Sodium–glucose cotransporter-2 (SGLT2) inhibitors, initially developed to manage type 2 diabetes mellitus by lowering hemoglobin A1c levels, have demonstrated significant cardiovascular benefits beyond glycemic control. Regulatory trials have highlighted their ability to reduce major adverse cardiac events, including heart failure hospitalizations and cardiovascular deaths, irrespective of ejection fraction or diabetes status. Consequently, SGLT2 inhibitors now hold a Class 1A recommendation for adults with heart failure and are favored as second-line agents for patients with type 2 diabetes accompanied by cardiovascular disease.
Impact on Ventricular Arrhythmias:
Ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation, are critical contributors to morbidity and mortality in patients with heart failure and reduced ejection fraction. These arrhythmias, though not prevalent in all heart failure patients, carry a high risk of sudden cardiac death. Traditional treatment options to mitigate this risk include beta blockers and implantable cardioverter–defibrillators (ICDs). However, despite their efficacy, ICD uptake remains low due to factors like cost, accessibility, and the invasiveness of the procedure, resulting in sudden cardiac death accounting for nearly 40% of deaths in this patient population.
Emerging Evidence on SGLT2 Inhibitors:
A meta-analysis encompassing 22 trials with over 52,000 participants indicated that SGLT2 inhibitors are associated with a reduced risk of ventricular tachycardia and atrial fibrillation/flutter [1]. Further supporting this, the DAPA-HF trial's post hoc analysis revealed that dapagliflozin users experienced fewer cardiac arrhythmias compared to placebo [2]. Additionally, observational studies have corroborated these findings, suggesting a lower incidence of ventricular tachycardia/fibrillation and cardiac arrest among SGLT2 inhibitor users [3].
The EMPA-ICD Trial
The EMPA-ICD trial [4] provides the most direct and robust evidence addressing the impact of SGLT2 inhibitors on ventricular arrhythmias. This randomized, placebo-controlled study involved 150 patients with type 2 diabetes who had either implantable cardioverter-defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). Over a 24-week period, the trial found that empagliflozin significantly reduced the number of ventricular arrhythmias compared to placebo, with a coefficient for the between-group difference of -1.07 (95% confidence interval [CI]: -1.29 to -0.86, P < 0.001). Despite this reduction in ventricular arrhythmias, there was no significant difference observed in appropriate device discharges between the empagliflozin and placebo groups.
The ERASe Trial:
The ERASe trial [5], conducted by Benedikt et al. (2024), directly examines the effect of ertugliflozin on arrhythmic burden in patients with implantable cardioverter-defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). This multicenter, double-blind, randomized, placebo-controlled study included 46 patients and found that ertugliflozin significantly reduced the frequency of incident sustained ventricular tachycardia/fibrillation by 84% and nonsustained ventricular tachycardia by 66% compared to placebo. However, the trial was prematurely terminated due to updates in clinical guidelines, resulting in a smaller sample size, which limits the strength of the evidence and calls for larger studies to further validate these results.
Implications:
The early termination of the ERASe trial underscores both the advancements and challenges in heart failure pharmacotherapy. On the positive side, it affirms the availability of effective treatments that improve patient outcomes. However, the limited sample size raises questions about the robustness of the findings. Nonetheless, the consistency of results between the ERASe and EMPA-ICD trials strengthens the evidence that SGLT2 inhibitors likely play a role in reducing the frequency of ventricular arrhythmias.
Conclusion:
SGLT2 inhibitors have emerged as a pivotal therapy in managing heart failure, offering benefits that extend to reducing ventricular arrhythmias. While more extensive trials are needed to solidify these findings, the current evidence supports the integration of SGLT2 inhibitors into treatment protocols for patients with heart failure and reduced ejection fraction to mitigate the risk of sudden cardiac death.
References
Li HL, Lip GYH, Feng Q, et al. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis. Cardiovasc Diabetol 2021;20(1).
Curtain JP, Docherty KF, Jhund PS, et al. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. Eur Heart J 2021;42:3727-3738.
Fawzy AM, Rivera-Caravaca JM, Underhill P, Fauchier L, Lip GYH. Incident heart failure, arrhythmias and cardiovascular outcomes with sodium-glucose cotransporter 2 (SGLT2) inhibitor use in patients with diabetes: insights from a global federated electronic medical record database. Diabetes Obes Metab 2023;25:602-610.
Fujiki S, Iijima K, Nakagawa Y, et al. Effect of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes treated with an implantable cardioverter-defibrillator: the EMPA-ICD trial. Cardiovasc Diabetol 2024;23:224.
Benedikt M, Oulhaj A, Rohrer U, et al. Ertugliflozin to reduce arrhythmic burden in patients with ICDs/CRT-Ds. NEJM Evid 2024;3(10).
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