Empagliflozin's role in reducing ventricular repolarization heterogeneity: Insights into cardiovascular mortality decline from the EMPATHY-HEART trial

Empagliflozin's role in reducing ventricular repolarization heterogeneity: Insights into cardiovascular mortality decline from the EMPATHY-HEART trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Empagliflozin's role in reducing ventricular repolarization heterogeneity: Insights into cardiovascular mortality decline from the EMPATHY-HEART trial Cristiane Lauretti, Graziella L. Antonio, Ariana E. Fernandes, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4183475/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH. Methods: Participants were adult outpatients with T2DM and CHD who exhibited TWH >80 µV at baseline. They received a 25mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p<0.05) change in TWH following empagliflozin administration. Results: An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 144 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p=0.01). Conclusions: The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population. Trial registration: NCT: 04117763. Type 2 Diabetes Mellitus Coronary Heart Disease Empagliflozin T-wave Heterogeneity Ventricular Arrhythmias Cardiovascular Mortality Non-invasive Diagnostic Tools EMPA-REG Trial Electrical Instability Arrhythmia Prevention Figures Figure 1 Figure 2 Figure 3 1. Background The global incidence of Type 2 Diabetes Mellitus (T2DM) is reaching critical levels, projected to affect approximately 600 million individuals by 2035 [ 1 ]. This condition markedly increases the prevalence of cardiovascular diseases (CVD) and generates a concern highlighted by the higher rates of post-myocardial infarction (MI) mortality and a greater frequency of sudden cardiac death (SCD) among those with diabetes, in comparison to non-diabetic individuals [ 2 , 3 ]. Often, SCD is the first clinical indication of an underlying, undetected cardiac disorder. Traditional risk factors fall short in accurately predicting these fatal arrhythmias, underscoring the need for more precise predictive tools [ 4 ]. SCD is generally preceded by an electrical disturbance, prompting recent shifts towards non-invasive methods for risk assessment using electrocardiographic indicators [ 5 ]. One such marker is the T-wave heterogeneity index (TWH) that measures the variance of waveforms around the T-wave's average waveform, effectively capturing the spatial disparity in heart repolarization [ 4 ]. TWH has proven valuable in accurately stratifying the risk of sudden cardiac death, overall cardiac mortality, and arrhythmic episodes in a diverse range of cardiovascular conditions [ 6 – 9 ]. Empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), has emerged as a key player in cardiovascular healthcare, a status underscored by EMPA-REG trial [ 10 ]. This study highlighted a 14% reduction in relative risk for a combined outcome of cardiovascular death, non-fatal MI, and non-fatal stroke, with a notable 38% decrease in cardiovascular mortality, including sudden death cases. These benefits were significant even in patients already under comprehensive cardiovascular risk management and were observable as soon as 27 days post-treatment initiation [ 11 ]. The rapid and significant effects of empagliflozin on cardiovascular outcomes in patients with high-risk T2DM are acknowledged, yet the mechanisms behind these effects remain partly unclear. Dapagliflozin, another SGLT2i, has been shown to reduce ventricular arrhythmias, cardiac arrests, and SCD in conjunction with standard heart failure treatments [ 12 ]. Additionally, preclinical studies bolster the hypothesis that empagliflozin may diminish the risk of fatal arrhythmias [ 13 ]. These findings are crucial for managing patients with high-risk cardiovascular diabetes and underscore the need for focused clinical trials to investigate further the potential effect of SGLT2i in the prevention of cardiac arrhythmias. While there's evidence suggesting a potential reduction in fatal arrhythmias with empagliflozin [ 14 ], its specific anti-arrhythmic actions and influence on SCD susceptibility in T2DM and CHD patients still require further elucidation. Our study aimed to explore whether empagliflozin can attenuate ventricular arrhythmogenesis and lower the risk of SCD by assessing TWH in diabetic patients with coronary artery disease, contributing to the evolving field of cardiovascular care in patients with diabetes. 2. Methods 2.1 Study Design The EMPATHY-HEART Trial employed an exploratory pilot study design to investigate the influence of empagliflozin on ventricular repolarization heterogeneity in patients diagnosed with both T2DM and CHD. The choice of an exploratory design emerged from the imperative to elucidate the potential impacts of empagliflozin on ventricular electrical instability, an aspect with limited prior exploration. Given the limited number of clinical trials utilizing interlead T-wave heterogeneity, the study aimed to establish the basis for future research and hypothesis development. 2.2. Participants Outpatients at Heart Institute of the Faculty of Medicine of the University of Sao Paulo (InCor), Brazil, were invited to participate. The study included individuals 18 years and older, diagnosed with T2DM, and showing evidence of CHD, indicated by a history of myocardial infarction, significant coronary stenosis, or a positive test for myocardial ischemia. Additionally, participants required a baseline TWH on ECG of 80 µV or higher, following the criteria established by Tan et al. [ 7 ]. Exclusion criteria comprised chronic kidney disease (glomerular filtration rate below 45 ml/min/1.73m²); advanced hepatic disease (Child-Pugh B or C); age over 85; an uninterpretable 12-lead baseline ECG, due to conditions like pacemaker rhythms or signal distortions; and a baseline ECG TWH under 80 µV. In this context, "baseline" ECG refers to the electrocardiogram conducted at the first study visit. 2.3. Intervention Under the guidance of a sole researcher (CL), all participants underwent comprehensive clinical assessments. They received a daily prescription of empagliflozin 25mg, aligning with current clinical guidelines emphasizing its cardiovascular benefits in high-risk diabetic populations. This dosage selection aimed specifically to investigate empagliflozin's effects on the prevention of cardiac arrhythmias. Tailored adjustments to hypoglycemic regimens were made as necessary to minimize the risk of hypoglycemia, ensuring a standardized yet personalized approach for participant safety and treatment efficacy. Patients performed a 12-lead ECG at their initial visit and again after 4 weeks. During the follow-up, a clinical reassessment and treatment adherence analysis were conducted. This 4-week period aligns with findings from a post-hoc analysis indicating a notable decrease in cardiovascular death or heart failure hospitalization starting from day 27 post-randomization [ 11 ]. Treatment adherence was evaluated through direct questioning of each participant [ 15 ]. 2.4. Data Collection Data Management and Statistical Analysis Data acquisition and management were conducted using the REDCap (Research Electronic Data Capture) platform [ 16 ]. Resting electrocardiograms were conducted using Mortara Eli 250C (2013) or GE Healthcare MAC 2000 (2019) equipment, capturing 12 leads simultaneously in a 4 x 3 format, with a paper speed of 25 mm/s and a 10-mV gain. Electrode placement followed standard technical guidelines [ 17 ]. TWH was calculated specifically in leads V4, V5, and V6, chosen for their lower variability due to electrode positioning and patient's body constitution [ 18 ], and their proven effectiveness in detecting electrical instability and arrhythmia risk [ 6 , 7 ]. Two independent researchers, CL and GLA, blinded to the patients' treatment status, performed the TWH calculations for each ECG. Participant ECGs were extracted from InCor's electronic records as PDFs, anonymized, and converted to TIFF format. ECGScan software (AMPS-LLC, New York, NY) translated the waveforms [ 19 ], which were then turned into text files using ISHNE and CalECG softwares (AMPS-LLC, New York, NY) [ 20 ]. These files were analyzed in Microsoft Excel (365 version). Data from leads V4, V5, and V6 were overlaid, aligned by the PR segment, and synchronized at the QRS complex onset. The second central moment algorithm was applied to the J-T wave interval of each cardiac cycle to determine the point of highest morphology variance. The square root of this variance provided the TWH value in microvolts per beat. The TWH index, representing the average TWH of all recorded beats, indicates repolarization nonuniformity; higher values suggest a greater risk of life-threatening ventricular arrhythmias [ 7 ]. Detailed TWH calculation methods from resting 12-lead ECGs are described elsewhere [ 4 , 5 , 9 ]. 2.5. Statistical Analysis The primary goal of our study was to investigate how TWH levels were altered by empagliflozin administration. To ensure reliability and agreement of ECG data analyzed by the independent researchers we utilized the Intraclass Correlation Coefficient (ICC). To enhance result precision, we excluded extreme outliers, namely, subjects whose TWH levels were more than 3 standard deviations above the population mean, to reduce data skewness. The Shapiro-Wilk test was employed for normality evaluation. Variables were analyzed using Student's t-test for normal distributions and the Wilcoxon rank-sum test for non-parametric data, including TWH, to determine empagliflozin's effects. Multivariate analysis utilized MANOVA, with all tests adhering to a significance threshold of p < 0.05, reflecting a 5% significance level. Statistical analyses were conducted using R, a software environment for statistical computing and graphics [ 21 ]. Data are presented as means ± standard deviation (S.D.) 2.6. Ethical Considerations Recruitment for this study occurred between October 2019 and October 2023. Each participant gave written informed consent, having been fully briefed on aims, methods, and potential risks. Adhering to the Declaration of Helsinki's principles, this clinical trial was approved by the Institutional Review Board of Clinical Hospital of the Medical School of the University of Sao Paulo, under registration number SDC: 4732/18/083. The research is registered on ClinicalTrials.gov with the identifier NCT04117763. 3. Results 3.1. Patient Characteristics Among the potential candidates screened, 412 had TWH equal to or greater than 80 µV. Of these, 90 participants were included in the study. The demographic and clinical profiles of the participants, as outlined in Table 1 , indicated a cohort with a notably high cardiovascular risk. This included the majority having experienced myocardial infarctions, over half displaying a tri-arterial pattern in invasive stratification, and nearly a quarter having undergone coronary artery bypass grafting. As expected in a specialized heart hospital setting, participants were optimized for cardiovascular risk reduction. The majority were on statins (90%) and beta-blockers (84%). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used by 77% of the patients. For diabetes management, 24% were on basal insulin therapy, and 11% adhered to a basal-bolus insulin therapy regimen. Only two subjects were not on antiplatelet agents. Table 1 Patient Characteristics Characteristic Sex: Male 89% Age: Mean (years) 64 ± 7.5 Race: White 80% DM2 Duration ≤ 10 years > 10 years 46% 54% Glycemic Control HbA1c < 8.0 HbA1c ≥ 8.0 69% 31% Hypertension 96% Obesity 26% Current smoking 10% Previous Stroke 7% Peripheral Arterial Disease 12% Previous Myocardial Infarction 87% Invasive Stratification Uniarterial Biarterial Triarterial 98% 15% 26% 58% Angina 48% Percutaneous Revascularization 61% Surgical Revascularization 24% Heart Failure Preserved EF Reduced EF 82% 61% 39% Dyslipidemia 100% Lipid Control (med, mg/dL) LDL HDL Triglycerides 78 ± 23 40 ± 11 134 ± 71 3.2. Clinical Parameters Adherence to treatment exceeded 80% across all participants. Consistent with prior evidence [ 10 ], our study found that empagliflozin significantly reduced blood pressure without significantly affecting heart rate (Table 2 ). Table 2 Clinical Characteristics of the Participants Measurements Baseline (mean) Follow-up (mean) p-value Systolic BP (mmHg) 137.0 126.0 0.0002 Diastolic BP (mmHg) 77.6 72.6 0.009 Heart Rate (bpm) 71.9 71.7 0.96 Weight (kg) 77.8 77.1 0.70 Hypoglycemia was noted in 13.3% of participants, with a predominant occurrence at Level 1 [ 15 ] (91.7%), and no reports of serious episodes. Urinary tract infections were observed in 4.4%, while genital fungal infections occurred in 11.1% of the patients. 3.3. T-Wave Heterogeneity TWH values for each ECG, assessed by independent researchers, showed high reliability, as reflected by ICC values of 0.9 for both baseline and follow-up phases, with p-values < 0.001. This robust concordance validated aggregating data from both researchers for subsequent data analysis and presentation. Following empagliflozin treatment, we noted a significant reduction in TWH values, indicating a decrease in ventricular repolarization heterogeneity. Specifically, mean baseline TWH values fell from 127 µV to 114 µV at follow-up, with a median reduction from 116 µV to 103 µV. This change, statistically significant with a p-value of 0.01, underscores a meaningful difference attributed to empagliflozin treatment. Visual analysis of the data presented in the Boxplot in Fig. 1 indicates increased variability in TWH values post-treatment, as shown by the rise in standard deviation from 43.9 to 55.7 µV and in the interquartile range from 46.2 to 67.8 µV. The presence of outliers above the third quartile, both before and after treatment, highlights a persistent dispersion in TWH values, irrespective of therapy. Representative digitized ECG tracings for a patient during the study are provided in Fig. 2 . The baseline ECG, depicted in the upper panel, shows pronounced T-wave heterogeneity, with significant variability in T-wave morphology across different leads. Following a 4-week treatment with empagliflozin, the lower panel presents ECG tracings that demonstrate a noticeable reduction in TWH, evidenced by a decrease in variability among T-wave forms. Figure 3 reveals a trend toward lower TWH levels after treatment across the study population. About one-third of the participants achieved a TWH reduction to 80 µV or below post-treatment. Predominantly, the optimal responders – those whose TWH diminished to 80 uV or less – initially had TWH values below 100 uV. A multivariate analytical method (MANOVA) was employed to explore the connections among clinical variables, including HbA1c levels, time since diabetes diagnosis, incidence of angina, previous MI, MI localization, classification in invasive stratification, and Left Ventricular Ejection Fraction (LVEF), with the goal of identifying a significant association with TWH reduction. LVEF and HbA1c were treated as categorical variables with cutoffs at 50% and 8%, respectively. Single-vessel disease and diabetes duration emerged as significant factors, leading to their inclusion in a refined linear multivariate analysis model, which revealed that only single-vessel disease had a significant effect on reducing TWH (p = 0.027). Inspecting this group of patients with single-vessel disease, it was observed that the majority had a prior myocardial infarction, with the anterior wall being the most affected. The model, with a multiple R 2 of 0.321 and an adjusted R 2 of 0.2791, alongside a p-value of 6.183e-06, reveals moderate explanatory power and significant statistical validity. 4. Discussion Participants characterized by high cardiovascular risk and treated at a specialized cardiology hospital, had increased baseline TWH, indicating a heightened susceptibility to arrhythmias or sudden cardiac death. Therapeutically, these patients were following optimal regimens, marked by widespread use of beta-blockers. Consequently, the positive effect of empagliflozin observed in this cohort point to a possible additional therapeutic benefit in addition to beta-blockers. This finding raises the intriguing possibility that beta-blockers might have slightly concealed an even greater potential of empagliflozin to diminish ventricular electrical instability. We employed the TWH level of 80 µV established by previous research to demonstrate that the risk of severe arrhythmias and SCD increases significantly when TWH levels exceed this level [ 7 , 8 ]. Electrocardiograms were performed in an ambulatory setting without provocative testing for ischemia or exertion. Within a relatively brief period of four weeks of empagliflozin treatment, there was a statistically significant reduction in the TWH median. This proof-of-concept trial showed that empagliflozin significantly reduces ventricular electrical vulnerability in patients with T2DM and CHD, evidenced by reduced T-wave heterogeneity. The findings complement recent evidence, offering new insights into these phenomena and their implications in a clinical setting for the first time. Research into the role of SGLT2i in arrhythmia prevention is rapidly evolving. Recent studies highlight SGLT2i's potential to reduce arrhythmia risk and SCD in diabetic and non-diabetic individuals. Key findings include the EMBODY trial's demonstration of empagliflozin’s improvement in heart rate variability [ 22 ], and studies from Taiwan [ 23 ] and the SGLT2-I AMI PROTECT [ 24 ] indicating a 17% reduction in new arrhythmias and fewer severe arrhythmic events among SGLT2i users, respectively. Our research corroborates a retrospective analysis of 46 T2DM patients, showing that SGLT2i decreases QTc dispersion on 12-lead ECGs without affecting heart rate, QTc interval, or Tpeak–Tend interval, particularly in those with elevated baseline QTc dispersion [ 25 ]. While not associated with HbA1c changes, a relationship was observed with systolic blood pressure variations, and post-treatment serum electrolyte levels were stable. The findings suggest that SGLT2i improves disparity in ventricular recovery times, irrespective of its effects on blood sugar levels [ 26 ]. This effect underscores the direct cardioprotective actions of SGLT2i, supported by evidence that glycemic control alone does not significantly affect QT and Tpeak-Tend dispersion [ 27 ]. While the exact mechanisms by which SGLT2i reduces arrhythmias are under investigation, it is believed that they involve multiple processes underlying cardiac arrhythmogenesis. Interest areas include their impact on cardiovascular autonomic function. Studies have shown SGLT2i decreases sympathetic activity and increases parasympathetic activity, improving autonomic balance [ 22 ]. Their influence on specific ionic currents in cardiomyocytes, reducing late-INa and spontaneous calcium transients similarly to ranolazine and lidocaine [ 28 ], has also been explored. It is relevant that blockade of sympathetic activity [ 29 ], increasing cardiac vagal tone [ 30 ], and blockade of late-INa current [ 31 ] have been shown to reduce T-wave heterogeneity. Experimental studies suggest empagliflozin directly inhibits the NHE1 exchanger and SGLT1 in cardiomyocytes [ 32 ], reducing sodium content, improving mitochondrial function, and decreasing oxidative stress, which are additional mechanisms proposed for arrhythmia reduction. Regarding ischemia-reperfusion-related arrhythmias, experimental studies on non-diabetic rats showed empagliflozin significantly reduced ventricular arrhythmias, including ventricular tachycardia and fibrillation, and eliminated SCD vulnerability [ 13 ]. Control groups had a 69.2% mortality rate, whereas empagliflozin-treated groups recorded no sudden cardiac death, indicating empagliflozin's cardioprotective capacity through ERK1/2 phosphorylation pathway activation. Similarly, in rabbit models, empagliflozin reduced ventricular arrhythmias by improving calcium cycling and mitochondrial function [ 33 ]. Pre-ischemic use of dapagliflozin significantly reduced infarct size and cardiomyocyte apoptosis, underscoring its cardioprotective ability and potential value in minimizing cardiac damage and enhancing post-injury cardiac function [ 34 ]. In our hypothesis-generating study, we employed the TWH index as a surrogate marker for arrhythmia and SCD, given the well-established efficacy of this marker [ 6 , 7 , 9 ]. The significance of TWH rests on three fundamental pillars: its capacity to stratify risk by identifying individuals with high susceptibility to adverse cardiac events; its effectiveness in predicting responses to therapeutic interventions, exemplified by cardiac resynchronization therapy; and its capability in monitoring the progression of cardiac electrical instability, aiding in the evaluation of treatment efficacy [ 9 ]. Following treatment, slightly over one-third of participants experienced a reduction in TWH to below the safety threshold of 80 µV, primarily among those with initially TWH levels around 100 µV. This finding could suggest that individuals with lower baseline TWH are more likely to experience significant treatment benefits, aligning with safer TWH levels post-treatment. However, patients’ responses to the treatment varied, as indicated by the wide distribution and high standard deviation of observed changes. This variation could be clinically significant, suggesting that while there is a general trend towards TWH reduction, individual reactions to the treatment can vary significantly. Surprisingly, a few patients experienced an increase in TWH after the intervention. This finding, emerging from this pilot study, signals a complexity that exceeds the initial scope of the research but warrants future investigation. Our study faces certain limitations, including a small sample size and limited duration, which may affect the generalizability of our results. Additionally, the particular demographics of our patient cohort call for careful consideration when applying these findings to wider populations. To substantiate and broaden our conclusions, future research should involve larger, more varied groups and longer observation times. The exact molecular mechanisms by which empagliflozin attenuates ventricular arrhythmogenesis remain to be fully elucidated. This gap highlights an opportunity for future research, particularly at the molecular and cellular levels, to unravel the intricate pathways involved in the antiarrhythmic effects of SGLT2 inhibitors. Our findings add a piece to the complex puzzle of cardiovascular management in diabetes mellitus, underscoring empagliflozin's potential in mitigating arrhythmic risks. While enhancing our understanding of empagliflozin’s cardiovascular benefits, our study paves the way for novel research directions and clinical applications, promising significant advancements in patient care. 5. Conclusions This pilot study demonstrated that empagliflozin reduces ventricular repolarization heterogeneity in patients with T2D and CAD, suggesting that a reduction in severe arrhythmias may be among the mechanisms contributing to the observed decrease in cardiovascular mortality with this treatment. Exploring TWH in diabetic patients with coronary artery disease opens new avenues for standardizing treatment and simplifying methodologies across this patient population. By delving into this area, we can lay the groundwork for developing products that directly calculate TWH. This approach not only has the potential to enhance clinical outcomes but also offers a basis for innovation in patient management and treatment optimization. Such advancements could significantly contribute to individualized medicine, ensuring that interventions are more accurately tailored to individual patient profiles, thereby improving efficacy and patient care in the field of coronary and diabetic health. Abbreviations CHD coronary heart disease ECG electrocardiogram ICC Intraclass Correlation Coefficient InCor Heart Institute of the Faculty of Medicine of the University of Sao Paulo Late-INa late sodium current LVEF Left Ventricular Ejection Fraction MANOVA Multivariate Analysis of Variance MI myocardial infarction PDF Portable Document Format REDCap Research Electronic Data Capture SCD sudden cardiac death SD standard deviation SGLT2i sodium-glucose cotransporter-2 inhibitor T2DM Type 2 Diabetes Mellitus TIFF Tagged Image File Format TWH T-wave heterogeneity Declarations Ethics approval and consent to participate The main study protocol was approved by the Institutional Review Board of Clinical Hospital of the Medical School of the University of São Paulo, under registration number SDC: 4732/18/083. All participants gave written informed consent. Consent for publication Not applicable. Availability of data and material Data are available from the authors upon request. Competing interests The authors declare that they have no competing interests. Funding Funding for this research was obtained from The Sao Paulo Research Foundation (FAPESP) under the record 2020/02668-2 and The National Council for Scientific and Technological Development (CNPQ) under the record 309454/2020-4. Authors’ contributions CL conducted the study as part of her PhD project. GLA and FGS assisted in screening participants and calculating TWH. AEF assisted in organizing participant visits and in editing figures. RLV developed the TWH analysis technique, reviewed the manuscript, and provided suggestions. ACCG and BC supervised the project's execution and contributed with suggestions and guidance. Acknowledgments We extend our deepest gratitude to the patients for their willing participation, which has significantly enriched our study. Our thanks also go to the teams at the Interdisciplinary Medicine Unit in Cardiology, the Fulvio Pileggi Research Center at the Heart Institute, and Professor Verrier's team at Harvard for their support and knowledge sharing. Authors’ information Interdisciplinary Medicine Unit in Cardiology, Heart Institute of the Clinical Hospital of the Medical School of the University of Sao Paulo, Sao Paulo, SP, Brazil, 05403000 Cristiane Lauretti, Graziella L. Antonio, Fernando G. Stocco, Ariana E. Fernandes and Bruno Caramelli Laboratory of Genetics and Molecular Cardiology, Heart Institute of the Clinical Hospital of the Medical School of the University of Sao Paulo, Sao Paulo, SP, Brazil, 05403000 Adriana C.C. Girardi Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02215, United States of America Richard L. Verrier References Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Abingdon, England: UK). 2014;42:698–702. Sarwar N, Gao P, Seshasai SRK, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet (London England). 2010;375:2215–22. Mukamal KJ, Nesto RW, Cohen MC, Muller JE, Maclure M, Sherwood JB, et al. Impact of diabetes on long-term survival after acute myocardial infarction. Diabetes Care. 2001;24:1422–7. Verrier RL, Huikuri H. Tracking interlead heterogeneity of R- and T-wave morphology to disclose latent risk for sudden cardiac death. Heart Rhythm. 2017;14:1466–75. Nearing BD, Verrier RL. Tracking cardiac electrical instability by computing interlead heterogeneity of T-wave morphology. J Appl Physiol. 2003;95:2265–72. Kenttä TV, Nearing BD, Porthan K, Tikkanen JT, Viitasalo M, Nieminen MS, et al. Prediction of sudden cardiac death with automated high-throughput analysis of heterogeneity in standard resting 12-lead electrocardiograms. Heart Rhythm. 2016;13:713–20. Tan AY, Nearing BD, Rosenberg M, Nezafat R, Josephson ME, Verrier RL. Interlead heterogeneity of R- and T‐wave morphology in standard 12‐lead ECGs predicts sustained ventricular tachycardia/fibrillation and arrhythmic death in patients with cardiomyopathy. J Cardiovasc Electrophysiol. 2017;28:1324–33. Hekkanen JJ, Kenttä TV, Haukilahti MAE, Rahola JT, Holmström L, Vähätalo J, et al. Increased beat-to-beat variability of T-wave heterogeneity measured from standard 12-lead electrocardiogram is associated with sudden cardiac death: a case-control study. Front Physiol. 2020;11:1045. Verrier RL, Nearing BD, D'Avila A. Spectrum of clinical applications of interlead ECG heterogeneity assessment: from myocardial ischemia detection to sudden cardiac death risk stratification. Ann Noninvasive Electrocardiol. 2021;26:e12894. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28. Verma S, Leiter LA, Sharma A, Zinman B, Mattheus M, Fitchett DH, et al. How early after treatment initiation are the CV benefits of empagliflozin apparent? A post Hoc analysis of EMPA-REG OUTCOME. Diabetes. 2020;69:28–OR. Curtain JP, Docherty KF, Jhund PS, Petrie MC, Inzucchi SE, Køber L, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J. 2021;42:3727–38. Hu Z, Ju F, Du L, Abbott GW. Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death. Cardiovasc Diabetol. 2021;20:199. Fernandes GC, Fernandes A, Cardoso R, Penalver J, Knijnik L, Mitrani RD, et al. Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: a meta-analysis of 34 randomized controlled trials. Heart Rhythm. 2021;18:1098–105. Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. Standardizing clinically meaningful outcome measures beyond HbA(1c) for type 1 diabetes: a consensus report of the American association of clinical endocrinologists, the American association of diabetes educators, the American diabetes association, the endocrine society, JDRF international, the Leona M. and Harry B. Helmsley charitable trust, the pediatric endocrine society, and the T1D exchange. Diabetes Care. 2017;40:1622–30. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42:377–81. Kligfield P, Gettes LS, Bailey JJ, Childers R, Deal BJ, Hancock EW, et al. Recommendations for the standardization and Interpretation of the Electrocardiogram. Circulation. 2007;115:1306–24. Kania M, Rix H, Fereniec M, Zavala-Fernandez H, Janusek D, Mroczka T, et al. The effect of precordial lead displacement on ECG morphology. Med Biol Eng Comput. 2014;52:109–19. Badilini F, Erdem T, Zareba W, Moss AJ. ECGScan: a method for conversion of paper electrocardiographic printouts to digital electrocardiographic files. J Electrocardiol. 2005;38:310–8. Badilini F. The ISHNE holter standard output file format. Ann Noninvasive Electrocardiol. 1998;3:263–6. R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2023. Shimizu W, Kubota Y, Hoshika Y, Mozawa K, Tara S, Tokita Y, et al. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol. 2020;19:148. Chen HY, Huang JY, Siao WZ, Jong GP. The association between SGLT2 inhibitors and new-onset arrhythmias: a nationwide population-based longitudinal cohort study. Cardiovasc Diabetol. 2020;19:73. Cesaro A, Gragnano F, Paolisso P, Bergamaschi L, Gallinoro E, Sardu C, et al. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med. 2022;9:1012220. Sato T, Miki T, Ohnishi H, Yamashita T, Takada A, Yano T, et al. Effect of sodium-glucose co‐transporter‐2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes. Diabet Med. 2017;34:1367–71. Inzucchi SE, Kosiborod M, Fitchett D, Wanner C, Hehnke U, Kaspers S, et al. Improvement in cardiovascular outcomes with empagliflozin is independent of glycemic control. Circulation. 2018;138:1904–7. Miki T, Tobisawa T, Sato T, Tanno M, Yano T, Akasaka H, et al. Does glycemic control reverse dispersion of ventricular repolarization in type 2 diabetes? Cardiovasc Diabetol. 2014;13:125. Philippaert K, Kalyaanamoorthy S, Fatehi M, Long W, Soni S, Byrne NJ, et al. Cardiac late sodium channel current is a molecular target for the sodium/glucose cotransporter 2 inhibitor empagliflozin. Circulation. 2021;143:2188–204. Justo F, Fuller H, Nearing BD, Rajamani S, Belardinelli L, Verrier RL. Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation. Heart Rhythm. 2016;13:1860–7. Nearing BD, Anand IS, Libbus I, Dicarlo LA, Kenknight BH, Verrier RL. Vagus nerve stimulation provides multiyear improvements in autonomic function and cardiac electrical stability in the ANTHEM-HF study. J Card Fail. 2021;27:208–16. Bonatti R, Silva AFG, Batatinha JAP, Sobrado LF, Machado AD, Varone BB, et al. Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity. Heart Rhythm. 2014;11:1827–35. Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart. 2021;107:1032–8. Azam MA, Chakraborty P, Si D, Du B, Massé S, Lai PFH, et al. Anti-arrhythmic and inotropic effects of empagliflozin following myocardial ischemia. Life Sci. 2021;276:119440. Lahnwong C, Palee S, Apaijai N, Sriwichaiin S, Kerdphoo S, Jaiwongkam T, et al. Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc Diabetol. 2020;19:91. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 16 Apr, 2024 Reviewers agreed at journal 10 Apr, 2024 Reviewers agreed at journal 10 Apr, 2024 Reviewers invited by journal 10 Apr, 2024 Editor assigned by journal 29 Mar, 2024 Submission checks completed at journal 29 Mar, 2024 First submitted to journal 28 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4183475","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":285428138,"identity":"1c1d6769-399a-4fd3-9cf2-3d27fe2b912b","order_by":0,"name":"Cristiane Lauretti","email":"","orcid":"","institution":"Universidade de São Paulo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cristiane","middleName":"","lastName":"Lauretti","suffix":""},{"id":285428139,"identity":"8f82a2db-08c7-4787-931e-628dfb3471f1","order_by":1,"name":"Graziella L. Antonio","email":"","orcid":"","institution":"Universidade de São Paulo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Graziella","middleName":"L.","lastName":"Antonio","suffix":""},{"id":285428140,"identity":"0c8129e3-65b6-434e-a267-72928e4c4e1a","order_by":2,"name":"Ariana E. Fernandes","email":"","orcid":"","institution":"Universidade de São Paulo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ariana","middleName":"E.","lastName":"Fernandes","suffix":""},{"id":285428141,"identity":"5411309e-943f-4643-a141-2d8363b6d6cd","order_by":3,"name":"Fernando G. Stocco","email":"","orcid":"","institution":"Universidade de São Paulo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fernando","middleName":"G.","lastName":"Stocco","suffix":""},{"id":285428142,"identity":"2d37fb8b-f571-4502-a291-7b8626281161","order_by":4,"name":"Adriana C. C. Girardi","email":"","orcid":"","institution":"Universidade de São Paulo","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Adriana","middleName":"C. C.","lastName":"Girardi","suffix":""},{"id":285428143,"identity":"d19a0fbc-3eab-4b87-932d-75958701502a","order_by":5,"name":"Richard L. Verrier","email":"","orcid":"","institution":"Harvard Medical School and Beth Israel Deaconess Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Richard","middleName":"L.","lastName":"Verrier","suffix":""},{"id":285428144,"identity":"ff3b74d2-7556-46d1-b688-278e12a4ba45","order_by":6,"name":"Bruno Caramelli","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsElEQVRIiWNgGAWjYBACAygtww8iGRtI0MIj2UCyFoMDxGoxZz/87MPPHBse4xvpzx4w7rhHWItlT5rxzN5taTxmN3LMDRjPFBPhsBsMxgy82w6DtLBJMLYlEKOF/TPj323/eYxnpD8jVguPMTPvtgM8BhIJZsRpsezJKWaW3ZbMI3HmjblB4hkitJizH9/M+HabnRx/OzDEPu4gQgsyYGMgUQNIyygYBaNgFIwCbAAAGm81d7EL6sEAAAAASUVORK5CYII=","orcid":"","institution":"Universidade de São Paulo","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Bruno","middleName":"","lastName":"Caramelli","suffix":""}],"badges":[],"createdAt":"2024-03-28 16:05:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4183475/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4183475/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54036797,"identity":"acd0862f-0f1d-457d-b95d-dce15c273108","added_by":"auto","created_at":"2024-04-03 17:04:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46173,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots of TWH levels in patients before (left) and after (right) empagliflozin treatment over 4 weeks.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4183475/v1/c453f48cf9e1a74c18c80a8d.png"},{"id":54036796,"identity":"6280fa24-6134-4121-b6b5-f9587b9446b2","added_by":"auto","created_at":"2024-04-03 17:04:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":7296,"visible":true,"origin":"","legend":"\u003cp\u003eDigitized ECG tracings illustrate T- wave heterogeneity (TWH) as interlead splay in repolarization morphology before (upper panel) and after empagliflozin for 4 weeks (lower panel) in a representative participant.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4183475/v1/22a58f22ed3569e1033c8229.png"},{"id":54036798,"identity":"65ee094a-c7b1-4fca-a0ef-443c04668d84","added_by":"auto","created_at":"2024-04-03 17:04:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":60683,"visible":true,"origin":"","legend":"\u003cp\u003eTWH before and after 4 weeks of empagliflozin (25mg daily). Green lines: patients with TWH ≤80 μV post-treatment. Dashed lines denote medians before and after treatment. Significant median reduction (p = 0.0159).\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4183475/v1/6139365a81af28eab2622401.png"},{"id":54037576,"identity":"e8642e6e-0372-4596-a48d-db905a348fd4","added_by":"auto","created_at":"2024-04-03 17:12:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":676695,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4183475/v1/802601f0-392a-421a-b9f8-bf428f98d1df.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Empagliflozin's role in reducing ventricular repolarization heterogeneity: Insights into cardiovascular mortality decline from the EMPATHY-HEART trial","fulltext":[{"header":"1. Background","content":"\u003cp\u003eThe global incidence of Type 2 Diabetes Mellitus (T2DM) is reaching critical levels, projected to affect approximately 600\u0026nbsp;million individuals by 2035 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This condition markedly increases the prevalence of cardiovascular diseases (CVD) and generates a concern highlighted by the higher rates of post-myocardial infarction (MI) mortality and a greater frequency of sudden cardiac death (SCD) among those with diabetes, in comparison to non-diabetic individuals [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOften, SCD is the first clinical indication of an underlying, undetected cardiac disorder. Traditional risk factors fall short in accurately predicting these fatal arrhythmias, underscoring the need for more precise predictive tools [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. SCD is generally preceded by an electrical disturbance, prompting recent shifts towards non-invasive methods for risk assessment using electrocardiographic indicators [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. One such marker is the T-wave heterogeneity index (TWH) that measures the variance of waveforms around the T-wave's average waveform, effectively capturing the spatial disparity in heart repolarization [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. TWH has proven valuable in accurately stratifying the risk of sudden cardiac death, overall cardiac mortality, and arrhythmic episodes in a diverse range of cardiovascular conditions [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEmpagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), has emerged as a key player in cardiovascular healthcare, a status underscored by EMPA-REG trial [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This study highlighted a 14% reduction in relative risk for a combined outcome of cardiovascular death, non-fatal MI, and non-fatal stroke, with a notable 38% decrease in cardiovascular mortality, including sudden death cases. These benefits were significant even in patients already under comprehensive cardiovascular risk management and were observable as soon as 27 days post-treatment initiation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The rapid and significant effects of empagliflozin on cardiovascular outcomes in patients with high-risk T2DM are acknowledged, yet the mechanisms behind these effects remain partly unclear. Dapagliflozin, another SGLT2i, has been shown to reduce ventricular arrhythmias, cardiac arrests, and SCD in conjunction with standard heart failure treatments [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Additionally, preclinical studies bolster the hypothesis that empagliflozin may diminish the risk of fatal arrhythmias [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These findings are crucial for managing patients with high-risk cardiovascular diabetes and underscore the need for focused clinical trials to investigate further the potential effect of SGLT2i in the prevention of cardiac arrhythmias. While there's evidence suggesting a potential reduction in fatal arrhythmias with empagliflozin [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], its specific anti-arrhythmic actions and influence on SCD susceptibility in T2DM and CHD patients still require further elucidation. Our study aimed to explore whether empagliflozin can attenuate ventricular arrhythmogenesis and lower the risk of SCD by assessing TWH in diabetic patients with coronary artery disease, contributing to the evolving field of cardiovascular care in patients with diabetes.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Design\u003c/h2\u003e \u003cp\u003eThe EMPATHY-HEART Trial employed an exploratory pilot study design to investigate the influence of empagliflozin on ventricular repolarization heterogeneity in patients diagnosed with both T2DM and CHD. The choice of an exploratory design emerged from the imperative to elucidate the potential impacts of empagliflozin on ventricular electrical instability, an aspect with limited prior exploration. Given the limited number of clinical trials utilizing interlead T-wave heterogeneity, the study aimed to establish the basis for future research and hypothesis development.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Participants\u003c/h2\u003e \u003cp\u003e Outpatients at Heart Institute of the Faculty of Medicine of the University of Sao Paulo (InCor), Brazil, were invited to participate. The study included individuals 18 years and older, diagnosed with T2DM, and showing evidence of CHD, indicated by a history of myocardial infarction, significant coronary stenosis, or a positive test for myocardial ischemia. Additionally, participants required a baseline TWH on ECG of 80 \u0026micro;V or higher, following the criteria established by Tan et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Exclusion criteria comprised chronic kidney disease (glomerular filtration rate below 45 ml/min/1.73m\u0026sup2;); advanced hepatic disease (Child-Pugh B or C); age over 85; an uninterpretable 12-lead baseline ECG, due to conditions like pacemaker rhythms or signal distortions; and a baseline ECG TWH under 80 \u0026micro;V. In this context, \"baseline\" ECG refers to the electrocardiogram conducted at the first study visit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Intervention\u003c/h2\u003e \u003cp\u003eUnder the guidance of a sole researcher (CL), all participants underwent comprehensive clinical assessments. They received a daily prescription of empagliflozin 25mg, aligning with current clinical guidelines emphasizing its cardiovascular benefits in high-risk diabetic populations. This dosage selection aimed specifically to investigate empagliflozin's effects on the prevention of cardiac arrhythmias. Tailored adjustments to hypoglycemic regimens were made as necessary to minimize the risk of hypoglycemia, ensuring a standardized yet personalized approach for participant safety and treatment efficacy.\u003c/p\u003e \u003cp\u003ePatients performed a 12-lead ECG at their initial visit and again after 4 weeks. During the follow-up, a clinical reassessment and treatment adherence analysis were conducted. This 4-week period aligns with findings from a post-hoc analysis indicating a notable decrease in cardiovascular death or heart failure hospitalization starting from day 27 post-randomization [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Treatment adherence was evaluated through direct questioning of each participant [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Data Collection\u003c/h2\u003e \u003cp\u003eData Management and Statistical Analysis Data acquisition and management were conducted using the REDCap (Research Electronic Data Capture) platform [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResting electrocardiograms were conducted using Mortara Eli 250C (2013) or GE Healthcare MAC 2000 (2019) equipment, capturing 12 leads simultaneously in a 4 x 3 format, with a paper speed of 25 mm/s and a 10-mV gain. Electrode placement followed standard technical guidelines [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTWH was calculated specifically in leads V4, V5, and V6, chosen for their lower variability due to electrode positioning and patient's body constitution [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and their proven effectiveness in detecting electrical instability and arrhythmia risk [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTwo independent researchers, CL and GLA, blinded to the patients' treatment status, performed the TWH calculations for each ECG.\u003c/p\u003e \u003cp\u003eParticipant ECGs were extracted from InCor's electronic records as PDFs, anonymized, and converted to TIFF format. ECGScan software (AMPS-LLC, New York, NY) translated the waveforms [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], which were then turned into text files using ISHNE and CalECG softwares (AMPS-LLC, New York, NY) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. These files were analyzed in Microsoft Excel (365 version). Data from leads V4, V5, and V6 were overlaid, aligned by the PR segment, and synchronized at the QRS complex onset. The second central moment algorithm was applied to the J-T wave interval of each cardiac cycle to determine the point of highest morphology variance. The square root of this variance provided the TWH value in microvolts per beat. The TWH index, representing the average TWH of all recorded beats, indicates repolarization nonuniformity; higher values suggest a greater risk of life-threatening ventricular arrhythmias [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Detailed TWH calculation methods from resting 12-lead ECGs are described elsewhere [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Statistical Analysis\u003c/h2\u003e \u003cp\u003eThe primary goal of our study was to investigate how TWH levels were altered by empagliflozin administration. To ensure reliability and agreement of ECG data analyzed by the independent researchers we utilized the Intraclass Correlation Coefficient (ICC). To enhance result precision, we excluded extreme outliers, namely, subjects whose TWH levels were more than 3 standard deviations above the population mean, to reduce data skewness. The Shapiro-Wilk test was employed for normality evaluation. Variables were analyzed using Student's t-test for normal distributions and the Wilcoxon rank-sum test for non-parametric data, including TWH, to determine empagliflozin's effects. Multivariate analysis utilized MANOVA, with all tests adhering to a significance threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, reflecting a 5% significance level. Statistical analyses were conducted using R, a software environment for statistical computing and graphics [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Data are presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (S.D.)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Ethical Considerations\u003c/h2\u003e \u003cp\u003eRecruitment for this study occurred between October 2019 and October 2023. Each participant gave written informed consent, having been fully briefed on aims, methods, and potential risks. Adhering to the Declaration of Helsinki's principles, this clinical trial was approved by the Institutional Review Board of Clinical Hospital of the Medical School of the University of Sao Paulo, under registration number SDC: 4732/18/083. The research is registered on ClinicalTrials.gov with the identifier NCT04117763.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Patient Characteristics\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAmong the potential candidates screened, 412 had TWH equal to or greater than 80 \u0026micro;V. Of these, 90 participants were included in the study. The demographic and clinical profiles of the participants, as outlined in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, indicated a cohort with a notably high cardiovascular risk. This included the majority having experienced myocardial infarctions, over half displaying a tri-arterial pattern in invasive stratification, and nearly a quarter having undergone coronary artery bypass grafting. As expected in a specialized heart hospital setting, participants were optimized for cardiovascular risk reduction. The majority were on statins (90%) and beta-blockers (84%). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used by 77% of the patients. For diabetes management, 24% were on basal insulin therapy, and 11% adhered to a basal-bolus insulin therapy regimen. Only two subjects were not on antiplatelet agents.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex: Male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge: Mean (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace: White\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDM2 Duration\u003c/p\u003e \u003cp\u003e\u0026le; 10 years\u003c/p\u003e \u003cp\u003e\u0026gt; 10 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46%\u003c/p\u003e \u003cp\u003e54%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlycemic Control\u003c/p\u003e \u003cp\u003eHbA1c\u0026thinsp;\u0026lt;\u0026thinsp;8.0\u003c/p\u003e \u003cp\u003eHbA1c\u0026thinsp;\u0026ge;\u0026thinsp;8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69%\u003c/p\u003e \u003cp\u003e31%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious Stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral Arterial Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious Myocardial Infarction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvasive Stratification\u003c/p\u003e \u003cp\u003eUniarterial\u003c/p\u003e \u003cp\u003eBiarterial\u003c/p\u003e \u003cp\u003eTriarterial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98%\u003c/p\u003e \u003cp\u003e15%\u003c/p\u003e \u003cp\u003e26%\u003c/p\u003e \u003cp\u003e58%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAngina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePercutaneous Revascularization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgical Revascularization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart Failure\u003c/p\u003e \u003cp\u003ePreserved EF\u003c/p\u003e \u003cp\u003eReduced EF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82%\u003c/p\u003e \u003cp\u003e61%\u003c/p\u003e \u003cp\u003e39%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyslipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLipid Control (med, mg/dL)\u003c/p\u003e \u003cp\u003eLDL\u003c/p\u003e \u003cp\u003eHDL\u003c/p\u003e \u003cp\u003eTriglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78\u0026thinsp;\u0026plusmn;\u0026thinsp;23\u003c/p\u003e \u003cp\u003e40\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e \u003cp\u003e134\u0026thinsp;\u0026plusmn;\u0026thinsp;71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Clinical Parameters\u003c/h2\u003e \u003cp\u003eAdherence to treatment exceeded 80% across all participants. Consistent with prior evidence [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], our study found that empagliflozin significantly reduced blood pressure without significantly affecting heart rate (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical Characteristics of the Participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeasurements\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline (mean)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFollow-up (mean)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic BP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e137.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e126.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic BP (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e77.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e72.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart Rate (bpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e71.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e77.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e77.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHypoglycemia was noted in 13.3% of participants, with a predominant occurrence at Level 1 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] (91.7%), and no reports of serious episodes. Urinary tract infections were observed in 4.4%, while genital fungal infections occurred in 11.1% of the patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3. T-Wave Heterogeneity\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eTWH values for each ECG, assessed by independent researchers, showed high reliability, as reflected by ICC values of 0.9 for both baseline and follow-up phases, with p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.001. This robust concordance validated aggregating data from both researchers for subsequent data analysis and presentation.\u003c/p\u003e \u003cp\u003eFollowing empagliflozin treatment, we noted a significant reduction in TWH values, indicating a decrease in ventricular repolarization heterogeneity. Specifically, mean baseline TWH values fell from 127 \u0026micro;V to 114 \u0026micro;V at follow-up, with a median reduction from 116 \u0026micro;V to 103 \u0026micro;V. This change, statistically significant with a p-value of 0.01, underscores a meaningful difference attributed to empagliflozin treatment.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eVisual analysis of the data presented in the Boxplot in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e indicates increased variability in TWH values post-treatment, as shown by the rise in standard deviation from 43.9 to 55.7 \u0026micro;V and in the interquartile range from 46.2 to 67.8 \u0026micro;V. The presence of outliers above the third quartile, both before and after treatment, highlights a persistent dispersion in TWH values, irrespective of therapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRepresentative digitized ECG tracings for a patient during the study are provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The baseline ECG, depicted in the upper panel, shows pronounced T-wave heterogeneity, with significant variability in T-wave morphology across different leads. Following a 4-week treatment with empagliflozin, the lower panel presents ECG tracings that demonstrate a noticeable reduction in TWH, evidenced by a decrease in variability among T-wave forms.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e reveals a trend toward lower TWH levels after treatment across the study population. About one-third of the participants achieved a TWH reduction to 80 \u0026micro;V or below post-treatment. Predominantly, the optimal responders \u0026ndash; those whose TWH diminished to 80 uV or less \u0026ndash; initially had TWH values below 100 uV.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA multivariate analytical method (MANOVA) was employed to explore the connections among clinical variables, including HbA1c levels, time since diabetes diagnosis, incidence of angina, previous MI, MI localization, classification in invasive stratification, and Left Ventricular Ejection Fraction (LVEF), with the goal of identifying a significant association with TWH reduction. LVEF and HbA1c were treated as categorical variables with cutoffs at 50% and 8%, respectively. Single-vessel disease and diabetes duration emerged as significant factors, leading to their inclusion in a refined linear multivariate analysis model, which revealed that only single-vessel disease had a significant effect on reducing TWH (p\u0026thinsp;=\u0026thinsp;0.027). Inspecting this group of patients with single-vessel disease, it was observed that the majority had a prior myocardial infarction, with the anterior wall being the most affected. The model, with a multiple R\u003csup\u003e2\u003c/sup\u003e of 0.321 and an adjusted R\u003csup\u003e2\u003c/sup\u003e of 0.2791, alongside a p-value of 6.183e-06, reveals moderate explanatory power and significant statistical validity.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eParticipants characterized by high cardiovascular risk and treated at a specialized cardiology hospital, had increased baseline TWH, indicating a heightened susceptibility to arrhythmias or sudden cardiac death. Therapeutically, these patients were following optimal regimens, marked by widespread use of beta-blockers. Consequently, the positive effect of empagliflozin observed in this cohort point to a possible additional therapeutic benefit in addition to beta-blockers. This finding raises the intriguing possibility that beta-blockers might have slightly concealed an even greater potential of empagliflozin to diminish ventricular electrical instability. We employed the TWH level of 80 \u0026micro;V established by previous research to demonstrate that the risk of severe arrhythmias and SCD increases significantly when TWH levels exceed this level [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Electrocardiograms were performed in an ambulatory setting without provocative testing for ischemia or exertion. Within a relatively brief period of four weeks of empagliflozin treatment, there was a statistically significant reduction in the TWH median.\u003c/p\u003e \u003cp\u003eThis proof-of-concept trial showed that empagliflozin significantly reduces ventricular electrical vulnerability in patients with T2DM and CHD, evidenced by reduced T-wave heterogeneity. The findings complement recent evidence, offering new insights into these phenomena and their implications in a clinical setting for the first time.\u003c/p\u003e \u003cp\u003eResearch into the role of SGLT2i in arrhythmia prevention is rapidly evolving. Recent studies highlight SGLT2i's potential to reduce arrhythmia risk and SCD in diabetic and non-diabetic individuals. Key findings include the EMBODY trial's demonstration of empagliflozin\u0026rsquo;s improvement in heart rate variability [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and studies from Taiwan [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and the SGLT2-I AMI PROTECT [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] indicating a 17% reduction in new arrhythmias and fewer severe arrhythmic events among SGLT2i users, respectively.\u003c/p\u003e \u003cp\u003eOur research corroborates a retrospective analysis of 46 T2DM patients, showing that SGLT2i decreases QTc dispersion on 12-lead ECGs without affecting heart rate, QTc interval, or Tpeak\u0026ndash;Tend interval, particularly in those with elevated baseline QTc dispersion [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. While not associated with HbA1c changes, a relationship was observed with systolic blood pressure variations, and post-treatment serum electrolyte levels were stable. The findings suggest that SGLT2i improves disparity in ventricular recovery times, irrespective of its effects on blood sugar levels [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This effect underscores the direct cardioprotective actions of SGLT2i, supported by evidence that glycemic control alone does not significantly affect QT and Tpeak-Tend dispersion [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the exact mechanisms by which SGLT2i reduces arrhythmias are under investigation, it is believed that they involve multiple processes underlying cardiac arrhythmogenesis. Interest areas include their impact on cardiovascular autonomic function. Studies have shown SGLT2i decreases sympathetic activity and increases parasympathetic activity, improving autonomic balance [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Their influence on specific ionic currents in cardiomyocytes, reducing late-INa and spontaneous calcium transients similarly to ranolazine and lidocaine [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], has also been explored. It is relevant that blockade of sympathetic activity [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], increasing cardiac vagal tone [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and blockade of late-INa current [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] have been shown to reduce T-wave heterogeneity. Experimental studies suggest empagliflozin directly inhibits the NHE1 exchanger and SGLT1 in cardiomyocytes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], reducing sodium content, improving mitochondrial function, and decreasing oxidative stress, which are additional mechanisms proposed for arrhythmia reduction. Regarding ischemia-reperfusion-related arrhythmias, experimental studies on non-diabetic rats showed empagliflozin significantly reduced ventricular arrhythmias, including ventricular tachycardia and fibrillation, and eliminated SCD vulnerability [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Control groups had a 69.2% mortality rate, whereas empagliflozin-treated groups recorded no sudden cardiac death, indicating empagliflozin's cardioprotective capacity through ERK1/2 phosphorylation pathway activation. Similarly, in rabbit models, empagliflozin reduced ventricular arrhythmias by improving calcium cycling and mitochondrial function [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Pre-ischemic use of dapagliflozin significantly reduced infarct size and cardiomyocyte apoptosis, underscoring its cardioprotective ability and potential value in minimizing cardiac damage and enhancing post-injury cardiac function [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our hypothesis-generating study, we employed the TWH index as a surrogate marker for arrhythmia and SCD, given the well-established efficacy of this marker [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The significance of TWH rests on three fundamental pillars: its capacity to stratify risk by identifying individuals with high susceptibility to adverse cardiac events; its effectiveness in predicting responses to therapeutic interventions, exemplified by cardiac resynchronization therapy; and its capability in monitoring the progression of cardiac electrical instability, aiding in the evaluation of treatment efficacy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFollowing treatment, slightly over one-third of participants experienced a reduction in TWH to below the safety threshold of 80 \u0026micro;V, primarily among those with initially TWH levels around 100 \u0026micro;V. This finding could suggest that individuals with lower baseline TWH are more likely to experience significant treatment benefits, aligning with safer TWH levels post-treatment.\u003c/p\u003e \u003cp\u003eHowever, patients\u0026rsquo; responses to the treatment varied, as indicated by the wide distribution and high standard deviation of observed changes. This variation could be clinically significant, suggesting that while there is a general trend towards TWH reduction, individual reactions to the treatment can vary significantly. Surprisingly, a few patients experienced an increase in TWH after the intervention. This finding, emerging from this pilot study, signals a complexity that exceeds the initial scope of the research but warrants future investigation.\u003c/p\u003e \u003cp\u003eOur study faces certain limitations, including a small sample size and limited duration, which may affect the generalizability of our results. Additionally, the particular demographics of our patient cohort call for careful consideration when applying these findings to wider populations. To substantiate and broaden our conclusions, future research should involve larger, more varied groups and longer observation times.\u003c/p\u003e \u003cp\u003eThe exact molecular mechanisms by which empagliflozin attenuates ventricular arrhythmogenesis remain to be fully elucidated. This gap highlights an opportunity for future research, particularly at the molecular and cellular levels, to unravel the intricate pathways involved in the antiarrhythmic effects of SGLT2 inhibitors.\u003c/p\u003e \u003cp\u003eOur findings add a piece to the complex puzzle of cardiovascular management in diabetes mellitus, underscoring empagliflozin's potential in mitigating arrhythmic risks. While enhancing our understanding of empagliflozin\u0026rsquo;s cardiovascular benefits, our study paves the way for novel research directions and clinical applications, promising significant advancements in patient care.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eThis pilot study demonstrated that empagliflozin reduces ventricular repolarization heterogeneity in patients with T2D and CAD, suggesting that a reduction in severe arrhythmias may be among the mechanisms contributing to the observed decrease in cardiovascular mortality with this treatment.\u003c/p\u003e \u003cp\u003eExploring TWH in diabetic patients with coronary artery disease opens new avenues for standardizing treatment and simplifying methodologies across this patient population. By delving into this area, we can lay the groundwork for developing products that directly calculate TWH. This approach not only has the potential to enhance clinical outcomes but also offers a basis for innovation in patient management and treatment optimization. Such advancements could significantly contribute to individualized medicine, ensuring that interventions are more accurately tailored to individual patient profiles, thereby improving efficacy and patient care in the field of coronary and diabetic health.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCHD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecoronary heart disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eelectrocardiogram\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntraclass Correlation Coefficient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eInCor\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHeart Institute of the Faculty of Medicine of the University of Sao Paulo\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLate-INa\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elate sodium current\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLVEF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLeft Ventricular Ejection Fraction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMANOVA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMultivariate Analysis of Variance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emyocardial infarction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePDF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePortable Document Format\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eREDCap\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResearch Electronic Data Capture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSCD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esudden cardiac death\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSGLT2i\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esodium-glucose cotransporter-2 inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eT2DM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eType 2 Diabetes Mellitus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTIFF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTagged Image File Format\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTWH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eT-wave heterogeneity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main study protocol was approved by the Institutional Review Board of Clinical Hospital of the Medical School of the University of S\u0026atilde;o Paulo, under registration number SDC: 4732/18/083. All participants gave written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and material\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available from the authors upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this research was obtained from The Sao Paulo Research Foundation (FAPESP) under the record 2020/02668-2 and The\u0026nbsp;National Council for Scientific and Technological Development (CNPQ) under the record 309454/2020-4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCL conducted the study as part of her PhD project. GLA and FGS assisted in screening participants and calculating TWH. AEF assisted in organizing participant visits and in editing figures. RLV developed the TWH analysis technique, reviewed the manuscript, and provided suggestions. ACCG and BC supervised the project's execution and contributed with suggestions and guidance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extend our deepest gratitude to the patients for their willing participation, which has significantly enriched our study. Our thanks also go to the teams at the Interdisciplinary Medicine Unit in Cardiology, the Fulvio Pileggi Research Center at the Heart Institute, and Professor Verrier's team at Harvard for their support and knowledge sharing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026rsquo; information\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterdisciplinary Medicine Unit in Cardiology, Heart Institute of the Clinical Hospital of the Medical School of the University of Sao Paulo, Sao Paulo, SP, Brazil, 05403000\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCristiane Lauretti, Graziella L. Antonio, Fernando G. Stocco, Ariana E. Fernandes and Bruno Caramelli\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory of Genetics and Molecular Cardiology, Heart Institute of the Clinical Hospital of the Medical School of the University of \u003c/strong\u003e\u003cstrong\u003eSao Paulo, Sao Paulo, SP, Brazil, 05403000\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdriana C.C. Girardi\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHarvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02215, United States of America\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRichard L. Verrier\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eForouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine (Abingdon, England: UK). 2014;42:698\u0026ndash;702.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarwar N, Gao P, Seshasai SRK, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet (London England). 2010;375:2215\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMukamal KJ, Nesto RW, Cohen MC, Muller JE, Maclure M, Sherwood JB, et al. Impact of diabetes on long-term survival after acute myocardial infarction. Diabetes Care. 2001;24:1422\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerrier RL, Huikuri H. Tracking interlead heterogeneity of R- and T-wave morphology to disclose latent risk for sudden cardiac death. Heart Rhythm. 2017;14:1466\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNearing BD, Verrier RL. Tracking cardiac electrical instability by computing interlead heterogeneity of T-wave morphology. J Appl Physiol. 2003;95:2265\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKentt\u0026auml; TV, Nearing BD, Porthan K, Tikkanen JT, Viitasalo M, Nieminen MS, et al. Prediction of sudden cardiac death with automated high-throughput analysis of heterogeneity in standard resting 12-lead electrocardiograms. Heart Rhythm. 2016;13:713\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan AY, Nearing BD, Rosenberg M, Nezafat R, Josephson ME, Verrier RL. Interlead heterogeneity of R- and T‐wave morphology in standard 12‐lead ECGs predicts sustained ventricular tachycardia/fibrillation and arrhythmic death in patients with cardiomyopathy. J Cardiovasc Electrophysiol. 2017;28:1324\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHekkanen JJ, Kentt\u0026auml; TV, Haukilahti MAE, Rahola JT, Holmstr\u0026ouml;m L, V\u0026auml;h\u0026auml;talo J, et al. Increased beat-to-beat variability of T-wave heterogeneity measured from standard 12-lead electrocardiogram is associated with sudden cardiac death: a case-control study. Front Physiol. 2020;11:1045.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerrier RL, Nearing BD, D'Avila A. Spectrum of clinical applications of interlead ECG heterogeneity assessment: from myocardial ischemia detection to sudden cardiac death risk stratification. Ann Noninvasive Electrocardiol. 2021;26:e12894.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerma S, Leiter LA, Sharma A, Zinman B, Mattheus M, Fitchett DH, et al. How early after treatment initiation are the CV benefits of empagliflozin apparent? A post Hoc analysis of EMPA-REG OUTCOME. Diabetes. 2020;69:28\u0026ndash;OR.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCurtain JP, Docherty KF, Jhund PS, Petrie MC, Inzucchi SE, K\u0026oslash;ber L, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J. 2021;42:3727\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu Z, Ju F, Du L, Abbott GW. Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death. Cardiovasc Diabetol. 2021;20:199.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFernandes GC, Fernandes A, Cardoso R, Penalver J, Knijnik L, Mitrani RD, et al. Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: a meta-analysis of 34 randomized controlled trials. Heart Rhythm. 2021;18:1098\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. Standardizing clinically meaningful outcome measures beyond HbA(1c) for type 1 diabetes: a consensus report of the American association of clinical endocrinologists, the American association of diabetes educators, the American diabetes association, the endocrine society, JDRF international, the Leona M. and Harry B. Helmsley charitable trust, the pediatric endocrine society, and the T1D exchange. Diabetes Care. 2017;40:1622\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42:377\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKligfield P, Gettes LS, Bailey JJ, Childers R, Deal BJ, Hancock EW, et al. Recommendations for the standardization and Interpretation of the Electrocardiogram. Circulation. 2007;115:1306\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKania M, Rix H, Fereniec M, Zavala-Fernandez H, Janusek D, Mroczka T, et al. The effect of precordial lead displacement on ECG morphology. Med Biol Eng Comput. 2014;52:109\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBadilini F, Erdem T, Zareba W, Moss AJ. ECGScan: a method for conversion of paper electrocardiographic printouts to digital electrocardiographic files. J Electrocardiol. 2005;38:310\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBadilini F. The ISHNE holter standard output file format. Ann Noninvasive Electrocardiol. 1998;3:263\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShimizu W, Kubota Y, Hoshika Y, Mozawa K, Tara S, Tokita Y, et al. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial. Cardiovasc Diabetol. 2020;19:148.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen HY, Huang JY, Siao WZ, Jong GP. The association between SGLT2 inhibitors and new-onset arrhythmias: a nationwide population-based longitudinal cohort study. Cardiovasc Diabetol. 2020;19:73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCesaro A, Gragnano F, Paolisso P, Bergamaschi L, Gallinoro E, Sardu C, et al. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med. 2022;9:1012220.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSato T, Miki T, Ohnishi H, Yamashita T, Takada A, Yano T, et al. Effect of sodium-glucose co‐transporter‐2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes. Diabet Med. 2017;34:1367\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInzucchi SE, Kosiborod M, Fitchett D, Wanner C, Hehnke U, Kaspers S, et al. Improvement in cardiovascular outcomes with empagliflozin is independent of glycemic control. Circulation. 2018;138:1904\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiki T, Tobisawa T, Sato T, Tanno M, Yano T, Akasaka H, et al. Does glycemic control reverse dispersion of ventricular repolarization in type 2 diabetes? Cardiovasc Diabetol. 2014;13:125.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePhilippaert K, Kalyaanamoorthy S, Fatehi M, Long W, Soni S, Byrne NJ, et al. Cardiac late sodium channel current is a molecular target for the sodium/glucose cotransporter 2 inhibitor empagliflozin. Circulation. 2021;143:2188\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJusto F, Fuller H, Nearing BD, Rajamani S, Belardinelli L, Verrier RL. Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation. Heart Rhythm. 2016;13:1860\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNearing BD, Anand IS, Libbus I, Dicarlo LA, Kenknight BH, Verrier RL. Vagus nerve stimulation provides multiyear improvements in autonomic function and cardiac electrical stability in the ANTHEM-HF study. J Card Fail. 2021;27:208\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonatti R, Silva AFG, Batatinha JAP, Sobrado LF, Machado AD, Varone BB, et al. Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity. Heart Rhythm. 2014;11:1827\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart. 2021;107:1032\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzam MA, Chakraborty P, Si D, Du B, Mass\u0026eacute; S, Lai PFH, et al. Anti-arrhythmic and inotropic effects of empagliflozin following myocardial ischemia. Life Sci. 2021;276:119440.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLahnwong C, Palee S, Apaijai N, Sriwichaiin S, Kerdphoo S, Jaiwongkam T, et al. Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc Diabetol. 2020;19:91.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Type 2 Diabetes Mellitus, Coronary Heart Disease, Empagliflozin, T-wave Heterogeneity, Ventricular Arrhythmias, Cardiovascular Mortality, Non-invasive Diagnostic Tools, EMPA-REG Trial, Electrical Instability, Arrhythmia Prevention","lastPublishedDoi":"10.21203/rs.3.rs-4183475/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4183475/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eParticipants were adult outpatients with T2DM and CHD who exhibited TWH \u0026gt;80 µV at baseline. They received a 25mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p\u0026lt;0.05) change in TWH following empagliflozin administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAn initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 144 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p=0.01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNCT: 04117763.\u003c/p\u003e","manuscriptTitle":"Empagliflozin's role in reducing ventricular repolarization heterogeneity: Insights into cardiovascular mortality decline from the EMPATHY-HEART trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-03 17:04:04","doi":"10.21203/rs.3.rs-4183475/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2024-04-16T19:55:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"e15665ae-bd62-455e-bbfd-9bfc1af6db77","date":"2024-04-10T22:37:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"e4772da6-4277-437b-9609-7e260e256579","date":"2024-04-10T21:41:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-10T12:08:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-29T15:20:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-29T14:45:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Diabetology","date":"2024-03-28T16:04:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cardiovascular-diabetology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cvdb","sideBox":"Learn more about [Cardiovascular Diabetology](http://cardiab.biomedcentral.com/)","snPcode":"12933","submissionUrl":"https://submission.nature.com/new-submission/12933/3","title":"Cardiovascular Diabetology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"229a8725-c664-4949-a2bd-d5fc3e519c3d","owner":[],"postedDate":"April 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-16T08:23:35+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-03 17:04:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4183475","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4183475","identity":"rs-4183475","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}