Abstract / Summary
To examine associations of metabolic obesity phenotypes with the onset and progression of ischaemic heart disease (IHD) and potential biomarker pathways. We analysed 336,386 UK Biobank participants free of IHD, heart failure, and arrhythmia at baseline. Participants were classified as metabolically healthy non-obesity (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO), and metabolically unhealthy obesity (MUO). Cox regression and multi-state models estimated risks for IHD and subsequent transitions. Counterfactual mediation analyses quantified the mediating roles of serum urate, gamma-glutamyl transferase (GGT), systemic inflammation response index (SIRI), and albumin. During follow-up, 27,183 participants developed IHD and 9,137 subsequently developed heart failure or arrhythmia. Compared with MHNO, adjusted HRs (95% CI) for incident IHD were 1.43 (1.37–1.50) for MHO, 1.63 (1.58–1.68) for MUNO, and 2.16 (2.09–2.22) for MUO; corresponding HRs were 1.58 (1.46–1.71), 1.59 (1.50–1.67), and 2.42 (2.29–2.55) for complications, and 1.18 (1.12–1.24), 1.29 (1.25–1.33), and 1.48 (1.43–1.54) for all-cause mortality. In multi-state analyses, MUO remained associated with progression from IHD to complications (HR 1.17; 95% CI 1.11–1.23) and from complications to death (HR 1.30; 95% CI 1.16–1.46). For MUO, GGT accounted for the largest mediation proportions for incident IHD (13.23%) and all-cause mortality (35.52%), while urate showed the greatest mediation proportion for IHD complications (14.51%). Metabolic obesity phenotypes showed distinct associations with IHD onset and progression. Urate, GGT, SIRI, and albumin explained part of MUO-related risk, supporting risk stratification integrating metabolic status and biomarkers.