SGLT2 inhibitors were associated with a significant reduction in atrial arrhythmias (AA) and all-cause mortality in patients with cardiac implantable electronic devices (CIED). The results of this real-world study indicate that SGLT2 inhibitors may have antiarrhythmic effects that add to the beneficial effects that these agents exert on patients with heart failure (HF). The study was presented during the virtual meeting of the American Heart Association Scientific Sessions. Physician’s Weekly interviewed Prof. Ilan Goldenberg (University of Rochester), first author of the study, to discuss the implications of these findings.1


 

“Sodium glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to reduce HF events in patients with HF and/or type-2 diabetes,” explained prof. Goldenberg during his presentation at the annual AHA meeting. In addition, SGLT2 inhibitors have been linked to hemodynamic alterations, such as a lowered intracardiac filling pressure, lowered arterial stiffness, and an increased hematocrit. The study hypothesized that these beneficial hemodynamic effects of SGLT2 inhibitors lead to a decrease in AA in patients with CIED.

Patients with CIED—including permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors—who were enrolled at tertiary medical centers in Israel or the USA between 2015 and 2020 (N=13,888) were included in the study. The primary endpoint was the total number of AA events detected by their CIED. In total, 898 patients were on SGLT2 inhibitor therapy at baseline. Patients treated with SGLT2 inhibitors showed significantly more comorbidities than patients who were not treated with SGLT2 inhibitors. A propensity score matching methodology was employed to adjust for baseline differences.

The number of registered AA events was 19,633 during a follow-up period of 24,442 patient years. The propensity score matched analysis showed a significant reduction of AA events among patients treated with SGLT2 inhibitors compared with other patients (HR, 0.77; P<0.001). Similarly, death was reduced by 44% in patients in the SGLT2 inhibitor arm versus patients in the non-SGLT2 inhibitor arm (HR, 0.56; P=0.001). Moreover, the annualized AA rates were 3.60 for patients in the non-SGLT2 inhibitor arm and 2.40 for patients in the SGLT2 inhibitor arm. The burden of ventricular arrhythmias was not significantly reduced in patients treated with SGLT2 inhibitors.

Physician’s Weekly spoke with Prof. Goldenberg to find out more.

 

PW: What was the rationale behind your hypothesis that SGLT2 inhibitors may affect arrhythmic events?

IG: We know that SGLT2 inhibitors have an effect on HF outcomes in patients who have a reduced ejection fraction. In this study, we hypothesized that SGLT2 inhibitors may have an incremental benefit on arrhythmic events. The rational for this hypothesis originated from the DAPA-HF trial (NCT03036124), in which the possible hemodynamic effects of SGLT2 inhibitors were well described. In addition, there have been some reports on the beneficial effect of SGLT2 inhibitors on atrial fibrosis.

Preliminary data from the DAPA-HF trial and some additional studies showed that the risk of atrial fibrillation (AF) was reduced among patients who did not have AF and were treated with dapagliflozin. However, these results came from preliminary subgroup analyses within the trial. Therefore, we aimed to confirm the hypothesis that the hemodynamic effects and the antifibrotic effects of SGLT2 inhibitors on the heart may translate into a reduction in the risk of arrhythmic events. We created a database of 13,888 patients with a CIED. The arrhythmic events were captured by our team. During the 5-year course of this multicenter study, approximately 20,000 atrial arrhythmic events and more than 3,000 ventricular arrhythmic events were registered. We compared the risk of arrhythmic events by use of SGLT2 inhibitors in the database.

 

How would you go about validating these promising results? 

We used both propensity score analysis and propensity score matching to analyze the data. The results turned out to be very consistent, with a 23% risk reduction of atrial arrhythmic events and a 44% reduction in the risk of all-cause mortality. Interaction term analysis adjustment demonstrated that the results were consistent by the type of drug that was prescribed and the type of device that was implanted. At the moment, we are running a prospective, randomized clinical trial on dapagliflozin versus placebo in patients who undergo AF ablation. Our aim is to investigate whether there is a reduction of AF burden associated with dapagliflozin therapy in this population after 1-year of follow-up. Although we did not find a significant reduction in ventricular arrhythmia with the use of SGLT2 inhibitors in our study, we are currently investigating this endpoint in another study. Furthermore, we are conducting an in-vitro study to evaluate the effects of these agents on lab values and atrial fibrosis.

 

How will this impact physicians in their practice?

I believe that patients who have, or are at risk for, AF should be prescribed SGLT2 inhibitors. The range of antiarrhythmic medications that we have is relatively limited, and most of the available agents may induce severe side effects in our patients. SGLT2 inhibitors, on the other hand, appear to be safe. Therefore, SGLT2 inhibitors may be an additional modality to treat AF, albeit that the evidence base needs to be increased by prospective randomized trials.