Cardiovascular-kidney-metabolic (CKM) syndrome is a clinically integrated framework that reflects the synergistic pathophysiological interplay between metabolic dysfunction (e.g., obesity, insulin resistance [IR], and dyslipidemia), chronic kidney disease (CKD), and cardiovascular disease (CVD) [1]. The American Heart Association has recently proposed a staging framework, ranging from 0–4, wherein stage 0 indicates no current cardiometabolic or renal risk factors, and extending to stage 4 denotes clinically manifested CVD [2]. This structured approach underscores the need to identify at-risk individuals in the early or subclinical stages before overt cardiovascular or renal complications occur. Advanced CKM syndrome stages (3 and 4) carry a notably heightened burden of morbidity and mortality, necessitating intensive lifestyle interventions and comprehensive guideline-directed pharmacotherapy to curb disease progression and improve clinical outcomes [1–4].

IR plays an integral role in the pathophysiology of CKM syndrome, driving the development of metabolic risk factors, accelerating kidney disease, and ultimately contributing to the development of CVD [2]. It is closely associated with increased cardiovascular risk [5]; however, a practical method for accurately evaluating IR in population-based settings remains elusive [6]. Although the euglycemic–hyperinsulinemic clamp is considered the gold standard, its high cost and complexity limit its widespread use. Similarly, the homeostasis model assessment of IR is commonly employed; however, it relies on measuring circulating insulin, which is not routinely quantified in clinical practice, thus limiting its clinical applicability [7]. The triglyceride-glucose (TyG) index, which is derived from fasting triglyceride and glucose levels, has emerged as a feasible and cost-effective marker of IR. Validation studies have indicated that it offers a performance comparable to or exceeding that of conventional markers and provides a robust prognostic value for type 2 diabetes, a range of CVDs, and mortality [8,9].

Considering the critical role of IR in CKM syndrome and its strong association with CVD, it is essential to understand whether the TyG index offers additional prognostic value beyond CKM staging. Despite its potential, evidence on the association between the TyG index and cardiovascular outcomes within CKM syndrome stages remains scarce. Therefore, this study aimed to assess the relationship between the TyG index and cardiovascular outcomes across all stages of CKM syndrome to enhance risk stratification and inform tailored management strategies.

This study investigated the association between TyG index and cardiovascular outcomes across CKM syndrome stages in a large nationwide cohort. Our findings suggested that the TyG index serves as an independent predictor of adverse outcomes beyond the CKM staging. This is the first large-scale study to evaluate the prognostic value of the TyG index across all stages of CKD. In this study, CKM Stages 0 and 1 were combined into a single reference category (Stage 0/1) because of their low event rates, and the distribution of the TyG index in Stage 0 was heavily skewed towards the lower values, such that no participants qualified for the highest TyG tertile (Group 3). CKM Stage 0 is defined as the absence of any metabolic risk factors, whereas stage 1 includes individuals with overweight or dysfunctional adiposity, but without metabolic or renal dysfunction [2]. Both groups represented populations at relatively low cardiometabolic risk, where the primary drivers of future disease are subclinical metabolic disturbances, such as IR. A separate analysis of Stages 0 and 1 for the primary composite outcomes is shown in Supplementary Table 8. The key findings were as follows: (1) the individuals in the highest TyG tertile (Group 3, TyG index > 8.81) had a significantly higher risk of the composite primary outcome than those in the lowest tertile (Group 1, TyG index < 8.27), with a dose-dependent relationship observed both in the total population and across most CKM syndrome stages, although the association was not statistically significant in Stage 4 after full adjustment; (2) this association was stronger in earlier CKM syndrome stages, particularly in Stages 0/1 and 2, and attenuated in advanced stages; and (3) similar trends were observed for secondary outcomes, including all-cause death, heart failure, stroke, and myocardial infarction. These findings indicated that the TyG index may serve as a valuable marker to enhance the prognostic utility of the CKM syndrome staging system, particularly for facilitating early risk stratification before the development of overt CVD.

CKM syndrome represents a complex, multidirectional interplay between metabolic risk factors, CKD, and the cardiovascular system, which contributes to adverse clinical outcomes [3]. IR is the fundamental driver of this syndrome and accelerates the progression of metabolic disturbances, CKD, and CVD [2,15–17]. The TyG index, a simple and cost-effective marker of IR, is associated with cardiovascular risk [8,18]. In previous cross-sectional studies, an elevated TyG index was associated with advanced CKM syndrome [19]. Moreover, a recent study in China demonstrated that a high TyG index was associated with kidney function deterioration in patients with CKM syndrome [20]. However, its prognostic significance in cardiovascular outcomes within the CKM staging framework remains largely unknown. While a modified version of the TyG index, the triglyceride glucose-BMI, previously correlated with cardiovascular risk in populations with CKM syndrome stages 0–3 [21], the study relied on survey-based self-reports for outcome assessment and had a relatively small sample size, limiting the consistency of findings across CKM subgroups. Our study extended these previous observations [19–21] by utilizing a large, comprehensive, and nationwide cohort data to accurately capture a range of outcomes, including all-cause death, across the entire CKM syndrome spectrum, thereby providing more robust evidence of the prognostic value of the TyG index for cardiovascular events across CKM syndrome stages.

Intriguingly, the cardiovascular risk in the highest TyG tertile (group 3, TyG > 8.81) was most pronounced in the earlier stages of CKM syndrome. Several mechanisms may explain these observations. In the early stages of CKM (particularly Stages 0/1 and 2), the predominant pathology involves IR, low-grade inflammation, and early vascular dysfunction, rather than irreversible organ damage [2]. Consequently, the TyG index may capture the subclinical metabolic disturbances that precede overt CVD, underscoring its role as an important early risk marker [22]. This suggests that, in populations with a relatively low baseline risk, the TyG index may serve as an early warning marker, identifying individuals who might benefit from timely lifestyle interventions to prevent progression to more advanced, high-risk stages. Furthermore, we observed that the impact of the TyG index on myocardial infarction and stroke was greater than its effect on heart failure or all-cause death, suggesting that IR may drive atherosclerotic processes more strongly [23]. These findings warrant further prospective studies to confirm and expand upon these observations.

These findings have important clinical implications. Incorporating the TyG index into routine clinical assessments can enhance early risk stratification in patients with CKM syndrome, particularly during the initial stages. This straightforward and cost-effective measure enables clinicians to identify individuals at an elevated risk of progressing to advanced CKM syndrome stages and developing CVD, before the overt disease manifests [19]. Early detection using the TyG index may help inform early lifestyle modification strategies, such as dietary changes, increased physical activity, and weight management, aimed at reducing IR and mitigating disease progression [24,25]. Specifically, individuals with elevated TyG levels in the early stages of CKM syndrome may benefit from structured lifestyle interventions combined with regular evaluations of IR and CKM stage progression, enabling the timely identification of candidates for pharmacological therapy. Ultimately, the integration of the TyG index into current screening protocols can refine patient management by providing a more nuanced understanding of cardiometabolic risk across the CKM spectrum.

The strengths of our study include its large, nationally representative sample size and long follow-up period of > 12 years, which allowed for a robust assessment of long-term outcomes. Furthermore, the comprehensive nature of the Korean NHID enabled detailed adjustment for potential confounders, including demographic, lifestyle, and pharmacological factors. By stratifying participants according to both the CKM syndrome stage and TyG index tertiles, we were able to delineate a clear, graded relationship between IR and adverse outcomes across different stages of cardiometabolic and renal health. Despite these strengths, this study had several limitations that warrant consideration. First, the retrospective observational design precluded definitive causal inferences regarding the relationship between TyG index and cardiovascular outcomes. Second, our reliance on claims data and health-screening records might have led to the misclassification or underestimation of some clinical events despite rigorous coding protocols. Third, although the homogeneity of the Korean population provided a consistent dataset, it may limit the generalizability of our findings to other ethnic groups and healthcare settings. Furthermore, the PREVENT risk score used in this study was developed based on U.S.-based cohorts. Therefore, its applicability to Koreans should be interpreted with caution. Fourth, unmeasured confounding factors, such as dietary habits, genetic predisposition, and socioeconomic status may have influenced both the TyG index and clinical outcomes. These factors were not fully accounted for in this study. Fifth, while the TyG index is a dynamic biomarker reflecting the ongoing metabolic status, our study was restricted to baseline measurements, which limited our ability to assess the impact of temporal changes on cardiovascular outcomes. Future longitudinal studies with more frequent measurements are essential for a better understanding of their prognostic roles. Finally, although the TyG index demonstrated an independent prognostic value across CKM stages, its applicability and method of integration into existing cardiovascular risk models remain unclear and requires further investigation. Future research should validate these findings in diverse populations and explore the mechanisms linking IR to CKM syndrome progression, including the potential role of longitudinal changes in the TyG index and the effects stratified by age and sex, which may inform personalized management strategies across the CKM stages. Prospective studies or randomized controlled trials evaluating whether aggressive lifestyle interventions and close monitoring in the early stages of CKM syndrome, specifically in individuals with a high TyG index, can effectively reduce the incidence of cardiovascular events would be particularly valuable.

In conclusion, our study demonstrated that the TyG index is a valuable prognostic marker for cardiovascular outcomes across the CKM syndrome stages. Individuals with a high TyG index, particularly those in the early stages of CKM syndrome, are at an increased risk of progressing to advanced CKM syndrome stages and developing adverse cardiovascular events. Integrating the TyG index into routine clinical assessments could enhance early risk stratification, enabling timely lifestyle interventions to mitigate the progression of cardiometabolic and renal dysfunctions. Future prospective studies in diverse populations are warranted to validate these findings and to elucidate the underlying mechanisms linking IR to CKM syndrome progression.