SYSTEMIC METABOLIC DISORDER STAGING TO ESTIMATE GLOBAL AND ORGAN-SPECIFIC DISEASE RISK IN THE GENERAL POPULATION

초록

Background and Aims: In 2025, the European Atherosclerosis Society introduced a staging system for systemic metabolic disorder (SMD) to quantify metabolic dysfunction and its organ-specific consequences. Whether SMD stages predict organ-specific clinical outcomes in the general population and whether stage transitions carry independent prognostic value remain unknown. Methods: In this prospective analysis of UK Biobank (UKBB) participants free of major cardiometabolic disease at baseline, people were classified as SMD Stage 0 (metabolically healthy), Stage 1 (risk factors), or Stage 2 (organ damage). Associations between SMD stages and fatal and non-fatal heart-, cardiovascular-, kidney-, liver-, and cancer-related events were examined using Fine-Gray competing-risk models, while a composite cardio-kidney-liver outcome was assessed using Cox regression. Stage transitions were analyzed using timedependent Cox models. Findings were externally evaluated in an independent Korean National Health Insurance Service (KNHIS) Senior cohort. Sex-stratified analyses were performed in the UKBB cohort. Results: After exclusions, 386,851 UKBB and 342,159 KNHIS participants were included, with consistent stage distributions across cohorts. SMD Stages 1 and 2 were progressively associated with higher risk of heart-, cardiovascular-, and kidney-related events, whereas only Stage 2 predicted liver-related events (Figure 1). The composite outcome increased stepwise across stages (Stage 1: HR 1.55 [1.51–1.59]; Stage 2: HR 2.16 [2.10–2.23]) (Figure 2). Cancer-related events showed no consistent association (Figure 2). Associations were confirmed in the KNHIS Senior cohort. The magnitude of association was greater in women than in men. Stage transitions were independently associated with risk of the composite outcome, with progression increasing risk (Stage 0→1: HR 1.53 [1.12–2.09]; Stage 0→2: HR 3.93 [2.90–5.34]; Stage 1→2: HR 2.48 [2.00–3.06]) and regression from Stage 2 to Stage 0 associated with lower risk (HR 0.62 [0.44–0.88]). Conclusions: SMD staging predicts global and organ-specific metabolic outcomes and provides a simple framework to stratify cardio-kidney-liver risk and monitor disease trajectories in the general population.