Antiarrhythmic effects of sodium-glucose cotransporter-2 inhibitors: a review of studies and mechanisms of action

Sodium-glucose cotransporter-2 inhibitors (SGLT2i), mainly used for the treatment of type 2 diabetes mellitus, have shown their potential benefits for the cardiovascular system. The direct effect of SGLT2i on the myocardium is widely recognized, their systemic effects also contribute to the cardioprotective effect within the framework of the «CаRеMe» concept of comorbidity in diabetes and a paradigm shift to a broader goal – reducing morbidity, mortality and target organs complications. Recent basic and clinical studies have shown that SGLT2i have antiarrhythmic effects. A number of meta-analyses have specifically focused on the effect of the SGLT2i class on the incidence of arrhythmias in different patient populations. A large meta-analysis of 34 RCTs assessing the effect of SGLT2i on arrhythmia-related outcomes showed a 19% reduction in the risk of AF (OR=0.81; P=0.008) and a 15% reduction in the risk of ventricular arrhythmias (OR=0.85; P=0.23). Other meta-analyses also confirmed a significant reduction in the AF/Aflu combination, but the effect on the risk of ventricular arrhythmias was not significant. Specific meta-analyses assessing the effect of SGLT2i on the risk of AF and stroke did not find significant differences in the incidence of stroke (OR=0.99). A recent analysis of the FDA Adverse Event Reporting System (USA) found a lower incidence of AF in diabetic patients treated with SGLT2 inhibitors compared with other antidiabetic agents (OR=0.55; P<0.001), including OR=0.47 for canagliflozin, OR=0.51 for dapagliflozin, and OR=0.71 for empagliflozin. Numerous mechanisms have been discussed as to the antiarrhythmic action of SGLT2 inhibitors, including direct effects such as activation of ketone bodies, utilization of free fatty acids that change the energy supply of the myocardium, counteraction of harmful intracellular changes and disturbances of ion homeostasis, anti-inflammatory action, modulation of sympathetic influences on the heart, as well as indirect effects including osmotic diuresis, reduction of blood pressure, hemodynamic load, cardiac remodeling and body weight.

Thus, SGLT2i have proven themselves in clinical practice, and the corresponding clinical studies and basic experiments have shown that they have an antiarrhythmic effect, however, the significance of SGLT2i for the treatment of arrhythmias and the exact extent of their influence will be clarified in new large clinical trials.