Since the Framingham Heart Study, traditional risk factors for coronary heart disease (CHD)—including hypertension, diabetes mellitus, dyslipidemia, smoking, and obesity—have been widely recognized [21,22,23,24,25]. However, one study evaluated whether the 256 clinical trials cited by current international guidelines (from the European Society of Cardiology [ESC] and the American College of Cardiology/American Heart Association [ACC/AHA]), drawn from a pool of 1,133 studies, reported the proportion of patients with each cardiovascular risk factor, such as hypertension, smoking, hypercholesterolemia, and diabetes. The results showed that among the 256 clinical trials, none explicitly reported the proportion of patients without traditional cardiovascular risk factors [26]. This highlights the fact that CHD patients lacking conventional risk factors have been underrepresented in both guidelines and clinical trials, posing significant challenges for their management in secondary prevention. As most traditional cardiovascular secondary prevention drugs, such as statins and ACEI/ARB, are designed to target specific risk factors, their efficacy may be limited in patients without such conditions. In real-world practice, a substantial number of patients still face residual cardiovascular risk and remain susceptible to cardiovascular events despite standard therapy [27,28,29,30].
Insulin resistance (IR) refers to reduced sensitivity of tissues to insulin, and is considered the central mechanism underlying the development of type 2 diabetes, often existing years before clinical diagnosis [31]. Studies have shown that the severity of insulin resistance exerts a significant and independent negative effect on myocardial mechanical efficiency, even in non-diabetic individuals, highlighting the potential role of IR in cardiovascular disease, especially among populations without diabetes. Regardless of diabetic status, IR and its accompanying metabolic disturbances can promote the onset and progression of CHD [32]. Individuals with IR are more prone to hyperglycemia, dyslipidemia, and hypertension, all of which are closely associated with adverse cardiovascular outcomes [33]. Therefore, IR is not only regarded as a potential pathophysiological mechanism of cardiovascular disease but also serves as an important marker for cardiovascular risk assessment. Furthermore, IR plays a particularly critical role in metabolic syndrome, being strongly associated with obesity, hypertension, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol [34, 35]. Notably, these metabolic abnormalities have been confirmed as independent risk factors for cardiovascular disease (CVD) [36,37,38], further underscoring the pivotal role of IR in the development and progression of CVD.
Due to the complexity and high cost of traditional IR assessment methods, researchers have proposed the triglyceride-glucose (TyG) index as a convenient and cost-effective surrogate marker [39, 40]. The TyG index does not rely on insulin measurements and is applicable to a wide range of populations, offering significant clinical value for metabolic health assessment and cardiovascular risk prediction [41].
In individuals with normal glucose metabolism, activation of insulin receptors triggers signaling to IRS-1 (insulin receptor substrate-1), which then interacts with and activates the downstream PI3-kinase (PI3K, a p85/p110 complex). This leads to activation of Akt, promoting the translocation of GLUT4 to the cell membrane and facilitating glucose uptake into cells for metabolism. Additionally, this pathway activates nitric oxide synthase (NOS), promoting vasodilation and maintaining endothelial function. In patients with hyperglycemia, impaired IRS-1 signaling results in reduced glucose metabolism and decreased eNOS activity, thereby impairing vasodilation. Meanwhile, the MAP kinase pathway remains sensitive to insulin. The insulin resistance of the IRS-1/PI3K pathway leads to compensatory hyperinsulinemia, which in turn excessively activates the MAPK pathway, promoting inflammation, cellular proliferation, and the progression of atherosclerosis. Dyslipidemia contributes to this process by triggering inflammatory storms mediated by NF-κB and inhibiting IRS-1 function, thus forming a vicious cycle between insulin resistance and atherosclerosis. As an integrated marker of glucose and lipid metabolism, the TyG index reflects the metabolic burden resulting from the combined dysregulation of triglycerides and fasting glucose. Compared to individual metabolic parameters, the TyG index more sensitively captures abnormal signals arising from the interaction between glucose and lipid metabolism. In recent years, studies have suggested that dynamic monitoring of biomarkers offers substantial advantages over single time-point measurements. Considering that triglyceride and fasting glucose levels may fluctuate over time, potentially leading to regression dilution bias, this study identified three distinct TyG trajectories in acute STEMI patients following PCI, based on serial TyG values: the persistently high group (trajectory 1), the moderate-level group (trajectory 2), and the rapid decline group (trajectory 3). The incidence of major adverse cardiovascular events (MACE) differed significantly among the three groups (P < 0.05). Compared with the persistently high group, the rapid decline group exhibited significantly lower rates of ischemia-driven target vessel revascularization, heart failure rehospitalization, nonfatal acute myocardial infarction, cardiac death, and total MACE events (all P < 0.05). Survival analysis demonstrated that the prognostic endpoints significantly differed among the groups, as indicated by the survival curves (P for log-rank < 0.001). To further explore the prognostic impact of different metabolic trajectories within various clinical subgroups, a subgroup analysis was performed. The persistently high group exhibited a consistently higher risk of major adverse cardiovascular events (MACE) across most subgroups, with statistically significant differences compared to the rapid decline group. This association was particularly pronounced among patients with multivessel disease and those classified as Killip class III–IV, suggesting that metabolic trajectories hold important prognostic value, especially for risk stratification in high-risk patients. Furthermore, multivariate Cox regression analysis, after adjusting for confounding variables including sex, age, low-density lipoprotein cholesterol, uric acid, body mass index (BMI), hypertension, diabetes mellitus, family history of coronary heart disease, smoking history, multivessel disease, ejection fraction, Killip classification, as well as baseline and final TyG values, confirmed that the trajectory grouping remained an independent prognostic factor (P < 0.05). These findings indicate that the predictive value of TyG trajectories for long-term prognosis in STEMI patients remains robust across different adjustment models, highlighting its independent prognostic significance. In addition to STEMI, the TyG index has also been reported as a valuable risk predictor in various cardiovascular diseases, including hypertension, heart failure, and atherosclerosis. Existing evidence preliminarily supports the potential of the TyG index as a metabolic biomarker for clinical risk assessment. In the following section, we will systematically summarize the current research progress on the TyG index across different cardiovascular diseases.
TyG index and hypertension: from risk prediction to target organ damage and clinical outcomes
In a longitudinal study of hypertension involving 4,600 Chinese adults, analysis showed that for each 1.0-unit increase in the TyG index, the risk of developing new-onset hypertension increased by 17%. Long-term follow-up further identified three distinct TyG index trajectories: the “low-level rising group,” the “moderate-level rising group,” and the “high-level stable group.” Compared with the “low-level rising group,” the risk of hypertension was significantly higher in the other two groups (HR = 1.38, 95% CI: 1.23–1.54; HR = 1.69, 95% CI: 1.40–2.02), with the risk being particularly pronounced in the female subgroup (HR = 2.63 and 4.66) [42]. Moreover, coronary heart disease patients with concomitant hypertension and elevated TyG index showed a 47% increased risk of MACE within one year [43, 44]. The TyG index is also significantly associated with the incidence of albuminuria, vascular injury, and cardiac remodeling in hypertensive patients. Patients with higher TyG index levels were found to have significantly increased left atrial volume index and left ventricular mass index, along with reduced E′ velocity and E/A ratio (P < 0.05). Multivariate regression analysis further confirmed that this association was independent of other risk factors (P < 0.001) [45, 46]. A retrospective study involving 4,710 patients demonstrated that individuals with persistently elevated and poorly controlled TyG index levels had a significantly increased risk of stroke (OR = 2.161, 95% CI: 1.446–3.228) [47]. The TyG index has been identified as an independent risk factor for stroke [48], and in hypertensive patients, the risk of first-ever stroke increases with higher TyG index levels. This association was especially prominent among elderly individuals (HR = 2.15, 95% CI: 1.50–3.07, P < 0.001) [49]. Further supporting evidence comes from a multicenter analysis conducted across 22 hospitals in Suzhou, which included 3,216 patients with acute ischemic stroke. The study revealed that a higher TyG index was closely associated with an increased risk of poor functional outcomes at discharge and higher in-hospital mortality, highlighting its potential value in short-term prognostic assessment [50]. Additionally, a study involving 356 hospitalized patients showed that the TyG index was significantly higher in the atrial fibrillation group compared to the non-atrial fibrillation group, and the TyG index was identified as an independent risk factor for atrial fibrillation. Subgroup analysis revealed that the association between the TyG index and atrial fibrillation was more evident in non-diabetic patients, whereas this correlation was not observed in diabetic individuals [51].
The relationship between TyG index and heart failure risk, and prognosis
Beyond hypertension, the TyG index has also been shown to be closely associated with the incidence of heart failure. Analyses from the Kailuan prospective cohort, which included 95,996 participants, and a retrospective Hong Kong cohort involving 19,345 participants — with 2,726 and 1,709 heart failure cases identified respectively — demonstrated that the TyG index is an independent risk factor for heart failure [52, 53]. Other studies have reported that a higher TyG index is significantly associated with increased risks of mortality and rehospitalization among patients with heart failure with preserved ejection fraction (HFpEF), suggesting that the TyG index could serve as a promising prognostic marker for this patient population [54]. In patients with acute decompensated heart failure, an elevated TyG index was significantly linked to an increased risk of all-cause mortality, cardiovascular death, and major adverse cardiovascular and cerebrovascular events (MACCEs). Particularly, patients with a TyG index ≥ 9.32 were at markedly higher risk for both mortality and MACCEs [55]. Among patients with chronic heart failure, those with a higher TyG index also exhibited significantly increased risks of all-cause and cardiovascular mortality. Specifically, patients with elevated TyG index had a 1.84-fold higher risk of all-cause death and a 1.94-fold higher risk of cardiovascular death compared to those with lower values. Moreover, incorporating the TyG index into existing risk prediction models significantly improved their predictive performance, further underscoring its critical role as a prognostic indicator for mortality in chronic heart failure patients [56,57,58].
The association between TyG index and arteriosclerosis
Arteriosclerosis, an early manifestation of vascular aging, is characterized primarily by reduced arterial elasticity and elevated pulse pressure, and it is closely associated with an increased risk of cardiovascular disease. A growing body of evidence has demonstrated a positive correlation between the TyG index and arteriosclerosis, as measured by parameters such as pulse wave velocity (PWV), and has suggested that the TyG index may outperform traditional insulin resistance measures like the HOMA-IR index in predicting arteriosclerosis. Lambrinoudaki et al. reported a positive association between the TyG index and brachial-ankle pulse wave velocity (baPWV), although their study population was limited to postmenopausal women [59]. Similarly, a Korean study confirmed an independent positive correlation between the TyG index and baPWV and showed that the TyG index was superior to HOMA-IR for predicting arteriosclerosis [60]. Li et al. further demonstrated that this association was particularly pronounced in men [61], whereas Nakagomi et al. found the correlation to be stronger in women [62], suggesting that sex and age differences may influence this relationship. Additionally, Wu et al. confirmed that the TyG index was correlated with changes in baPWV among hypertensive patients, indicating a possible synergistic effect of insulin resistance and hypertension in promoting the development of arteriosclerosis [63, 64]. Wang et al. reported, in a cohort of 3,185 patients with type 2 diabetes, that the TyG index was positively correlated with arteriosclerosis and again showed superior predictive value compared to HOMA-IR [65]. Guo et al. further demonstrated that the TyG index was significantly and positively associated with the 10-year cardiovascular disease risk in patients with arteriosclerosis [66]. These findings collectively highlight the potential of the TyG index as a predictive marker for arteriosclerosis and provide valuable guidance for clinical management.
The clinical significance of the TyG index in predicting cardiovascular disease and All-Cause mortality
The TyG index has shown significant value in predicting the development, severity, and prognosis of coronary artery disease (CAD). A meta-analysis including 12 cohort studies with 6,354,990 participants confirmed that higher TyG levels are associated with increased risks of CAD (moderate certainty), myocardial infarction, and cardiovascular disease (very low certainty). A linear relationship was observed between the TyG index and the risk of CAD and composite cardiovascular events, though further prospective studies are needed, especially in non-Asian populations [67]. Additionally, an elevated TyG index is closely related to coronary lesion complexity (SYNTAX score > 22) in ACS patients, independent of diabetes status [68, 69]. In a 10-year cohort of 6,095 non-diabetic subjects, higher TyG quartiles were linked to a significantly increased risk of CVD, CHD, and stroke, and the inclusion of the TyG index improved the predictive performance of traditional risk models [70]. NHANES-based studies also revealed that the TyG index is positively associated with chest pain and nonlinearly linked to all-cause mortality, independent of chest pain status [71]. Moreover, the TyG index outperformed other markers in predicting long-term mortality in non-diabetic STEMI patients, particularly when TyG ≥ 9.83 [72]. The TyG index also correlates with coronary lesion severity, abdominal aortic calcification [73, 74]. Furthermore, a large NHANES-based study (20,194 participants) demonstrated that the TyG index is nonlinearly associated with all-cause and cardiovascular mortality, particularly in individuals under 65 years. Compared to HOMA-IR, the TyG index showed superior predictive power for mortality outcomes [75].
The clinical value of the TyG index in predicting complications after PCI in coronary artery disease patients
Studies based on the MIMIC-III database have suggested that the TyG index holds potential value for predicting complications following percutaneous coronary intervention (PCI) ([76]. Several studies have demonstrated that the TyG index is associated with an increased risk of in-stent restenosis and repeated revascularization, and has been identified as an independent predictor of major adverse cardiovascular events (MACE) in patients with premature coronary artery disease. A study [77, 80] conducted by Fuwai Hospital in 2017 investigated the relationship between the TyG index, repeated revascularization, and in-stent restenosis in patients with chronic coronary syndrome who underwent drug-eluting stent implantation. A total of 1,414 patients were consecutively enrolled and followed for a median of 60 months. During follow-up, 548 patients (38.76%) experienced at least one major endpoint event. The incidence of major endpoints increased progressively with higher TyG index levels. After adjusting for potential confounders, the TyG index remained independently associated with major adverse outcomes in patients with chronic coronary syndrome (HR: 1.191, 95% CI: 1.038–1.367, P = 0.013) ([77,78,79], These findings suggest that an elevated TyG index is associated with a higher risk of post-PCI complications, including repeated revascularization and in-stent restenosis. However, its incremental predictive value for major adverse events remains limited, highlighting the need for further multicenter and large-scale clinical studies to clarify the role of the TyG index in long-term risk stratification and prognostic management after PCI ([81, 82].
As a surrogate marker of insulin resistance (IR), the triglyceride-glucose (TyG) index is closely associated with the onset and progression of the aforementioned diseases. Accumulating evidence has shown that the TyG index serves as a reliable predictor for cardiovascular outcomes in various populations. Notably, several nomogram-based models incorporating the TyG index have demonstrated good predictive performance for MACEs in patients with HFpEF post-CABG, new-onset hypertension, STEMI undergoing PCI, and chronic coronary disease. These models consistently reported satisfactory C-index values (ranging from 0.73 to 0.82), improved net reclassification, and clinical utility via DCA, indicating the wide applicability of TyG in cardiovascular risk prediction I [83,84,85,86].
From a systemic pathological perspective, metabolic dysregulation caused by insulin resistance involves multiple tissues and signaling pathways. The underlying mechanisms mainly involve endothelial dysfunction, chronic inflammatory responses, and oxidative stress. Under physiological conditions, insulin regulates blood flow and glucose metabolism by promoting nitric oxide (NO) production in vascular endothelial cells. However, in the IR state, NO synthesis is reduced, impairing vascular relaxation function [33]. In addition, IR can induce the sustained release of pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP), as well as reactive oxygen species (ROS). These processes mutually reinforce each other, forming a vicious cycle of “inflammation-oxidative stress,” which further aggravates endothelial injury [87, 88]. Meanwhile, a persistently elevated TyG index may also disrupt insulin secretion, promote myocardial fibrosis and left ventricular hypertrophy, ultimately leading to cardiac dysfunction [89]. These pathological changes not only impair myocardial structure and function but may also destabilize coronary plaques and increase the risk of thrombosis. Furthermore, studies have shown that IR and hyperinsulinemia can activate serum/glucocorticoid-regulated kinase 1 (SGK1) through multiple signaling pathways and stimulate aldosterone secretion, which in turn further activates SGK1. As a shared node in insulin and aldosterone signaling, SGK1 increases intracellular sodium ion concentration in vascular smooth muscle cells by activating sodium channels, while inhibiting nitric oxide synthase activity and reducing NO production. This cascade ultimately leads to increased vascular tone, endothelial dysfunction, and vascular stiffening [33]. In addition, the TyG index may contribute to the development of coronary artery disease (CAD) through its roles in dyslipidemia, diabetes, and hypertension, highlighting its central role in metabolic syndrome [90, 91]. From the perspective of molecular signaling pathways, hyperglycemia impairs the IRS-1/PI3K signaling pathway, reducing glucose metabolism and endothelial nitric oxide synthase (eNOS) activity, thereby contributing to endothelial dysfunction. Concurrently, hyperinsulinemia abnormally activates the MAPK pathway, promoting inflammation and vascular smooth muscle cell proliferation, which accelerates atherosclerosis. Lipid dysregulation further aggravates insulin resistance via NF-κB–mediated inflammatory cascades and inhibition of IRS-1 signaling, creating a vicious cycle in the progression of atherosclerosis. As a composite indicator reflecting the metabolic burden of both glucose and lipid dysregulation, the TyG index may more sensitively capture these interactive abnormalities and underlying metabolic stress. Although no significant differences in FBG and TG levels were observed among groups in this study, the observed differences in TyG index suggest that it may better represent the overall metabolic risk and possess independent prognostic value.
Based on the above mechanistic analysis, this study found that the group with a rapidly decreasing TyG index exhibited the lowest incidence of major adverse cardiovascular events (MACE). This finding may be attributed to improved insulin sensitivity, reduced inflammatory levels, and restored coronary circulation function. Future research could further explore whether lifestyle interventions (such as low-carbohydrate diets and exercise training) or pharmacological therapies (such as sodium-glucose co-transporter 2 [SGLT2] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) can improve the TyG index and thereby reduce the long-term cardiovascular risk in patients with ST-segment elevation myocardial infarction (STEMI).
The results of this study suggest that the TyG index trajectory holds significant clinical value in risk assessment for patients with ST-segment elevation myocardial infarction (STEMI). Trajectory-based monitoring of the TyG index can provide a more accurate prediction of major adverse cardiovascular events (MACE) and assist in formulating more proactive metabolic management and cardiovascular protection strategies. These findings indicate that a single measurement of the TyG index is insufficient for comprehensive risk assessment, and regular monitoring of its trajectory may improve the accuracy of prognosis prediction. Future studies could explore the incorporation of the TyG trajectory into existing STEMI risk assessment models and evaluate the effectiveness of targeted interventions. Overall, as a simple and effective metabolic biomarker, the TyG index demonstrates considerable value for the early identification and personalized management of cardiovascular disease.