Associations between cardiovascular-kidney-metabolic syndrome staging and risks of all-cause and cardiovascular mortality: a systematic review and meta-analysis

TL;DR

This study shows that higher stages of cardiovascular-kidney-metabolic syndrome are linked to greater risks of death from all causes and heart disease.

Contribution

The study quantitatively synthesizes evidence linking CKM syndrome stages to mortality risks for the first time.

Findings

Stage 4 CKM syndrome is associated with significantly higher all-cause and cardiovascular mortality compared to Stage 0.

Women consistently show higher all-cause mortality across CKM stages, while CVD mortality patterns differ by sex and stage.

Age and educational attainment are key factors modifying the relationship between CKM stages and mortality.

Abstract

Cardiovascular, kidney, and metabolic disorders are closely interconnected and jointly increase atherosclerotic burden and mortality risk. In 2023, the American Heart Association introduced the cardiovascular–kidney–metabolic (CKM) syndrome as a staged framework to characterize this multisystem risk. However, evidence linking CKM stages to mortality has not yet been quantitatively synthesized.

We conducted a PROSPERO-registered (CRD420251161180) systematic review and meta-analysis following MOOSE and PRISMA guidelines. Four databases (PUBMED,Web of science, Embase, Cochrane library)were searched through August 8, 2025. Cohort studies assessing CKM stages (0–4) and reporting all-cause, cardiovascular disease (CVD), coronary heart disease (CHD), or stroke mortality were synthesized using random-effects models, with subgroup, meta-regression, and sensitivity analyses.

9 cohort studies including 10,330,498 participants were analyzed. Mortality risk increased significantly with advancing CKM stages. Compared with Stage 0, Stage 4 was associated with markedly higher risks of all-cause mortality (HR = 3.82, 95% CI: 2.24–6.52), CVD mortality (HR = 6.38, 95% CI: 5.22–7.80), CHD mortality (HR = 9.19, 95% CI: 6.93–12.20), and stroke mortality (HR = 5.48, 95% CI: 4.28–7.02). Meta-regression identified age and educational attainment as significant effect modifiers and sources of heterogeneity. In sex-stratified analyses, all-cause mortality was consistently higher in women across CKM stages, whereas CVD mortality was higher in women at earlier stages but higher in men at later stages. Leave-one-out (LOO) sensitivity analyses and publication bias assessments supported the robustness of these findings.

Advancing CKM stages are associated with progressively higher mortality risks, highlighting their value for early risk assessment and targeted prevention.

Figures