Abstract / Summary
Cardiometabolic multimorbidity (CMM) is a major global public health challenge associated with metabolic dysregulation and obesity. Cholesterol, high-density lipoprotein cholesterol, and glucose (CHG) is an emerging metabolic risk index; however, the associations of CHG combined with obesity-related indices with the incidence and progression of CMM remain unclear. This study aimed to assess these associations and compare the predictive performance of eight CHG-related indices. This study included participants from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2020; n = 5,355) and the English Longitudinal Study of Ageing (ELSA, 2008–2018; n = 2,096). Cumulative exposure and longitudinal exposure patterns of CHG-related indices were derived from repeated measurements. Cox regression models, multi-state Markov models, and time-dependent Receiver Operating Characteristic (ROC) curve analyses were used to assess associations and discrimination, with cross-cohort replication in ELSA. Exploratory pathway analyses were used to evaluate the potential roles of blood pressure and glucose-lipid metabolism in CMM progression. An RSF model was further developed using the CHG-related index to predict CMM risk. During a median follow-up of 5.0 and 6.0 years in the CHARLS and ELSA cohorts, respectively, 433 (8.09%) and 85 (4.06%) incident CMM cases occurred. All CHG-related indices were associated with CMM onset and progression, with cumulative exposure and exposure patterns yielding higher HRs compared to baseline measures. Among them, CuCHG-WHtR (HR = 1.68, 95% CI: 1.52–1.85) and CuCHG-WC (HR = 1.65, 95% CI: 1.49–1.81) showed stronger associations with incident CMM. CuCHG-CVAI showed a relatively prominent association with progression, with 32% and 39% higher transition risks from no cardiometabolic disease (NCMD) to first cardiometabolic disease (FCMD) and from FCMD to CMM, respectively. Findings were replicated in ELSA. Exploratory pathway analyses showed stage-specific metabolic pathways, with glycated hemoglobin and blood pressure mainly involved in early progression and dyslipidemia in advanced progression. For the RSF model incorporating CHG-WHtR, the 5-year AUC for predicting incident CMM was 0.811 (95% CI: 0.806–0.816), indicating good predictive capacity. All eight cumulative CHG-related indices were positively associated with both incident CMM and its progression, and cumulative CHG-related central obesity indices (CuCHG-WHtR and CuCHG-WC) and CuCHG-CVAI may serve as valuable indicators of incident CMM and CMM progression, respectively. Dynamic metabolic assessment may facilitate risk stratification, and stage-specific metabolic contributions may support tailored prevention strategies during CMM progression.