Deadly Arrhythmias Less of a Risk for HF Patients on Dapagliflozin

An SGLT2 inhibitor seemed to offer protection from reduced ventricular arrhythmias in heart failure patients, according to a post hoc analysis of DAPA-HF.

In that trial, the cohort randomized to dapagliflozin (Farxiga) had a reduced first occurrence of any ventricular arrhythmia, resuscitated cardiac arrest, or sudden death (5.9% vs 7.4% for placebo group; HR 0.79, 95% CI 0.63-0.99) over a median 18.2 months.

Dapagliflozin’s antiarrhythmic benefit in heart failure with reduced ejection fraction (HFrEF) was consistent across the individual components of that endpoint, according to John McMurray, MD, of Scotland’s Cardiovascular Research Centre at the University of Glasgow, and colleagues.

Their analysis was presented during a late-breaking scientific session at this year’s virtual European Society of Cardiology congress. A full manuscript was published simultaneously in European Heart Journal.

SGLT2 inhibitors, originally developed as diabetes drugs, were able to make the jump to heart failure following surprisingly good results in cardiovascular safety trials. This was confirmed in studies like DAPA-HF, which found that dapagliflozin reduced cardiovascular death and worsening heart failure independent of glycemic control.

Less clear is how exactly SGLT2 inhibitors are able to confer heart benefits — some proposed actions have to do with a decreased risk of the ventricular arrhythmias that often trigger sudden cardiac death in heart failure patients, McMurray and colleagues noted.

Notably, their new report shows that people implanted with a defibrillating device trended toward less protection from dapagliflozin, though the test for interaction didn’t reach significance.

This suggests that “SGLT2is [SGLT2 inhibitors] may directly influence the synchronicity of cardiac excitation. However, it may be the case that patients with ICDs are at a later stage of heart failure progression and are therefore unreceptive to the potential benefits afforded by SGLT2i pharmacotherapy,” said Peter Light, PhD, of University of Alberta in Edmonton.

Indeed, the DAPA-HF report showed that patients with lower baseline NT-proBNP levels had significantly more benefit from dapagliflozin.

“Taken together, these results provide evidence for a protective effect of dapagliflozin against life-threatening electrical disturbances and that dapagliflozin may bestow additional protection in patients who were in the earlier stages of HFrEF at the time of enrolment,” Light wrote in an accompanying editorial.

“The strongest separation of the HR values was observed >9 months post-randomization, suggesting that the observed beneficial effects of dapagliflozin require time to develop and may involve cellular mechanisms that slow the progression of HFrEF,” he surmised.

FDA granted dapagliflozin an expanded indication for HFrEF last year on the basis of DAPA-HF.

DAPA-HF investigators had randomized 4,744 people (mean age 67 years, 77% men) to dapagliflozin or placebo. All were heart failure patients in New York Heart Association functional class ≥II who had a left ventricular ejection fraction ≤40% within the last year.

Participants stayed on standard device and pharmacological therapy for heart failure, with most taking a renin-angiotensin system blocker, beta-blocker, and a mineralocorticoid receptor antagonist.

For the present post hoc analysis, McMurray’s group probed serious adverse event reports related to ventricular arrhythmias or cardiac arrest without adjudication. The incidence of ventricular arrhythmias was 2.4%, and it was 0.5% for cardiac arrest (with 35% of the latter surviving).

Of the 500 cardiovascular deaths in the trial, 41% were adjudicated as sudden.

The study authors acknowledged that the post hoc nature of their report means the results are only hypothesis-generating. Moreover, the team likely underestimated the true prevalence of ventricular arrhythmias due to the lack of systematic monitoring.

“Whether or not the SGLT2is reduced the composite outcome primarily as a result of a reduction in ionic disturbances that are associated with HF, and the subsequent decrease of a proarrhythmic electrophysiological substrate, or secondary to the beneficial effects of SGLT2is on structural remodeling, remains to be determined in future studies,” Light said.

He also urged further studies to determine if the reduction in ventricular arrhythmias may be considered a class effect of SGLT2 inhibitors in general.