Metabolic improvement without structural reverse remodelling in diabetic atrial fibrillation patients receiving lifestyle modification: A post-hoc analysis of the PRAGUE-25 trial

Background Diabetes mellitus (DM) affects approximately 24% of obese atrial fibrillation (AF) patients and may modify response to treatment. The PRAGUE-25 trial demonstrated catheter ablation (CA) superiority over lifestyle modification plus antiarrhythmic drugs (LFM+AAD) for AF freedom in obese patients (73.0% vs 34.6%, P<0.001). Whether DM modifies treatment effect, and particularly whether metabolic improvements from lifestyle modification translate to structural cardiac remodelling in diabetic patients, remains unknown. Methods We performed a post-hoc analysis of the PRAGUE-25 randomised trial (n=203; body mass index 30–40 kg/m²), including 49 patients (24.1%) with DM. Patients were analysed in four subgroups: CA-DM (n=19), CA-NonDM (n=81), LFM+AAD-DM (n=30), LFM+AAD-NonDM (n=73). The primary endpoint was AF freedom at 12 months. We assessed treatment × diabetes interaction using Cox regression, evaluated left atrial volume index (LAVI) change and NT-proBNP trajectories by subgroup, and performed ROC analysis for biomarker prediction of AF recurrence. Results Diabetic patients showed a numerically greater CA benefit (hazard ratio [HR] 3.80, 95% CI: 1.68–8.61, P=0.001) compared with non-diabetic patients (HR 2.51, 95% CI: 1.63–3.87, P<0.001); however, the treatment × diabetes interaction was not statistically significant (P=0.547). Despite achieving metabolic improvements including HbA1c reduction (−3.4 mmol/mol) and weight loss (−3.3 kg), diabetic patients in the LFM+AAD group showed the worst structural remodelling trajectory: LAVI increased by +11.37 mL/m², compared with −5.60 mL/m² in DM-CA, +3.38 mL/m² in NonDM-LFM+AAD, and −3.45 mL/m² in NonDM-CA (Table). The treatment effect differential on LAVI was 2.5-fold greater in diabetic patients (Δ 16.97 mL/m²) than non-diabetic patients (Δ 6.83 mL/m²). NT-proBNP change emerged as the strongest predictor of AF recurrence (AUC 0.715, 95% CI: 0.619–0.811, P<0.001; specificity 89.1%), outperforming HbA1c (AUC 0.521, P=0.685) and LDL changes (AUC 0.544, P=0.399). Diabetic LFM+AAD patients achieved the smallest NT-proBNP reduction (−74.9 pg/mL) versus >180 pg/mL in all other subgroups (Figure). Conclusions In obese AF patients with diabetes, lifestyle modification achieves metabolic improvement without structural reverse remodelling — a “metabolic-structural disconnect” that may explain the limited efficacy of non-invasive management. Catheter ablation overcomes this disconnect by directly restoring sinus rhythm and enabling structural recovery. NT-proBNP change, rather than traditional metabolic markers, should guide treatment response monitoring. These exploratory findings from a post-hoc analysis require confirmation in adequately powered prospective trials.