Highlights
- The DARE-AF trial is the first randomized controlled trial to evaluate dapagliflozin for preventing AF recurrence specifically in patients without established SGLT2 inhibitor indications (diabetes, heart failure, or CKD).
- At 3 months post-ablation, there was no statistically significant difference in AF burden between the dapagliflozin group (7.5%) and the control group (8.1%).
- The incidence of atrial arrhythmia recurrence was comparable between groups (29.6% vs 28.0%; Hazard Ratio: 1.11).
- Secondary outcomes, including quality of life scores and left atrial diameter remodeling, showed no significant therapeutic advantage for the intervention group.
Background
Atrial fibrillation (AF) remains the most prevalent sustained cardiac arrhythmia worldwide, contributing significantly to morbidity through stroke, heart failure, and cognitive decline. Catheter ablation has emerged as a cornerstone of rhythm control, particularly for symptomatic patients. However, the efficacy of ablation is often hampered by early and late recurrence, with rates ranging from 20% to 50% depending on the AF subtype and patient comorbidities. Early recurrence within the first three months is particularly problematic, as it is often a precursor to long-term failure and necessitates repeat procedures or long-term antiarrhythmic drug therapy.
Recent years have seen intense interest in the pleiotropic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors. Beyond their glucose-lowering effects, these agents have demonstrated profound cardiovascular benefits in patients with heart failure (HF) and chronic kidney disease (CKD). Sub-analyses of landmark trials like EMPEROR-Reduced and DAPA-HF suggested a secondary benefit: a reduction in the incidence of new-onset AF. Furthermore, multiple observational studies indicated that AF patients with diabetes or heart failure who were treated with SGLT2 inhibitors experienced lower recurrence rates following catheter ablation. However, these observational cohorts are prone to selection bias, and until the DARE-AF trial, it remained unknown whether these benefits extended to a broader AF population without these high-risk comorbidities.
Key Content
The DARE-AF Trial: Study Design and Population
The DARE-AF (Dapagliflozin on Recurrence After Catheter Ablation for Atrial Fibrillation) trial was a prospective, open-label, parallel-assignment randomized controlled trial conducted between July 2024 and March 2025. The study targeted a specific gap in clinical knowledge: the efficacy of dapagliflozin in patients with persistent AF who do not have established indications for the drug. This excluded patients with type 2 diabetes, symptomatic heart failure, or significant renal impairment.
Two hundred patients scheduled for their first catheter ablation procedure were randomized in a 1:1 ratio. The intervention arm received 10 mg of dapagliflozin daily for three months post-procedure, while the control arm received standard care. The primary endpoint was AF burden—defined as the percentage of time in AF—measured at the 3-month mark using a continuous 7-day single-lead ECG patch. This methodology provides a more granular assessment than intermittent 12-lead ECGs or brief Holter monitoring.
Clinical Outcomes and Statistical Synthesis
Of the 200 randomized patients (mean age 58.5 years), 198 were included in the final analysis. The cohort reflected a typical persistent AF population, though with a relatively low representation of women (19.5%). Approximately 29% of patients had a history of persistent AF exceeding one year.
The results were definitively neutral. The primary endpoint of AF burden at three months showed no significant difference: 7.5 ± 23.6% in the dapagliflozin group vs 8.1 ± 25.5% in the control group (P=0.48). When analyzing clinical recurrence (defined as any atrial arrhythmia lasting >30 seconds), 29 patients (29.6%) in the dapagliflozin group and 28 patients (28.0%) in the control group reached the endpoint (HR 1.11; 95% CI, 0.66-1.86; P=0.70).
Furthermore, the study examined surrogate markers of atrial health. Changes in left atrial diameter, a key metric for structural remodeling, did not differ significantly between the two groups. Quality of life metrics, which are paramount in AF management, also remained similar, suggesting that the addition of dapagliflozin did not confer a subjective symptomatic benefit in the immediate post-ablation period.
Mechanistic Insights and Atrial Remodeling
The lack of efficacy in DARE-AF invites a critical re-evaluation of the mechanisms by which SGLT2 inhibitors might influence atrial electrophysiology. It has been hypothesized that SGLT2 inhibitors reduce AF via several pathways: reduction of epicardial adipose tissue (which secretes pro-inflammatory cytokines), inhibition of the sodium-hydrogen exchanger (NHE-1) in the myocardium, and reduction of oxidative stress.
The neutrality of DARE-AF suggests that in the absence of systemic metabolic dysfunction (like diabetes) or hemodynamic stress (like heart failure), these mechanisms may not be sufficiently potent to overcome the acute inflammatory and electrical triggers associated with catheter ablation. It is possible that the “substrate” of AF in patients without comorbidities is more driven by mechanical/structural factors than by the metabolic pathways that SGLT2 inhibitors effectively target.
Expert Commentary
The results of the DARE-AF trial provide a necessary “reality check” for the enthusiasm surrounding SGLT2 inhibitors in electrophysiology. While observational data were promising, they likely reflected the drug’s efficacy in managing the underlying drivers of AF in sicklier patients—namely, reducing filling pressures in heart failure or improving glycemic control and renal function. In a “healthier” cohort where these drivers are absent, the drug appears to have a negligible impact on the immediate post-ablation blanking period.
One critical limitation of DARE-AF is the 3-month duration of the intervention. While this covers the “blanking period” where inflammation-driven recurrence is high, it may be too short to observe the long-term benefits of reverse structural remodeling. However, the lack of difference in left atrial diameter suggests that even early structural changes were not significantly influenced. Another consideration is the use of an open-label design; however, the primary endpoint (ECG patch burden) is an objective metric, minimizing the risk of observer bias.
Clinicians should continue to prescribe SGLT2 inhibitors according to established guidelines for HF, DM, and CKD. However, DARE-AF suggests that initiating dapagliflozin solely to improve ablation outcomes in patients without those comorbidities is not currently supported by high-level evidence.
Conclusion
The DARE-AF trial concludes that short-term (3-month) treatment with dapagliflozin does not reduce AF burden or clinical recurrence after a first catheter ablation for persistent AF in patients without diabetes, heart failure, or CKD. These findings highlight the importance of patient selection when applying the pleiotropic benefits of SGLT2 inhibitors. Future research should perhaps focus on longer-term follow-up or investigate whether patients with subclinical metabolic syndrome—not yet meeting full diagnostic criteria for DM or HF—might still derive benefit from this therapeutic class in the context of rhythm control.
References
- Jiang C, et al. Dapagliflozin to Reduce Early Recurrence After Catheter Ablation for Atrial Fibrillation: The DARE-AF Randomized Clinical Trial. Circulation. 2026 Feb 3;153(5):297-306. PMID: 41206792.
- Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263-e421. PMID: 35379503.
- Zannad F, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819-829. PMID: 32861314.
