Association of various insulin resistance surrogate indices with aging acceleration and future risk of cardiovascular disease in individuals with cardiovascular-kidney-metabolic syndrome stages 0-3: insights from CHARLS 2011-2020 data.

19.5% of participants with CKM syndrome stages 0-3 developed new-onset CVD over the study period.

• 1231 of 6318 participants developed new-onset CVD
• Participants were drawn from the China Health and Retirement Longitudinal Study (CHARLS) 2011-2020
• The study was a prospective analysis
• Participants were restricted to CKM syndrome stages 0-3

All twelve insulin resistance surrogates demonstrated significant associations with CVD risk in CKM stages 0-3.

• Twelve IR surrogates were evaluated in relation to incident CVD
• Elevated TyG-derived indices, METS-IR, CTI, and TG/HDL-C showed positive associations with CVD
• eGDR exhibited an inverse relationship with CVD risk
• All associations reached statistical significance with P-trend < 0.05
• Multivariable-adjusted logistic regression, restricted cubic splines (RCS), and quantile-based models were used

Nonlinear relationships between IR surrogates and CVD risk were identified for METS-IR, CTI, and eGDR.

• Restricted cubic spline (RCS) analyses revealed nonlinear dose-response relationships
• METS-IR, CTI, and eGDR specifically showed nonlinear patterns
• Other TyG-derived indices and TG/HDL-C showed linear associations by implication

Significant modification effects on the IR-CVD association were observed by biological aging acceleration, gender, and CKM stage.

• Biological aging acceleration was identified as a significant effect modifier
• Gender was identified as a significant effect modifier
• CKM stage was identified as a significant effect modifier
• These modification effects were assessed across the twelve IR surrogates

Biological aging acceleration mediated the association between IR indices and new-onset CVD, with the largest mediation observed for TyG-ABSI.

• Biological aging acceleration accounted for 14.9-16.4% of the TyG-ABSI-CVD association
• Biological aging acceleration accounted for 1.3-4.2% of other IR-CVD relationships
• Mediation analyses were used to assess the mediating role of biological aging acceleration
• TyG-ABSI showed substantially larger mediation proportions compared to other IR surrogates

Insulin resistance was considered a core manifestation of metabolic dysfunction playing a pivotal role in CKM progression and CVD development.

• CKM syndrome imposes a substantial global health burden
• Most adults are clustered in early stages 0-3 of CKM syndrome
• The relative impact of diverse IR surrogates and the mediating role of biological ageing acceleration had remained unclear prior to this study
• The study evaluated twelve distinct IR surrogate measures

Integrating multiple IR surrogate measures into risk stratification could enable early identification and targeted intervention for high-risk individuals with CKM syndrome.

• Multiple IR surrogate indices independently predicted cardiovascular disease in CKM stages 0-3
• Biological aging acceleration was identified as a mediator of the IR-CVD relationship
• The study covered stages 0-3, representing the majority of adults with CKM syndrome
• The findings support incorporating these measures into clinical risk assessment frameworks