Metabolically Unhealthy Obesity: Novel Subtypes Defined by Integrated Metabolomics and Hematology

Objectives: The aim was to identify metabolic subtypes within metabolically unhealthy obesity (MUO) using integrated metabolomics and hematology data and evaluate their differential risks for cardiovascular-kidney-metabolic (CKM)-related outcomes. Methods: Among 62,341 obese UK Biobank participants (43,577 MUO; 18,764 non-MUO), least absolute shrinkage and selection operator regression selected 67 biomarkers from 96 metabolites and serological parameters, followed by K-means clustering. Cox proportional hazards models assessed subtype-specific associations with incident CKM-related outcomes over a median 14.81-year follow-up. Results: Four metabolic subtypes were identified within MUO, characterized by distinct amino acid, renal, and lipid profiles. Subtype-specific associations with CKM-related outcomes differed substantially. Compared with non-MUO participants, Subtype II and Subtype IV were associated with higher coronary heart disease risk (HR, 1.34; 95% CI, 1.11-1.61 and HR, 1.37; 95% CI, 1.15-1.64, respectively), Subtype IV was associated with lower atrial fibrillation risk (HR, 0.73; 95% CI, 0.60-0.90), Subtype III with higher heart failure risk (HR, 1.42; 95% CI, 1.10-1.82), and Subtype I with higher chronic kidney disease risk (HR, 1.52; 95% CI, 1.22-1.91). Conclusions: Integrated metabolomic and hematologic profiling identified variation in the metabolic profiles of individuals with MUO. The four subtypes showed different patterns of association with CKM-related outcomes, suggesting that MUO encompasses diverse metabolic profiles that may not be fully captured by conventional metabolic syndrome criteria.