Objective ·To construct a cardiovascular-kidney-metabolic (CKM) index based on the Global Burden of Disease (GBD) 2021 study, systematically evaluate the synergistic burden of cardiovascular diseases, chronic kidney diseases, and metabolic disorders, and reveal their spatiotemporal distribution patterns and interrelationships worldwide. Methods ·The data were derived from the GBD 2021 project, encompassing 204 countries and regions over the period from 1990 to 2021. The disability-adjusted life year (DALY) rates for ischemic heart disease, chronic kidney disease, and type 2 diabetes mellitus were extracted, age-standardized DALY rates were calculated, and then the CKM index was computed through equal-weighted averaging of these rates after Z-score standardization. The Joinpoint regression models were applied to the CKM index time series for segmented trend fitting, to identify turning points and annual percentage changes at different developmental stages. Countries and regions were categorized and compared according to their socio-demographic index (SDI) levels. Spearman's rank correlation was used to assess the correlations among DALY rates for the three disease categories. Results ·In 2021, the global CKM index value was 0.201. Temporal trend analysis showed that global CKM syndrome burden generally increased from 1990 to 2021, with an average annual increase of 0.002 9. Among these, middle-SDI countries showed the most significant growth, with CKM index rising from -0.130 to 0.783, representing an average annual increase of 0.029 4. High-middle SDI and low-middle SDI countries also demonstrated steady upward trends, with average annual increases of 0.009 7 and 0.009 2, respectively. In high-SDI countries, the CKM index declined from 0.847 in 1990 to its lowest point of 0.783 in 2010, and then rose slightly to 0.792 in 2021. Correlation analysis across 204 countries and regions globally revealed varying degrees of positive correlation among the three types of diseases in terms of DALY rates, with the strongest correlation observed between chronic kidney disease and type 2 diabetes mellitus (r=0.66, P<0.001), while the correlation between ischemic heart disease and chronic kidney disease was weaker (r=0.20, P=0.004). Conclusion ·The CKM index developed in this study provides a categorized and quantitative tool for assessing the burden of multimorbidity. The application of CKM index analysis revealed that cardiovascular diseases, chronic kidney diseases, and metabolic diseases not only share common risk factors but also have synergistic pathological pathways, which should be key clues for global chronic disease prevention and control. Public health policies should break down system silos, strengthen rapid identification and comprehensive management of CKM, and improve the efficiency of chronic disease prevention and treatment.