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.