Insulin resistance (IR) can induce disorders of glucose and lipid metabolism, which are important risk factors for the incidence and prognosis of cardiovascular diseases (1, 2). The hyperinsulinemia-glucose clamp test and homeostatic model assessment for insulin resistance (HOMA-IR) are recognized as accurate and reliable methods for evaluating IR; however, they are costly and complicated to perform. Epidemiological studies and clinical practice require easy-to-use markers of IR. The triglyceride-glucose index (TyG index) (composed of fasting glucose and triglycerides) not only has high sensitivity and specificity for IR identification but also correlates closely with the hyperinsulinemia-normal glucose clamp test and HOMA-IR and has been suggested to be a reliable alternative marker of IR (3). In addition, the TyG index has been proven to be closely associated with predicting the occurrence, progression, and prognosis of coronary heart disease (CHD) (4–6).

Even with percutaneous coronary intervention (PCI) and adequate antiplatelet drugs, the prognosis of some patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) remains poor (7). Early risk stratification is important for clinical decision-making and prognostic assessment. The Global Registry of Acute Coronary Events (GRACE) risk score is currently the most widely used method for prognostic determination of patients with NSTE-ACS (8). Studies have shown that the GRACE risk score exhibits high predictive accuracy in both the inpatient phase and during long-term follow-up of major adverse cardiovascular events (MACEs) in patients with NSTE-ACS and guides clinicians in adjusting treatment regimens to reduce long-term cardiovascular risk (9). However, the TyG index, a new and powerful predictor of cardiovascular disease, has not been considered in the GRACE risk scoring system, which may result in a proportion of patients at high risk of adverse cardiovascular events being overlooked. Studies on the application of the TyG index in the GRACE score are limited; thus, the aim of this study was to investigate whether the predictive ability of the GRACE risk score improves when combined with the TyG index for 2-year adverse cardiovascular events in patients with NSTE-ACS and PCI.

In this study, we examined the prognostic and predictive effects of the GRACE score combined with the TyG index on 2-year adverse cardiovascular events in patients with NSTE-ACS who underwent elective PCI. The major findings of this study are as follows: (1) The GRACE score and TyG index could independently predict adverse cardiovascular events in patients with NSTE-ACS undergoing PCI; (2) the TyG index was weakly correlated with the GRACE score; and (3) in contrast to other glucose- and lipid-related parameters, adding the TyG index to the GRACE score showed the best performance in predicting adverse cardiovascular events.

Patients with IR are susceptible to a variety of metabolic disorders, such as hyperglycemia, dyslipidemia, and hypertension, which are closely related to a poor prognosis of CVD (cardiovascular disease) (11). The hyperinsulinemia-glucose clamp test and HOMA-IR are well-established methods for assessing IR but are difficult to implement in clinical practice because of their high cost, time requirement, and complexity (12). The TyG index is a newly discovered alternative marker for IR, which is simple, inexpensive, and convenient for clinicians. In addition, the TyG index shows a direct correlation with the hyperinsulinemia-glucose clamp test and HOMA-IR (3). At present, the TyG index is widely used in the assessment of CVD risk, and a clear correlation has been confirmed in various CVDs such as acute coronary syndrome, arteriosclerosis, heart failure, and coronary artery calcification (13–15).

However, the mechanisms responsible for the association between the TyG index and CVD remain uncertain. The potential relationship between the TyG index and CVD is as follows. First, IR can induce blood glucose and lipid metabolism disorders, leading to inflammation and oxidative stress, and these changes further aggravate the progression of CVD (16). Second, IR can induce increased production of glycosylated products and free radicals, resulting in NO inactivation and impaired vascular diastolic function (17). Moreover, IR can mediate the relevant signaling that sensitizes platelets to the anti-aggregation effects of prostaglandin I2 (PGI2) and NO, which, in turn, can lead to thrombosis (18). In addition, IR can induce excessive glycosylation, which promotes smooth muscle cell proliferation and collagen deposition, leading to increased ventricular stiffness, cardiac fibrosis, and ultimately, heart failure (11, 19). Finally, IR also plays an important role in hyperlipidemia. Increased TG levels can increase free fatty acid (FFA) levels and promote FFA flux from adipose tissue to non-adipose tissue (20). Furthermore, the retention of cholesterol- and TG-rich remnants of Apo B in coronary artery walls may play a role in the pathogenesis of atherosclerosis (21).

Owing to its ease of use, the convenience of data acquisition, and high accuracy, most of the current guidelines recommend the GRACE score to evaluate the prognosis of patients with NSTE-ACS. However, the biochemical indicators of the GRACE score include only myocardial necrosis markers and creatinine, leaving room for improvement in predicting adverse cardiovascular events. According to current research, pro-brain natriuretic peptides, C-reactive protein, and other biomarkers can contribute to the predictive power of the GRACE score (22, 23). The TyG index can reflect disorders of glucose and lipid metabolism and predict the prognosis of patients with ACS (4, 6, 24); however, the effect of the TyG index on the predictive ability of the GRACE scoring system for the occurrence of adverse cardiovascular events in patients with NSTE-ACS undergoing PCI remains unknown. Among our patients, we found that the GRACE score increased with an increasing TyG index, and a correlation was found between the two variables. Similar to previous studies, we found that an elevated TyG index and GRACE score were significantly associated with 2-year adverse cardiovascular events in patients with NSTE-ACS who underwent PCI. We found that the predictive ability can be significantly improved by including the TyG index in the GRACE score since the AUC went from 0.798 to 0.845 when the TyG index was combined with the GRACE score. Moreover, multiple novel methods were used to evaluate the improvement in discrimination and clinical usage of the TyG index when added to the GRACE score, including the IDI, NRI, and DCA curves. Using a continuous, category-free NRI, 29% of patients without events were reclassified as low risk and 43% of patients with events were reclassified as high risk. Furthermore, IDI analysis showed that incorporation of the TyG index with the GRACE scores significantly improved the discriminatory accuracy for adverse cardiovascular events with an IDI of 8.6% (p < 0.001). Finally, by plotting DCA curves, we found that the predictive value of the new model with the combined TyG index was higher than that of the traditional GRACE model, with a probability range of 0.04 to 0.32 for endpoint events. Therefore, with the assistance of this new model (GRACE score combined with TyG index), major endpoint events can be predicted more accurately and better clinical decisions can be made for patients with NSTE-ACS.

We then further compared the gain effect of the Tyg index and the levels of HbA1C, FBG, TG, and LDL-C on the GRACE score for predicting adverse cardiovascular events, considering that the TyG index is closely associated with lipid and glucose metabolism. We found that the TyG index was strongly correlated with TG levels and moderately correlated with FBG, TG, LDL-C, and HbA1C levels. Given the relatively small number of patients with diabetes in our study cohort and the small range of glycemic fluctuations, the TyG index and TG levels correlated more strongly. ROC curve analyses, NRI, and IDI were used to quantify the improvement in the different prediction models. Although previous studies have shown that HbA1C is an independent risk factor for cardiovascular events (25, 26), HbA1C did not significantly improve the predictive power of the GRACE score in this study. Since HbA1C reflects blood glucose levels over the past 3 months, and most hospitalized patients in this study did not have diabetes, there was less difference in HbA1C values. Patients with the acute coronary syndrome often have stress hyperglycemia. Acute elevated blood glucose levels can induce oxidative stress, leading to direct injury of myocardial cells, endothelial dysfunction, and activation of clotting pathways, which can lead to enlarged infarct size, restenosis, and adverse cardiac remodeling (27–30). Numerous studies have shown a strong association between hyperglycemia and poor outcomes in patients with ACS (31–33). In this study, fasting glucose improved the ability of the GRACE score to distinguish patients at high risk of major adverse cardiovascular events (MACE) (NRI: P = 0.010). In previous studies, low-density lipoprotein was a very important indicator of the prognosis of patients with AMI (34), but this study showed a limited additional effect on the GRACE score. This may be because patients had been treated with statins before hospitalization for CHD-related symptoms with or without PCI. Surprisingly, in this study, triglycerides played a significant role in enhancing the ability of the GRACE score to predict MACE. Studies have shown that in addition to LDL, hypertriglyceridemia plays an important role in the development of coronary artery disease (35–38). In a large cohort study by Ambrosy et al. elevated triglyceride levels were associated with an increased risk of atherosclerotic cardiovascular disease events and a reduced risk of death in a cohort treated with statins (39). Hypertriglyceridemia is closely related to patients' eating habits (40), so a healthy diet after discharge is essential. The TyG index reflects the status of insulin resistance and has a good predictive effect on the occurrence of MACE. Including these parameters into the GRACE score system, we found that the TyG index had a greater incremental impact on risk prediction and stratification than the other parameters. Thus, the TyG index may provide more information on recurrent adverse cardiovascular events.

Patients with multivessel coronary artery disease have a high risk of MACE (41). We found that patients with NSTE-ACS and a high TyG index were more likely to have the multivessel disease. Similar to our research, a recent study found that a high TyG was significantly associated with the risk of multivessel coronary artery disease regardless of confounders, such as age, sex, SBP, DBP, history of smoking and alcohol consumption, and drug therapy (42). This may be another reason the TyG index can predict primary endpoints independent of the GRACE score in some patients. Unfortunately, there are few studies on the relationship between TyG and multivessel coronary artery disease at present, and further large-sample studies are needed.

Combining the TyG index and GRACE score could improve the prediction of the occurrence of 2-year adverse cardiovascular events. This new risk model could identify patients with NSTE-ACS at higher risk of adverse events following PCI so that they can be monitored more carefully.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the First Affiliated Hospital of Zhengzhou University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

SP, GM, and XZ contributed to the conception and design of the study. SP, GM, YZ, and ZR collected the clinical information. SP wrote the first draft of the manuscript. SP, GM, and YD wrote sections of the manuscript. All authors have revised, read, and approved the final version of the manuscript.

This study was supported by the Science and Technology Development of Henan Province (Grant No. 212102310210).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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