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

Abstract Introduction The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM). Predictive measures for fatal arrhythmias are often inadequate, highlighting the need for novel non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index, which measures variations in ventricular repolarization, 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 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, exhibiting a baseline TWH of at least 80 µV. They received a 25mg daily dose of empagliflozin and were evaluated clinically, including 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 the alteration in TWH following empagliflozin administration, assessed via the Wilcoxon test, with a significance threshold of p<0.05. 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 mostly Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced median TWH from 116 to 103 µV (p=0.01), as detailed in Figure 1. Conclusion 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.Table 1 Figure 1