The Triglyceride-Glucose Index Is Associated With Atherosclerosis in Patients With Symptomatic Coronary Artery Disease

The triglyceride-glucose index (TyG index) has been suggested as a credible surrogate marker of insulin resistance (IR) for many years. Its value in predicting and diagnosing cardiovascular disease has been reported recently. However, few studies have reported that it can be used as a marker for atherosclerosis and coronary artery disease (CAD), which is one of the main causes of cardiovascular-related death. This study will attempt to prove that the TyG index can be a useful marker for predicting atherosclerosis and has diagnostic signicance for symptomatic CAD. in of was by the formula (fasting was dened as a Gensini score on Participants were into four according to TyG index tertiles.


Background
The triglyceride-glucose index (TyG index) has been suggested as a credible surrogate marker of insulin resistance (IR) for many years. Its value in predicting and diagnosing cardiovascular disease has been reported recently. However, few studies have reported that it can be used as a marker for atherosclerosis and coronary artery disease (CAD), which is one of the main causes of cardiovascular-related death. This study will attempt to prove that the TyG index can be a useful marker for predicting atherosclerosis and has diagnostic signi cance for symptomatic CAD.

Methods
The baseline data of 3059 cardiology patients, as well as their clinical data, biochemical parameters and medical histories, were collected from our clinical cases over the last three years. Further screening resulted in 1581 data points of symptomatic CAD. The TyG index was calculated by the formula Ln (fasting triglycerides (mg/dl) × fasting blood glucose (mg/dl)/2). CAD was de ned as a nonzero Gensini score on coronary angiography. Participants were divided into four groups according to TyG index tertiles.

Results
We evaluated 1581 patients, and the majority were male (41.9%) and elderly (59.5%). Cardiometabolic risk factors were positively associated with the TyG index. Arterial damage, including carotid and coronary damage, was highly associated with the TyG index. After adjustment for sex, age and multiple risk factors, Poisson regression analysis indicated that the prevalence ratios for carotid plaque and coronary stenosis were 1.11 (95% Cl 0.55-2.11; P = 0.01) and 2.94 (95% Cl 0.58-1.50; P = 0.01), respectively. Moreover, the TyG index has better diagnostic e cacy for symptomatic CAD than do fasting glucose and triglycerides (AUC TyG = 0.734; AUC fasting glucose = 0.611; AUC triglyceride = 0.717).

Conclusion
The TyG index is a useful marker for predicting atherosclerosis and may be a diagnostic indicator for symptomatic CAD.
Background Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide [1], and in 2015, it led to the deaths of 7.4 million people. Due to the atherosclerosis process, CAD occurs when the coronary arteries are obstructed, which is highly associated with risk factors [2]. CAD can develop slowly and often without symptoms [3] and is classi ed as asymptomatic CAD. The main manifestation in its symptomatic phase is angina, de ned as chest pain radiating to the shoulders, arms, and jaw [3]. Insulin resistance (IR) has been proven to play an important role in CAD [4]. The triglyceride-glucose (TyG) index, calculated from fasting triglycerides and blood glucose, has been suggested to be a reliable marker instead of IR for metabolic disorders [5,6].
Recently, the TyG index has been reported to be associated with cardiovascular disease (CVD) risk in apparently healthy individuals [7]. Last year, da Silva et al. [3] published an article on how the TyG index was associated with symptomatic CAD in patients in secondary care. Another article by Zhao et al. [8] showed that an elevated TyG index is associated with a higher risk of arterial stiffness and nephric microvascular damage. There are also some articles studying the effect of the TyG index on the prognosis of cardiovascular diseases [9]. However, the prognostic value of the TyG index in patients with CAD has not been determined [10]. Atherosclerosis is the pathological basis of CAD, among which coronary artery calci cation (CAC) is a risk factor for cardiovascular events [11]. In recent years, research on TyG and CAC has also made progress [7]. Therefore, it is necessary to study the relationship between the TyG index and atherosclerosis. Diabetes and hyperlipidaemia are both risk factors for CAD [12,13], and these two variables have a direct relationship with a high TyG index (based on the formula). In this sense, controlling for these two variables is necessary. Comparing the diagnostic values of fasting glucose and triglyceride levels with the TyG index is another important point [14]. Therefore, the primary objective of the study was to prove that the TyG index has a better diagnostic ability for CAD than either blood glucose or triglyceride alone.

Population and study design
From 2016 to 2019, we diagnosed and treated approximately 5000 patients with symptomatic CAD, and 3059 of them completed our follow-up for this study. In addition, 1581 of them who had accurate fasting triglyceride and fasting blood glucose results were divided into four groups according to TyG index tertiles. Patients with symptomatic CAD were those with a history of angina, a clinical diagnosis including diagnosis without complementary tests, or a history of a positive stress test, and patients with treated CAD were those with angioplasty/stent/revascularization [15]. We strati ed them into four groups: (a) only symptomatic CAD, (b) symptomatic CAD with diabetes (here referred to as T2DM), (c) symptomatic CAD with hyperlipidaemia, and (d) symptomatic CAD with both diabetes and hyperlipidaemia (Hyperlipidaemia was de ned as an adult with a fasting serum total cholesterol of more than 5.72 mmol/L and triglycerides of more than 1.7 mmol/L [16]. T2DM was de ned as fasting serum glucose ≥ 7.0 mmol/L or the 2-h serum glucose of the oral glucose tolerance test ≥ 11.1 mmol/L or current use of hypoglycaemic drugs or insulin [10].) Among these patients, 270 underwent coronary artery angiography, and 1290 underwent carotid Doppler ultrasound. These two parts were also divided into four groups according to TyG index tertiles. Ultimately, we can study the relationship between TyG and symptomatic CAD and central and peripheral vascular atherosclerosis.

Data collection
Height and weight were measured, and body mass index (BMI) was calculated as weight divided by height squared. Family history and personal medical history, including diabetes, hypertension and previous cerebrovascular or cerebrovascular diseases, were collected from self-reported medical history. A smoker was de ned as a subject who reported having smoked cigarettes regularly over the previous six months. Blood samples were obtained from participants who were in a fasting state in the morning of the exam day. Concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured using an automatic biochemistry analyzer (Hitachi 7150, Japan). The TyG index was calculated using the formula Ln (fasting triglycerides (mg/dl) × fasting blood glucose (mg/dl)/2) [17]. The results of carotid colour Doppler ultrasound and coronary angiography were determined by our trained doctors from department of radiology and cardiology the Department of Radiology and Cardiology.

Statistical analysis
Continuous variables were expressed as the mean ± SD (variables with a normal distribution) or median (variables with a skewed distribution) and the number (percentage) for the categorical variables. Categorical variables were compared by chi square tests. The associations between the TyG index and cardiovascular risk factors were obtained by linear regression. Relationships between the TyG index and different groups of coronary artery angiography and carotid Doppler ultrasound were examined by Poisson regression and adjusted by confounders. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve and a 95% con dence interval (Cl) were calculated to compare the diagnostic e cacy of the TyG index with fasting glucose and triglycerides for symptomatic CAD. All statistical analyses were performed using SPSS statistical package, version 23.0 (SPSS, Inc., Chicago, IL, USA) and STATA 13.0. P values of < 0.05 were considered statistically signi cant.

Baseline characteristics
A total of 1581 patients experienced symptomatic CAD who had accurate TyG results, with a mean age of 68.0 ± 11.4 years, mean BMI of 24.9 ± 3.3 kg/m2; 41.9% were male. The most prevalent was symptomatic CAD with hyperlipidaemia (37.8%), followed by symptomatic CAD with diabetes (30.1%) and only symptomatic CAD (18.7%). Regarding the history of diseases, 35.8% had arterial hypertension, 37.0% had diabetes and 78.2% had dyslipidaemia. Furthermore, 62.8% of the included patients had a family history of CAD, and 33.6% and 31.9% used hypoglycaemic and lipid-lowering medication, respectively.
The patients were strati ed according to TyG index. As shown in Table 1, patients in the highest TyG index group presented higher values of BMI, SBP, DBP, TC, LDL-C, LDL-C/HDL-C ratio, TG, blood glucose, smoking rate, and Hb1Ac (%) than those in the lowest TyG index group. Additionally, lower values of HDL-Page 5/16 C and age were present in those in the highest TyG index group. In addition, patients who had diabetes and hypertension were more present in the last group of TyG index. Data are represented as the mean ± SD or number (%).
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, HDL-C high-density lipoprotein, LDL-C low-density lipoprotein

Cardiovascular risk factors according to quartiles of the TyG index
We also analyzed the association between quartiles of the TyG index (I quart n = 133, II quart n = 767, III quart n = 595, IV quart n = 86) and cardiovascular risk factors. As shown in Table 2, the TyG index was positively associated with BMI, LDL-C, LDL-C/HDL-C ratio and family history of CAD, as well as the presence of diabetes, hypertension and smoking. On the other hand, it was negatively related to age and HDL-C (Additional Table 1) (all P < 0.05). Data are represented as the mean ± SD or number (%).
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, HDL-C high-density lipoprotein, LDL-C low-density lipoprotein Association between TyG index and carotid plaque    Diagnostic e cacy of the TyG index for symptomatic CAD By analysing the diagnostic e ciency of the TyG index in symptomatic CAD based on the ROC curves, Fig. 1 shows that the TyG index has a certain diagnostic value in symptomatic CAD compared with fasting glucose and triglycerides, and the maximum AUC was 0.734. When the critical value was set at 8.97, the sensitivity and speci city of the TyG index in symptomatic CAD diagnosis were 62.40% and 90.00%, respectively.

Discussion
The TyG index has been reported to be positively associated with cardiovascular risk factors [14,18]. In addition, some studies found that the TyG index was also related to the prevalence of CVD [10,19].
However, the prognostic value of the TyG index in patients with symptomatic CAD remains undetermined.
In this study, we investigated whether the TyG index was associated with the prevalence of atherosclerosis, which was independent of conventional cardiovascular risk factors. We con rmed the prognostic value of the TyG index in symptomatic CAD. To the best of our knowledge, there are few studies on the relationship between the TyG index and the presence of carotid and coronary atherosclerosis among patients with symptomatic CAD. Furthermore, the TyG index showed higher predictability for symptomatic CAD than did fasting triglycerides and glucose.
The TyG index was rst studied as a marker of identifying insulin resistance (IR) with a high sensitivity and speci city [4,20,21], which has been proposed as an important cause of cardiovascular disease (CVD) [22]. It was demonstrated that the TyG index was a useful predictor of T2DM, as well as CVD [19,23,24]. Moreover, studies showed that the TyG index is associated with the risk of CVD compared to the usual tool for insulin resistance evaluation [25]. Subsequently, several studies veri ed the relationship between the TyG index and atherosclerosis and CAD.
To date, very few studies have examined the relationship between the TyG index and atherosclerosis.
Irace et al. [26] evaluated the association between carotid atherosclerosis and the TyG index after adjustment for traditional cardiovascular risk factors and positive results. Whereafter, Alizargar and Bai [27] reported that the TyG index could predict only CCA-IMT independent of other risk factors. In a recent study, Lambrinoudaki et al. [28] con rmed that the TyG index is associated with carotid atherosclerosis and arterial stiffness mainly in lean postmenopausal women. In the same year, Lee et al. [29] showed an independent relationship between the TyG index and coronary artery stenosis in patients with type 2 diabetes. However, all these studies have limitations, such as using only postmenopausal women or patients with type 2 diabetes.
In the present study, we demonstrated that the TyG index was independently associated with the prevalence of atherosclerosis in patients with symptomatic CAD. We analyzed the carotid artery and coronary artery separately, indicating that the TyG index can predict arteriosclerosis from the peripheral vascular and central vascular aspects.
On the other hand, in recent years, there have been relatively more studies on the relationship between the TyG index and CAD [22,30,31]. da Silva et al. [3] reported that the TyG index was positively associated with CAD in the symptomatic phase, independent of social, clinical and food consumption characteristics. However, it did not compare the diagnostic values of fasting glucose and triglyceride levels with the TyG index [14]. Whereafter, Won et al. [32] found that the TyG index is an independent predictor for the progression of CAC, especially in adults without heavy baseline CAD. Recently, Park et al. [33] reported that the TyG index is an independent marker for predicting subclinical CAD in individuals conventionally considered healthy.
On this basis, the predictive and diagnostic value of the TyG index for CAD with clinical symptoms is worth studying.
In this study, on the basis of verifying the relationship between the TyG index and cardiovascular risk factors, we compared the diagnostic e cacy of the TyG index and fasting glucose and triglycerides on symptomatic CAD. We proved that the TyG index has a better diagnostic value for symptomatic CAD.
According to the formula of the TyG index, we can see that fasting glucose and triglycerides have a direct impact on the results, but this study veri ed that the predictive value of the TyG index for symptomatic CAD is much higher than that of the former two.
There were several limitations in the present study. First, the sample size might not be large enough, and the follow-up period might not be long enough. Second, this is a retrospective observational study that has a memory lapse, and the description of symptoms is not accurate. Third, other confounding factors, such as exercise habits and job category, were not included. Thus, we could not adjust for nutritional habits, which can affect blood glucose and triglyceride levels. Last, we veri ed the relationship only between the TyG index and symptomatic CAD but not subclinical CAD. Thus, it can also be seen from the bar chart that whether there is a relationship between the TyG index and patients without diabetes and hyperlipidaemia still needs to be studied.

Conclusions
The TyG index was positively associated with a higher prevalence of arteriosclerosis, regardless of conventional in uencing factors. In addition, The TyG index has better diagnostic e cacy for symptomatic CAD than fasting glucose and triglycerides according to the ROC curve. Based on the ndings of this study, the TyG index is a useful marker for predicting atherosclerosis and may be a diagnostic basis for symptomatic CAD in the future. Further prospective large-scale studies are required to clarify the mechanisms of this relationship.

Declarations
Not applicable.
Ethics approval and consent to participate The study protocol was approved by the EthicsCommittee of Tianjin Union Medical Center.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.