| Title: | Joint association of Insulin resistance and frailty index with incident ASCVD and MACE in individuals with cardiovascular-kidney-metabolic syndrome stages 0-3: a multi-cohort study |
| Journal: | Cardiovascular Diabetology |
| Published: | 6 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42410584/ |
| DOI: | https://doi.org/10.1186/s12933-026-03275-0 |
Publication 20426
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Abstract
BackgroundWhile insulin resistance (IR) and frailty are mechanistically intertwined via shared pathways of chronic inflammation and metabolic dysregulation, their synergistic impact on cardiovascular risk has yet to be fully elucidated. We aimed to evaluate the joint association of IR and frailty index (FI) with the risk of incident atherosclerotic cardiovascular disease (ASCVD) and major adverse cardiovascular events (MACE) in individuals with Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 0-3.MethodsThis study enrolled 259,714 and 2632 CKM syndrome stages 0-3 from the UK Biobank (UKB), and China Health and Retirement Longitudinal Study (CHARLS). Three IR-related indices, namely the triglyceride-glucose index (TyG), metabolic score for IR (METS-IR), and estimated glucose disposal rate (eGDR), were each combined with two frailty assessments, the FI and physical FI (PFI), yielding six composite IR-FI indices for analysis. In the UKB, MACE and ASCVD were the co-primary outcomes, with heart disease and stroke as secondary outcomes. In the CHARLS, the outcomes included CVD, heart disease, and stroke. Multivariate Cox proportional hazards models, restricted cubic spline analyses, Kaplan-Meier analyses and time-dependent receiver operating characteristic curves were employed to assess associations. Mediation analysis and functional proteomic enrichment provided a framework for exploring the potential biological mechanisms.ResultsIn the UKB, elevated levels of the IR-FI were associated with increased risks of ASCVD and MACE, with consistent findings observed for CVD, heart disease, and stroke in the CHARLS. Significant positive nonlinear relationships were established for the METS-IR-FI and eGDR-FI regarding cardiovascular outcomes. Mediation analysis revealed that Creactive protein, neutrophils, and leucocyte partially mediated these associations (ratio range: 1.5-12%). Proteomic analyses identified Cytokine-cytokine receptor interaction as a primary regulatory hub, while leukocyte migration, chemotaxis, and neutrophil degranulation were characterized as the central pathological execution mechanisms in this process.ConclusionsThe IR-FI are significantly associated with the incidence of cardiovascular events, an association that appears to be mediated through systemic inflammatory pathways. These novel integrated indices represent promising biomarkers for early screening and targeted clinical intervention among individuals with CKM syndrome stages 0-3.</p>
13 Authors
- Yanqiu Huang
- Yadan Xu
- Wen Gu
- Lijun Chang
- Haojia Zhang
- Yang Yang
- Tian Wang
- Tangyi Su
- Yangchen Lhamu
- Xia Shen
- Yang Yang
- Hui Wang
- Wei Zhou
1 Application
| Application ID | Title |
|---|---|
| 194423 | Interplay among dietary pattern, lifestyles, mental well-being, and genetic predispositions in non-communicable diseases |
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