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Mediation Analysis: Weight Loss vs Non-Weight Loss Pathways A formal mediation analysis using causal inference methodology estimated that: Weight loss mediated approximately 40% (95% CI: 25-55%) of the total MACE reduction CRP reduction (as a proxy for anti-inflammatory effects) mediated approximately 25-30% of the MACE reduction, with significant overlap with the weight loss pathway The remaining 30-40% of the MACE reduction was not explained by measured mediators, suggesting direct vascular or cardiac effects that were not captured by standard biomarkers This mediation analysis has important clinical implications