Sodium‐glucose cotransporter 2 inhibitors: An additional management option for patients with atrial fibrillation?

To meet the goal of obtaining antidiabetic medications that will have a favourable impact on the cardiovascular outcomes of patients with type 2 diabetes mellitus (T2DM), the sodium-glucose cotransporter (SGLT2) inhibitor class of drugs has emerged. The lesson learned in the past was to separate the mechanism of action of the new antidiabetic agents from insulin secretion and therefore avoid hypoglycaemic episodes, which are associated with aggressive control of glycaemic levels and have detrimental effects on cardiovascular health. Accordingly, SGLT2 inhibitors inhibit SGLT2-mediated glucose reabsorption at the level of the proximal convoluted tubule of the nephron, achieving steadier control of blood glucose levels. The four SGLT2 inhibitors currently licensed by the European Medicines Agency and the US Food and Drug Administration, empaglifozin, canagliflozin, dapagliflozin and ertugliflozin, have been tested in large clinical randomized controlled trials (RCTs): the EMPA-REG Outcome trial, CANVAS Program, DECLARE-TIMI 58 trial and VERTIS CV, respectively. All patients with T2DM and a high risk for cardiovascular disease achieved a significant reduction in hospitalization for heart failure. In addition, EMPA-REG Outcome also reported a significant reduction in cardiovascular mortality. Further extension of the findings of reduction in hospitalization and mortality to a population with heart failure, with or without T2DM, and with either preserved or reduced ejection fraction, has paved the way to the description of multiple mechanisms of benefit beyond blood glucose-lowering, including metabolic, anti-inflammatory antifibrotic action, and systemic and myocardial energetic and electrolytes homeostasis regulation. On this basis, SGLT2 inhibitors were hypothesized to have antiarrhythmic properties, and this has been assessed in secondary analyses of major RCTs, with contradictory findings. The main evidence of a possible anti-arrhythmic effect of SGLT2 inhibitors has been put forward by post hoc analysis of the DECLARE-TIMI 58 trial, which investigated the risk of atrial fibrillation (AF) and atrial flutter (AFL) among patients with T2DM and high cardiovascular risk profiles, with or without history AF/AF. The authors reported a significant decrease in the incidence of new episodes of AF/AFL on the arm treated with dapaglifozin; the effect was consistent regardless of the patient's history of AF, atherosclerotic cardiovascular disease or heart failure. Conversely, treatment with empagliflozin failed to show an impact on AF/AFL reduction. Subsequent meta-analyses have found a significant reduction, from 19% up to 34% in the risk of AF/AFL with SGLT2 inhibitor treatment, although the effect seems to have been mainly driven by the weight of the DECLARE-TIMI subanalysis. Notwithstanding these controversial clinical findings, several underlying pathological mechanisms support the biological plausibility of SGLT2 inhibitor action on atrial arrhythmia susceptibility (Figure 1). Due to the well-established connection between inflammation and AF, anti-inflammatory actions of SGLT2 inhibitors have been advanced as an explanation for the anti-arrhythmic effects. SGLT2 inhibitors have also been shown to decrease plasma levels of uric acid, which is a direct activator of NLRP3 inflammasome. In addition, SGLT2 inhibitors may have a direct effect on ion channels, promoting the reabsorption of magnesium at distal convoluted tubule of the nephron level and preventing hypomagnesaemia. Indeed, low levels of magnesium have been associated with increased risk of AF and supraventricular arrhythmias. At cellular level, SGLT2 inhibits the sodium-proton exchanger and reduces the intracellular levels of sodium, which can be high in patients with AF. It has also been suggested that there is modulation of sympathetic and parasympathetic activity, mediated by suppression of GPR41 activity in the sympathetic ganglia by ketone bodies, production of which is in turn promoted by SGLT2. More recently, in a small randomized trial, dapagliflozin treatment has been associated with a reduction in epicardial adipose tissue volume, and related leptin and tumour necrosis factor release in patients with T2DM. Of note, epicardial adipose tissue is highly metabolically active, secreting a plethora of profibrotic Received: 10 June 2022 Revised: 11 July 2022 Accepted: 12 July 2022