Diabetes, Obesity, and Early Rhythm Control in Atrial Fibrillation: Insights from the EAST-AFNET 4 Trial

Highlights

• Early rhythm control therapy reduces cardiovascular events in atrial fibrillation (AF) patients regardless of diabetes or obesity status.
• Obesity and diabetes, despite being risk factors, do not modify the treatment effect of early rhythm control in the EAST-AFNET 4 trial.
• Patients with obesity and diabetes were younger yet had higher cardiovascular risk scores but similar benefit and safety profiles with early rhythm control.

Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia, significantly increasing risks of stroke, heart failure, and mortality. Given the rising prevalence of obesity and diabetes worldwide—both key comorbidities increasing AF incidence and severity—understanding how these metabolic conditions affect treatment outcomes is critical. Prior randomized trials have established the benefit of early rhythm control in AF management, yet its efficacy in patients stratified by body mass index (BMI) and diabetes status remained unclear before the EAST-AFNET 4 secondary analysis.

Key Content

The EAST-AFNET 4 Trial Design and Primary Findings

The EAST-AFNET 4 trial was a multicenter, international randomized clinical trial enrolling patients with recently diagnosed AF (≤1 year) and cardiovascular conditions, across 11 European countries. Patients were randomized to early rhythm control versus usual care, with most receiving standard anticoagulation and management of concomitant conditions. Early rhythm control included antiarrhythmic drugs and catheter ablation strategies.

The primary composite outcome comprised cardiovascular death, stroke, hospitalization due to heart failure, or acute coronary syndrome. The trial demonstrated that early rhythm control reduced this composite outcome compared to usual care.

Secondary Analysis: Impact of BMI and Diabetes

This prespecified secondary analysis categorized patients by obesity (BMI ≥30) and diabetes status to evaluate if these factors influenced early rhythm control effectiveness and safety.

– Among 2776 patients analyzed, 1086 were obese (mean BMI 34.5), and 1690 were non-obese (mean BMI 25.9).
– Obese patients were younger (mean age 68 vs 72 years) and exhibited more persistent AF patterns than non-obese patients.
– Diabetes prevalence corresponded with younger age and higher CHA2DS2-VASc scores, indicating greater thromboembolic risk.

Figure. Primary Outcome for Patients With Body Mass Index (BMI) <30 (A), BMI ≥30 (B), Without Diabetes (C), and With Diabetes (D)^a.

Crucially, the analysis found no significant interaction between BMI category or diabetes status and the effect of early rhythm control on the primary cardiovascular composite outcome. Hazard ratios for early rhythm control vs. usual care were comparable across groups (BMI <30: HR 0.84; BMI ≥30: HR 0.69; diabetes HR 0.77 vs no diabetes HR 0.78). Safety profiles, including adverse events, were also similar.

Comparison with Previous Literature

Several observational studies and meta-analyses have identified obesity and diabetes as independent risk factors for AF incidence and poor cardiovascular outcomes. Moreover, prior data suggested that obesity might reduce ablation success rates and increase AF recurrence. Yet, the EAST-AFNET 4 analysis provides prospective randomized evidence that early rhythm control retains benefit irrespective of metabolic status. This aligns with guideline recommendations emphasizing early rhythm intervention but extends understanding to diverse patient phenotypes.

Expert Commentary

This secondary analysis confirms early rhythm control therapy’s robust cardiovascular benefit across metabolic subgroups and underscores its role in personalized AF management. While obesity and diabetes contribute to AF progression and comorbidity burden, they should not preclude early rhythm control strategies. Given the younger profile and higher AF burden among obese/diabetic patients, early intervention may be particularly impactful.

It is essential to consider that treatment protocols in EAST-AFNET 4 were comprehensive and included optimized anticoagulation and management of comorbidities, which likely contributed to favorable outcomes. Future research might explore mechanistic pathways linking metabolic dysfunction to atrial remodeling and response to rhythm control.

Limitations include the trial’s European setting, which may limit generalizability to more diverse populations, and limited granularity on glycemic control or weight management interventions that could influence outcomes.

Conclusion

The EAST-AFNET 4 secondary analysis provides strong evidence that early rhythm control therapy is effective and safe in AF patients irrespective of obesity and diabetes status. This supports the adoption of early rhythm control as a cornerstone of AF management across metabolic phenotypes, potentially improving cardiovascular outcomes in this growing patient population.

References

• Metzner A et al. Diabetes and Obesity and Treatment Effect of Early Rhythm Control vs Usual Care in Patients With Atrial Fibrillation: A Secondary Analysis of the EAST-AFNET 4 Randomized Clinical Trial. JAMA Cardiol. 2025;10(9):932-941. doi:10.1001/jamacardio.2025.2374 IF: 14.1 Q1 B1. PMID: 40737012 IF: 14.1 Q1 B1.
• Kirchhof P et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383(14):1305-1316. doi:10.1056/NEJMoa1915101 .
• January CT et al. 2019 AHA/ACC/HRS Focused Update on Atrial Fibrillation Management. Circulation. 2019;140(2):e125-e151.