Table 3.

Proposed clinical-context framework for evaluating metabolic and antifibrotic interventions in atrial fibrillation.

Clinical context	Primary objective and informative endpoint	What current evidence supports	Required mechanistic test or inference boundary
Cardiometabolic risk before documented AF	Prevent incident AF. Endpoint: adjudicated or monitor-detected first AF over a prespecified interval.	Four SGLT2-inhibitor meta-analyses reported fewer AF events (59, 61, 85, 86), whereas one placebo-controlled analysis found no statistically significant effect (60). In the largest placebo-controlled analysis the benefit was confined to trials enrolling heart failure with reduced ejection fraction (61). In most underlying trials, AF was captured as an adverse event rather than a prespecified efficacy endpoint. Epidemiological studies link obesity and diabetes to AF risk (37, 40).	Fewer AF events cannot establish substrate reversal. Pair clinical surveillance with serial atrial structure/function measures; fibroblast-specific biomarkers remain exploratory.
AF with limited measured substrate	Slow AF progression and reduce burden. Endpoints: continuous AF burden, transition to persistent AF, left atrial function and volume.	Cohort and trial data from mixed AF populations support improvements in symptoms and several remodeling measures, but these studies were not designed around this clinical context and did not demonstrate fibroblast target engagement (38, 81, 82). None of them measured atrial fibrosis directly, so their placement in this context is retrospective.	Define baseline substrate and repeat imaging/function measures. A change in atrial volume or symptoms should not be labeled fibrosis regression.
Progressive or persistent AF	Reduce AF burden and limit substrate progression. Endpoints: continuous burden, left atrial function, and quantitative fibrosis imaging.	An ovine obesity model with inducible AF supports reverse atrial remodeling after weight reduction (87), but it does not establish efficacy in persistent or progressive AF. Human evidence for regression of established interstitial fibrosis remains insufficient.	Stratify by baseline fibrosis and metabolic phenotype; test whether an intervention changes fibrosis independently of loading conditions and rhythm status.
Peri- or post-ablation	Reduce recurrence after the blanking period. Endpoints: continuous or protocolized rhythm monitoring, repeat ablation, cardioversion, and antiarrhythmic-drug use.	Randomized trials of weight and risk-factor management yielded different results: SORT-AF was neutral for its primary endpoint, whereas ARREST-AF showed lower recurrence (83, 84). SGLT2-inhibitor evidence is mixed: observational post-ablation associations were favorable, whereas DARE-AF was neutral for early recurrence (62, 63). GLP-1RA data are mainly observational or meta-analytic (74).	Recurrence reduction does not prove fibrosis regression. Measure substrate change and fibroblast target engagement separately from rhythm outcome.
Advanced/high-fibrosis substrate	Test reversal of established substrate. Endpoints: prespecified quantitative fibrosis reduction, functional recovery, AF burden, and durability.	Within the reviewed evidence, no intervention demonstrates both human atrial fibroblast target engagement and regression of established atrial fibrosis.	Require high baseline fibrosis, serial imaging with validated methods and, when clinically available, tissue analysis. Limited reversibility must remain an a priori possibility.

This framework is intended for evidence interpretation and is not a validated AF staging system or treatment algorithm. Clinical contexts may overlap. AF, atrial fibrillation; GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2, sodium–glucose cotransporter 2.