Associations of the atherogenic index of plasma and its modified indices with the incidence and progression of cardiometabolic multimorbidity in individuals with cardiovascular-kidney-metabolic syndrome stages 0–3: a prospective cohort study

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 reflect a heterogeneous continuum of metabolic, kidney, and cardiovascular abnormalities that are closely associated with the development of cardiometabolic diseases (CMDs). Although the atherogenic index of plasma (AIP) and obesity-related composite indices have been associated with individual CMDs, their associations with cardiometabolic multimorbidity (CMM) among individuals with CKM syndrome remain unclear. This study primarily investigated whether AIP-related indices were associated with the incidence and progression of CMM in individuals with CKM syndrome stages 0-3. METHODS: This prospective cohort study included 346,868 UK Biobank participants without baseline type 2 diabetes (T2DM), coronary heart disease (CHD), or stroke. CMM was defined as the coexistence of at least two of these conditions. Cox proportional hazards models were used to estimate associations with incident CMM, while multistate models were applied to characterize disease progression. As secondary analyses, the added predictive value of each index was assessed using discrimination and reclassification metrics. Exploratory biomarker analyses examined whether inflammatory, liver, and renal biomarkers statistically accounted for part of the associations. RESULTS: During a median follow-up of 15.9 years, 8573 participants developed CMM. All eight AIP-related indices were positively associated with incident CMM, with hazard ratios per 1-SD increment ranging from 1.12 to 1.37 (all P < 0.001). Multistate analyses suggested stage-specific associations during CMM progression, with stronger associations observed for the transition from baseline to T2DM and from single CMD to CMM involving CHD (all P < 0.001). In secondary prediction analyses, adding each index to conventional risk factors improved discrimination and reclassification, with the AIP-body roundness index (AIP-BRI) showing the greatest overall incremental predictive value. Exploratory biomarker analyses indicated that inflammatory, liver, and renal biomarkers jointly accounted for 32.5-46.4% of the associations, although these findings should not be interpreted as evidence of causal mediation. CONCLUSION: Among individuals with CKM syndrome stages 0-3, AIP-related indices were positively associated with the incidence and progression of CMM, supporting their potential utility for CMM risk stratification within the CKM framework. These indices, particularly AIP-BRI, may provide additional predictive information. Exploratory biomarker findings might provide preliminary clues for future mechanistic research.