG parameter in the monitoring of cardiovascular effects of empagliflozin in type 2 DM patients with CVD.
We have no commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
By Mehmet Eyuboglu and Atac Celik
Reported by Author; Author
