Skip to main content

Associations of the triglyceride-glucose index and remnant cholesterol levels with the prevalence of Carotid Plaque in patients with type 2 diabetes: a retrospective study

Abstract

Background

The triglyceride-glucose (TyG) index has been identified as an alternative biomarker for insulin resistance (IR), while residual cholesterol (RC) is a simple, cost-effective, and easily detectable lipid metabolite. However, the associations of these two markers with carotid plaque presence remain unclear. Thus, this study aimed to explore their associations with carotid plaque presence.

Methods

Participants were chosen from patients with T2DM admitted to The Second Affiliated Hospital of Anhui Medical University from October 2023 to April 2024, and they were separated into two groups (patients without carotid plaque and patients with carotid plaque) based on their carotid ultrasound results. By comparing the general information and biochemical indicators of the two groups, we employed multivariate logistic regression models and RCS regression models to investigate the associations of the TyG index and RC levels with carotid plaque presence, and made adjustments based on multiple confounding factors to identify the differences between subgroups.

Results

This study comprised 278 patients with T2DM in total, including 165 males and 113 females. A multivariate logistic regression study indicated that, after adjusting statistically significant variables screened in LASSO regression, TyG index [OR (95% CI): 1.810 (1.077, 3.113)] and RC [OR (95% CI): 1.988 (1.034, 3.950)] remained the risk factors for carotid plaque presence. According to restricted cubic splines (RCS), RC levels increased linearly with carotid plaque presence (P - nonlinear > 0.05). Conversely, the TyG index and carotid plaque presence did not associate linearly (P - nonlinear < 0.05). Results of subgroup analyses showed no grouping variables exhibited association with TyG index or RC (p for interaction > 0.05).

Conclusions

In patients with T2DM, both TyG index and RC levels were strongly linked to carotid plaque presence, and could serve as independent risk factors for this presence. Monitoring the TyG index and RC levels can help gain a better understanding and knowledge of carotid plaque presence in patients with T2DM, offering guidance for the clinical prevention and treatment of cardiovascular and cerebrovascular diseases (CCVDs) in patients with T2DM.

Background

Globally, the prevalence of type 2 diabetes mellitus (T2DM) has sharply increased, leading to significant medical and financial consequences. Most patients with T2DM often suffer from several macrovascular complications, including coronary heart disease (CHD) and ischemic stroke. Chronic hyperglycemia in patients with T2DM may cause increased free radical production, enhanced oxidative stress and endothelial dysfunction. Meanwhile, combined insulin resistance (IR), changes in hemorheology and other factors may further aggravate vascular injury, ultimately leading to atherosclerotic plaque presence [1]. The presence of carotid plaque is often used as a predictor of cardiovascular disease or ischemic stroke, while carotid plaque presence is a surrogate marker for elevated risk of systemic atherosclerotic diseases [2, 3].

Atherosclerosis is the primary pathological basis of cardiovascular diseases. Moreover, the carotid artery is one of the superficial arteries in the body, which can be detected by simple, convenient and non-invasive methods. A carotid ultrasound is used to measure the thickness of carotid intima, the presence of plaques, the size and location of the plaques, the presence of thrombosis, the existence of vascular stenosis and the severity of stenosis. It also can perform hemodynamic analysis of blood flow within the vessels. Thus, this method is an important way to assess carotid arteries and veins, and also helps in identifying the atherosclerosis in the whole body. Early diagnosis and early prevention of carotid plaque presence are of great importance for the prevention and control of CCVDs [4]. Studies have indicated that, compared with carotid intima-media thickness (a measure used to show the severity of atherosclerosis), carotid plaque presence was associated with increased future risk of atherosclerosis, and had better predictive value for atherosclerotic cardiovascular diseases [5,6,7].

IR, characterized by the decreased sensitivity and responsiveness to insulin action, is the main pathogenesis of T2DM and generally occurs several years before the onset of diabetes [8]. A growing body of research has demonstrated that IR and its resulting pathophysiological changes were strongly linked to an increased risk of cardiovascular diseases (CVDs) and ischemic stroke in patients with and without diabetes [9,10,11]. Currently, glucose clamp techniques and the intravenous glucose tolerance test have been extensively used to determine insulin secretion and IR, and served as “gold standards” for evaluating and identifying the responsiveness of β-cells to insulin. These methods are primarily applied to academic research rather than clinical practice due to their complicated procedures and high prices [12]. A study [13] suggested that TyG index, a valid tool for assessment of glycemic control in patients with T2DM, is positively associated with glycated hemoglobin (HbA1c) and IR, and can be used as a reliable biomarker to replace IR [14]. IR was calculated and assessed by measuring fasting plasma glucose (FPG) and triglyceride (TG) levels. These methods are simple to perform and easy to operate. According to previous studies, a higher TyG index was found to be positively associated with the risk of multi-vessels CAD. Thus, it has the potential to predict vascular severity in patients with coronary heart diseases (CHDs) [15]. However, the connection between carotid plaque presence and the TyG index continues to be disputed. Additionally, there is currently no definitive conclusion on whether the TyG index is substantially associated with carotid plaque presence.

Remnant cholesterol (RC) is a kind of lipoprotein rich in cholesterol triglyceride (TG). Several studies discovered that RC was associated with the occurrence of CHDs [16], ischemic stroke [17] and T2DM [17]. Additionally, in patients with T2DM, higher levels of RC were linked to a greater risk of diabetic microvascular complications, including diabetic nephropathy [18] and diabetic retinopathy [19]. However, there are few studies on whether higher levels of RC raise the possibility of macrovascular complications in patients with T2DM, and where they are associated with carotid plaque presence. The purpose of this study was to investigate the associations of the TyG index and RC levels with carotid plaque presence in patients with T2DM.

Methods

Study population

This retrospective study randomly included patients with T2DM admitted to The Second Affiliated Hospital of Anhui Medical University from October 2023 to April 2024. inclusion criteria met the diagnostic criteria and classification of diabetes specified in the Guideline for the Prevention and Treatment of Type 2 Diabetes Mellitus in China (2020 Edition) [20]. All patients underwent carotid ultrasound, and were separated into two groups (patients with carotid plaque and patients without carotid plaque) based on their carotid ultrasound results. Exclusion criteria: (1) Individuals with type 1 diabetes mellitus or gestational diabetes mellitus; (2) Patients who experienced diabetic ketoacidosis, presented hyperglycemic hyperosmolar status or repeated episodes of hypoglycemia in the last three months; (3) Patients with diabetes combined with severe infection, severe hepatic and renal insufficiency or acute cardiovascular and cerebrovascular accidents; (4) Patients who had a history of malignant tumor, with autoimmune disorder or psychiatric disorders. This study was approved by the ethics committee of The Second Affiliated Hospital of Anhui Medical University (YX2024-134). Informed consent was waived in this retrospective study.

Data collection

Basic clinical data of patients

Collected general clinical data included age, gender, height, weight, calculated body mass index (BMI = kg/m2), smoking history, drinking history, duration of diabetes, systolic blood pressure (SBP), diastolic blood pressure (DBP), past medical history (hypertension, stroke, CHDs, hyperlipidemia) and medication history (oral hypoglycemic agents, injectable hypoglycemic medications, antihypertensives, antiplatelet drugs and statins).

Biochemical indicators

All patients were fasted for at least eight hours. Then, a 3 ml of fasting blood was sampled through the cubital vein for every patient, and the following indicators were measured by a fully automatic biochemical analyzer, including FPG, TC, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), HbA1c, uric acid, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell count, neutrophil count, lymphocyte count, monocyte count, platelet count and hemoglobin levels. Then, we calculate the TyG index and RC levels using the following formula: TyG index = ln [TG(mg/dL) × glucose (mg/dL)/2]. RC = TC - (LDL-C + HDL-C).

Carotid ultrasound

The carotid ultrasound tests were performed using the Philips EPIQ 7 Ultrasound System and probes with a frequency range of 5.0–12.0 Mhz in strict accordance with steps detailed in the Guidelines for Vascular Ultrasound Examination of Stroke in China [21]. The intima-media thickness (IMT) of bilateral common carotid arteries and the carotid bulb was then measured and documented, and the size, location, shape, and acoustic characteristics of atherosclerotic plaque were evaluated. In this study, atherosclerotic plaque presence is defined as an IMT ≥ 1.5 mm with a protrusion of the vessel wall into the lumen, or a focal IMT of greater than 50% of the surrounding area according to the criteria for plaque presence defined in the Guidelines for Vascular Ultrasound Examination of Stroke in China [21].

Statistical methods

All of the data in this study were statistically analyzed using the R software (version 4.4.1), where normally distributed continuous variables were presented as \(\:\overline{X}\pm\:\:\text{S}\), and t-tests were employed for intergroup comparison. Non-normally distributed continuous variables were shown as \(\:M\:(Q1,Q3)\) and the Mann-Whitney U test was utilized for intergroup comparison. Categorical variables were presented as percentages (%) and the χ2 test was utilized for intergroup comparison. Factors associated with carotid plaque presence were identified using the Least Absolute Shrinkage and Selection Operator (LASSO), which were included in the subsequent analysis as covariates. To examine the associations of the TyG index and RC levels with carotid plaque presence, multivariate logistic regression models were adopted in this study. Moreover, the potential nonlinear relationships of the TyG index and RC levels with carotid plaque presence were examined using RCS models. Differences in the associations of the TyG index and RC levels with carotid plaque presence were investigated using subgroup and interaction analyses in different populations. There was a statistically significant difference when the two-sided p-values did not exceed 0.05. To assess the statistical power of this study, we performed a power analysis using the pwr package in R software. A sample size of 278 was used to examine the associations of TyG index and RC levels with the presence of carotid plaques, and the estimated statistical power for this study was 0.99.

Results

Baseline characteristics

This study enrolled 278 patients with T2DM in total, including 146 patients with carotid plaque and 132 patients without carotid plaque. Among them, the mean age was 59.5 ± 14 years for the group with carotid plaque and 51.5 ± 18.25 years for the group without carotid plaque. In terms of gender, 165 males and 113 females were finally included. Demographic and clinical characteristics of each group are detailed in Table 1. The following characteristics of the two groups did not differ significantly: gender, height, weight, BMI, DBP, TC, TG, HDL-C, LDL-C, UA, AST, ALT, FPG, HbAlc, white blood cell count, neutrophil count, lymphocyte count, monocyte count, platelet count, hemoglobin levels, smoking and drinking history, CHDs, history of hyperlipidemia and history of use of hypoglycemic medications (P > 0.05). Patients with carotid plaque had greater ages, higher SBP, longer duration of diabetes, higher levels of RC, creatinine and TyG index, in contrast to those without carotid plaque. Thus, carotid plaque is more likely to develop in patients with T2DM who also have hypertension and stroke. Moreover, compared to individuals without carotid plaque, those with carotid plaque were much more likely to be using statins, antihypertensive and antiplatelet medications (P < 0.05).

Table 1 Baseline characteristics in patients without carotid plaque and patients with carotid plaque

Further, violin chart results demonstrated that, in patients with T2DM, there was a significant association between the TyG index and RC levels and carotid plaque presence (P < 0.05), as shown in Fig. 1.

Fig. 1
figure 1

(A) TyG levels in patients with carotid plaque and those without carotid plaque; (B) RC levels in patients with carotid plaque and those without carotid plaque

Results of screening using the LASSO regression

Based on 5-fold cross-validation, the LASSO regression algorithm (λ = 0.026) screened the plaque-related indicators from the above 28 variables with non-zero coefficients, including gender, age, SBP, history of stroke and hyperlipidemia, use of antiplatelet drugs, levels of uric acid (blood), serum creatinine, AST and HbAlc, white blood cell count and neutrophil count. (Figures 2 and 3)

Fig. 2
figure 2

The process of screening the regularization parameter λ

Fig. 3
figure 3

Changes of 28 variables with changes in the regularization parameter λ

The associations of the TyG index and RC levels with carotid plaque presence

According to multivariate logistic regression analyses, in patients with T2DM, the TyG index and RC levels were both substantially linked to carotid plaque presence (Table 2). The risk of carotid plaque presence increased by 0.496 for each one-unit increase in TyG index without covariate adjustment (Model 1: odds ratio [OR] = 1.496, 95% CI 1.054–2.145, P = 0.026). Similarly, the likelihood of developing carotid plaque increased by 1.055 for each one-unit increase in RC (Model 1: OR = 2.055, 95% CI 1.205–3.628, P = 0.01). Following further adjustments for the variables identified by the LASSO regression algorithm (including gender, age, SBP, history of stoke and hyperlipidemia, use of antiplatelet drugs, levels of uric acid (blood), serum creatinine, AST and HbAlc, white blood cell count and neutrophil count), the risk of carotid plaque presence increased by 0.81 for each unit increase in TyG index (Model 2: OR = 1.810, 95% CI 1.077–3.113, P = 0.028).In the same way, the risk of carotid plaque presence increased by 0.988 for each unit increase in RC (Model 2: OR = 1.988, 95% CI 1.034–3.950, P = 0.043).

Table 2 LASSO logistic regression for assessing the association of TyG and RC with carotid plaque

Multivariable-adjusted RCS analysis of the associations of the TyG index and RC levels with carotid plaque presence

The results from RCS models indicated a non-linear connection between the TyG index and carotid plaque presence in patients with T2DM (p-nonlinear: 0.0496). When the TyG index is below 9.12, the risk of carotid plaques increases. The risk decreases when the index is between 9.12 and 9.83, but increases again when it exceeds 9.83. In contrast, RC was found to be linearly associated with carotid plaque presence in patients with T2DM (p-nonlinear: 0.3346). Elevated RC levels raised the likelihood of carotid plaque presence. (Fig. 4)

Fig. 4
figure 4

(A) RCS linear regression analysis of TyG and carotid plaque; (B) RCS linear regression analysis of RC and carotid plaque

Subgroup analysis and interaction tests of the associations of the TyG index and RC levels with carotid plaque presence

Subgroup analyses were carried out to further assess the stability of the associations between the TyG index and RC levels and the development of carotid plaque in patients with T2DM. Patients were grouped based on the following indicators, including gender, age, BMI, SBP, DBP, duration of diabetes, smoking and drinking history, history of hypertension, stroke and hyperlipidemia, use of oral hypoglycemic agents, injectable hypoglycemic medications, statins and antiplatelet drugs, levels of HbAlc, as presented in Fig. 5. In the following subgroups of patients, we have shown association of TyG index and a higher risk of carotid plaque presence: women; younger than 60 years old; diastolic blood pressure less than 90 mmHg; no prior alcohol consumption; with a history of combined hypertension; no history of stroke; no history of hyperlipidemia; with use of oral hypoglycemic agents; no use of injectable hypoglycemic medications; no use of statins; and with use of antihypertensive medications (all P < 0.05). Additionally, In the following subgroups of patients we have shown association of RC and a higher risk of carotid plaque presence: women; younger than 60 years old; BMI > 28 kg/m2; SBP ≥ 140 mmHg; DBP < 90 mmHg; duration of diabetes < 120 months; no prior alcohol consumption; no history of stroke; no history of hyperlipidemia; no use of injectable hypoglycemic medications; no use of statins; and HbAlc ≥ 7% (all P < 0.05). Results of subgroup analyses showed no grouping variables exhibited association with TyG index or RC (p for interaction > 0.05).

Fig. 5
figure 5

(A) Subgroup analysis of the association between TyG and carotid plaque; (B) Subgroup analysis of the association between RC and carotid plaque

Sensitivity analysis

To minimize heterogeneity in the results, statistically significant variables from Table 1 were included in the LASSO analysis, with the final results presented in Table 3 and Figure S1. The variables screened by the LASSO analysis (age, SBP, duration of DM, stroke, antiplatelet drugs, and Cr) were incorporated into a multivariate logistic regression analysis. The adjusted results indicated that both the TyG index and RC were significantly associated with carotid plaques presence (P < 0.05). For each unit increase in the TyG index, the risk of developing carotid plaques increased by 1.232 (Model 1: odds ratio [OR] = 2.232, 95% confidence interval [CI] 1.432–3.576, P < 0.001). Similarly, for each unit increase in RC, the risk of carotid plaques increased by 0.934 (Model 1: OR = 1.934, 95% CI 1.030–3.761, P = 0.045). Furthermore, treatments had a major effect on the outcomes as well. Therefore, oral hypoglycemic agents, injectable hypoglycemic medications, antihypertensives, antiplatelet agents, and statins were included in the model, which yielded similar results. Specifically, for each unit increase in the TyG index, the risk of carotid plaques increased by 1.134 (Model 2: OR = 2.134, 95% CI 1.355–3.452, P = 0.001). For each unit increase in RC, the risk of carotid plaques increased by 1.008 (Model 2: OR = 2.008, 95% CI 1.055–3.975, P = 0.038).

Table 3 Sensitivity analysis between TyG and RC assessed by LASSO logistic regression and carotid plaque

Discussion

According to our results, in patients with T2DM, both TyG index and RC levels were strongly linked to carotid plaque presence and could serve as independent risk factors for this presence. TyG index and RC levels are affordable, convenient, and non-invasive biomarkers that can be used extensively in clinical practice. They also have guiding significance for the early detection of high-risk groups in patients with T2DM with carotid plaque, and can offer effective monitoring and preventive measures for the clinical management of CCVDs in patients with T2DM.

Previous studies have shown that there are different opinions on whether the TyG index and carotid plaque presence are significantly associated. A cross-sectional study on the prevalence of carotid plaque in patients with prediabetes and newly diagnosed T2DM found that a high TyG index was positively associated with a high carotid plaque burden [22]. Zhang et al. [23] conducted a three-year follow-up study on 2,370 patients without a history of carotid plaque, and 444 subjects were found to have newly developed carotid plaque. The overall three-year cumulative incidence of carotid plaque was 18.7%. Findings revealed that a high TyG index was positively associated with an increased incidence of carotid plaque. Conversely, Zhao et al. [24] discovered that the TyG index was not considerably connected with carotid plaque presence in a study of 2,830 older adults. According to the findings of this retrospective analysis, in patients with T2DM, the TyG index and carotid plaque presence exhibited a strong connection. A high TyG index was found to be associated with an increased risk of carotid plaque presence in patients with T2DM despite adjustment for its common risk factors (such as gender, age, SBP, history of stroke and hyperlipidemia, use of antiplatelet drugs, levels of uric acid (blood), serum creatinine, AST and HbAlc, white blood cell count and neutrophil count). Furthermore, in patients with T2DM, there was no linear association between the TyG index and carotid plaque presence. When the TyG index is below 9.12, the risk of carotid plaques increases. The risk decreases when the index is between 9.12 and 9.83, but increases again when it exceeds 9.83. This may be associated with vascular endothelial function caused by extremely high or low IR, oxidative stress or inflammatory mediators. According to previous studies, extremely low levels of FPG or TG may facilitate the occurrence and the development of the disease [25]. Moreover, increased secretion of adrenaline stimulated by hypoglycemia through negative feedback in the body could further lead to vasoconstriction and platelet aggregation, advance vascular endothelial damage and induce the occurrence of CCVDs [26]. A study on the associations of TyG index and the risk of developing newly diagnosed diabetic nephropathy indicated that, both extremely low or high levels of TyG index could elevate the risk of diabetic nephropathy. The study defined a threshold for the TyG index at 9.07 (95% CI: 9.05–9.09) [27]. A study investigating the predictive value of the TyG index for the risk of new-onset diabetes found that compared to individuals with a TyG index < 8.7, those with a TyG index between 8.21 and 8.56 did not show a significant increase in the risk of T2DM. However, the risk increased for those with a TyG index between 8.57 and 8.96, and was significantly elevated when the TyG index was ≥ 8.97 [28]. Another study examining the association between the TyG index and coronary artery stenosis indicated that patients with a TyG index of 8.9 were at a greater risk of coronary artery stenosis compared to those with a TyG index of 8.2, and those with a TyG index of 9.7 were at a considerably higher risk [29]. Furthermore, the TyG index was categorized as a categorical variable based on percentiles, which offers relatively limited information. In contrast, the TyG index in this study was presented as a continuous variable, allowing for a more accurate dose-response relationship to be derived using the RCS regression model. Previous research has indicated a linear association between the TyG index and carotid plaques [30, 31], which differs from the findings of this study. The causes for this finding may be attributed to the small sample size, multidimensional data, complexity of the disease, settings of RCS curve parameters, and the selection of model。Nonetheless, our findings demonstrated that a higher level of TyG index (> 9.83) substantially raised the risk of carotid plaque.

Although intensive lipid-lowering with statins aimed to minimize LDL-C levels, significant residual risk of ASCVD still remained [32]. Therefore, it is recommended to combine medications targeting triglycerides (TG) and RC with statins to achieve potentially greater efficacy in LDL-C reduction [33]. TG are primarily found in triglyceride-rich lipoproteins (TRLs), with RC representing the cholesterol content within these TRLs [34]. Thus, it is one of the markers of dyslipidemia in diabetes that cannot be adequately controlled by statins [35]. Previous studies have predominantly focused on the association between LDL-C levels and ASCVD risk, which has certain limitations. However, recent findings indicated that elevated RC levels could be an independent risk factor for ASCVD and ischemic stroke [36, 37], offering diagnostic information about the potential risks of other atherosclerotic diseases. A study by Yuan et al. [38] enrolled 11,468 nondiabetic individuals in rural China and followed up with them after 6 years. Findings manifested that high RC levels raise the risk of T2DM in Chinese people living in rural areas. A real-world, cross-sectional study [39] recruited 12,317 Chinese general population, and results showed that RC can be used for the early risk management of subclinical carotid atherosclerosis in health examinations. A study on the association between RC levels and peripheral arterial disease (PAD) in patients with T2DM [40] concluded that RC levels were higher in patients with T2DM and PAD and independently RC levels were higher associated with its severity. According to this study, in patients with T2DM, a significant association was observed between RC and carotid plaque presence. Similarly, in the same population, higher RC levels were observed to be connected with a greater risk of carotid plaque presence after adjustments for its common risk factors (such as gender, age, SBP, history of hyperlipidemia, use of antiplatelet drugs, levels of uric acid (blood), serum creatinine, AST and HbAlc, white blood cell count and neutrophil count). Additionally, it was discovered that in patients with T2DM, a positive linear association was noted between RC levels and carotid plaque presence.

Although the exact mechanisms of how the TyG index and RC levels relate to carotid plaque presence in patients with T2DM are not fully understood, previous research has demonstrated that IR and lipid metabolism disorders contribute to endothelial cell injury and inflammatory cell infiltration [41, 42], providing the pathological basis for atherosclerotic diseases.

The TyG index, calculated as the natural logarithm of the product of TG and FPG divided by 2, can assess IR and glucose metabolism disorders. Through a variety of metabolic pathways and cell signaling mechanisms, IR can facilitate the accumulation of inflammatory mediators, which can cause endothelial dysfunction and, eventually, vascular remodeling that results in atherosclerosis [22, 43, 44]. Additionally, IR may inhibit the synthesis of nitric oxide (NO) in vascular endothelium, resulting in endothelial dysfunction [22]. It can also meditate the presence of atherosclerosis and plaque by affecting platelet adhesion, activation and aggregation [45]. Based on the multiple mechanisms mentioned above, IR is of great importance to carotid plaque presence and progression.

Generally, RC has been identified as a biomarker for lipid metabolism. Plaques and foam cells are more likely to form and occur when lipid metabolism is disrupted [46]. Meanwhile, higher RC levels are crucial for the early onset and progression of atherosclerotic plaques as it can lead to endothelial vasomotor dysfunction [47]. Besides, RC may induce endothelial cells to overexpress proatherothrombogenic molecules through a redox-sensitive mechanism, which has direct and pathogenic effects on atherosclerotic thrombosis [48]. Finally, remnant lipoproteins within the endarterium could trigger immuno-inflammatory responses by activating the immune system [49]. According to the above pathological mechanisms, there is a close association between RC and atherosclerotic plaque formation as well as progression.

This study investigated the TyG index and RC levels in patients with T2DM, and highlighted the importance of IR and lipid metabolism disorders in carotid plaque presence, providing new insights into future diagnosis and prevention of CCVDs in patients with T2DM. Additionally, it examined the associations of the TyG index and RC levels with carotid plaque presence in patients with T2DM. However, this study possesses certain limitations. First, this study is retrospective and cross-sectional, which cannot further explore the progression of a disease and the impacts of health interventions as a longitudinal study. Second, the use of Fibrates was not investigated in this study, nor the lipid reduction control targets were set for the patients. Similarly, the association between RC and other vascular diseases (such as peripheral vascular diseases, myocardial infarction, etc.) needs further investigation. Finally, the enrollment of inpatients from a single center and limited sample size could introduce some selection bias in this study. Thus, the universality of the results needs to be further verified by multi-center studies with large sample sizes.

Conclusion

The TyG index and RC levels can serve as independent risk factors for carotid plaque presence in patients with T2DM. Both indicators are simple and readily available clinical parameters that can be widely employed in clinical settings, for example, to estimate the chance of developing carotid plaque in patients with T2DM and to early identify high-risk groups who may develop CCVDs. Thus, they can offer simpler, more effective and convenient means for early detection and monitoring of CCVDs in patients with T2DM.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ALT:

Alanine aminotransferase

ASCVD:

Arteriosclerotic cardiovascular disease

AST:

Aspartate aminotransferase

BMI:

Body mass index

CAD:

Coronary artery disease

CCVDs:

Cardiovascular and cerebrovascular diseases

CHD:

Coronary heart disease

CVDs:

Cardiovascular diseases

DBP:

Diastolic blood pressure

FPG:

Fasting plasma glucose

HbA1c:

glycated hemoglobin

HDL-C:

High-density lipoprotein cholesterol

IMT:

Intima-media thickness

IR:

Insulin resistance

LDL-C:

Low-density lipoprotein cholesterol

NO:

Nitric oxide

PAD:

Peripheral arterial disease

RC:

Remnant cholesterol

RCS:

Restricted cubic splines

SBP:

Systolic blood pressure

T2DM:

Type 2 diabetes mellitus

TC:

Total cholesterol

TG:

Triglyceride

TRLs:

Triglyceride rich lipoproteins

TyG:

Triglyceride-glucose

UA:

Urine acid

References

  1. Viigimaa M, Sachinidis A, Toumpourleka M, Koutsampasopoulos K, Alliksoo S, Titma T. Macrovascular complications of type 2 diabetes Mellitus. Curr Vasc Pharmacol. 2020;18(2):110–6. https://doiorg.publicaciones.saludcastillayleon.es/10.2174/1570161117666190405165151.

    Article  CAS  PubMed  Google Scholar 

  2. Mitchell C, Korcarz CE, Gepner AD, Kaufman JD, Post W, Tracy R, et al. Ultrasound carotid plaque features, cardiovascular disease risk factors and events: the multi-ethnic study of atherosclerosis. Atherosclerosis. 2018;276:195–202. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.atherosclerosis.2018.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hollander M, Bots ML, Del Sol AI, Koudstaal PJ, Witteman JC, Grobbee DE, et al. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study. Circulation. 2002;105(24):2872–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.cir.0000018650.58984.75.

    Article  CAS  PubMed  Google Scholar 

  4. Moradi SZ, Jalili F, Hoseinkhani Z, Mansouri K. Regenerative Medicine and Angiogenesis; focused on Cardiovascular Disease. Adv Pharm Bull. 2022;12(4):686–99. https://doiorg.publicaciones.saludcastillayleon.es/10.34172/apb.2022.072.

    Article  CAS  PubMed  Google Scholar 

  5. Li Z, He Y, Wang S, Li L, Yang R, Liu Y, et al. Association between triglyceride glucose index and carotid artery plaque in different glucose metabolic states in patients with coronary heart disease: a RCSCD-TCM study in China. Cardiovasc Diabetol. 2022;21(1):38. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-022-01470-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhao YC, Zhang J, Wang F, He YM, Xu MJ, Wang DH, et al. Value of carotid intima thickness in assessing advanced carotid plaque vulnerability: a study based on carotid artery ultrasonography and carotid plaque histology. Quant Imaging Med Surg. 2024;14(2):1994–2007. https://doiorg.publicaciones.saludcastillayleon.es/10.21037/qims-23-1193.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Inaba Y, Chen JA, Bergmann SR. Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis. Atherosclerosis. 2012;220(1):128–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.atherosclerosis.2011.06.044.

    Article  CAS  PubMed  Google Scholar 

  8. Defronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–95. https://doiorg.publicaciones.saludcastillayleon.es/10.2337/db09-9028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mancusi C, de Simone G, Best LG, Wang W, Zhang Y, Roman MJ, et al. Myocardial mechano-energetic efficiency and insulin resistance in non-diabetic members of the strong heart study cohort. Cardiovasc Diabetol. 2019;18(1):56. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-019-0862-9.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yang Y, Huang X, Wang Y, Leng L, Xu J, Feng L, et al. The impact of triglyceride-glucose index on ischemic stroke: a systematic review and meta-analysis. Cardiovasc Diabetol. 2023;22(1):2. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-022-01732-0.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Huang Z, Ding X, Yue Q, Wang X, Chen Z, Cai Z, et al. Triglyceride-glucose index trajectory and stroke incidence in patients with hypertension: a prospective cohort study. Cardiovasc Diabetol. 2022;21(1):141. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-022-01577-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sánchez-García A, Rodríguez-Gutiérrez R, Mancillas-Adame L, González-Nava V, Díaz González-Colmenero A, Solis RC et al. ,. Diagnostic Accuracy of the Triglyceride and Glucose Index for Insulin Resistance: A Systematic Review. Int J Endocrinol. 2020; 2020:4678526. https://doiorg.publicaciones.saludcastillayleon.es/10.1155/2020/4678526.

  13. Selvi NMK, Nandhini S, Sakthivadivel V, Lokesh S, Srinivasan AR, Sumathi S. Association of triglyceride-glucose index (TyG index) with HbA1c and Insulin Resistance in type 2 diabetes Mellitus. Maedica (Bucur). 2021;16(3):375–81. https://doiorg.publicaciones.saludcastillayleon.es/10.26574/maedica.2021.16.3.375.

    Article  PubMed  Google Scholar 

  14. Tao LC, Xu JN, Wang TT, Hua F, Li JJ. Triglyceride-glucose index as a marker in cardiovascular diseases: landscape and limitations. Cardiovasc Diabetol. 2022;21(1):68. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-022-01511-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang X, Xu W, Song Q, Zhao Z, Meng X, Xia C, et al. Association between the triglyceride-glucose index and severity of coronary artery disease. Cardiovasc Diabetol. 2022;21(1):168. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-022-01606-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Saeed A, Feofanova EV, Yu B, Sun W, Virani SS, Nambi V, et al. Remnant-like particle cholesterol, low-density lipoprotein triglycerides, and Incident Cardiovascular Disease. J Am Coll Cardiol. 2018;72(2):156–69. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2018.04.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu Y, Wei Q, Li H, Yang H, Wu Y, Yu Y, et al. Association of remnant cholesterol with hypertension, type 2 diabetes, and their coexistence: the mediating role of inflammation-related indicators. Lipids Health Dis. 2023;22(1):158. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12944-023-01915-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wu Z, Yu S, Zhu Q, Li Z, Zhang H, Kang X, et al. Association of baseline and cumulative remnant cholesterol with incidence of diabetic nephropathy: a longitudinal cohort study. Diabetes Res Clin Pract. 2022;191:110079. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.diabres.2022.110079.

    Article  CAS  PubMed  Google Scholar 

  19. Chen S, Xu Y, Chen B, Lin S, Lu L, Cheng M, et al. Remnant cholesterol is correlated with retinal vascular morphology and diabetic retinopathy in type 2 diabetes mellitus: a cross-sectional study. Lipids Health Dis. 2024;23(1):75. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12944-024-02064-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Diabetes Society of Chinese Medical Association. China Type 2 Diabetes Prevention and Treatment Guidelines (2020 edition). Chin J Diabetes. 2021;13(4):315–409. https://doiorg.publicaciones.saludcastillayleon.es/10.3760/cma.j.cn115791-20210221-00095.

    Article  Google Scholar 

  21. Stroke Prevention and Control Engineering Committee NHaFPC. Chinese guidelines for vascular ultrasound examination of stroke. Chin J Med Ultrasound (Electronic Edition). 2015;12(8):599–610. https://doiorg.publicaciones.saludcastillayleon.es/10.3877/cma.j.issn.1672-6448.2015.08.004.

    Article  Google Scholar 

  22. Jiang ZZ, Zhu JB, Shen HL, Zhao SS, Tang YY, Tang SQ, et al. A high triglyceride-glucose index value is Associated with an increased risk of carotid plaque burden in subjects with prediabetes and New-Onset type 2 diabetes: a real-world study. Front Cardiovasc Med. 2022;9:832491. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fcvm.2022.832491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang Y, Wu Z, Li X, Wei J, Zhang Q, Wang J. Association between the triglyceride-glucose index and carotid plaque incidence: a longitudinal study. Cardiovasc Diabetol. 2022;21(1):244. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-022-01683-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhao S, Yu S, Chi C, Fan X, Tang J, Ji H, et al. Association between macro- and microvascular damage and the triglyceride glucose index in community-dwelling elderly individuals: the Northern Shanghai Study. Cardiovasc Diabetol. 2019;18(1):95. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12933-019-0898-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abbasi F, Reaven GM. Comparison of two methods using plasma triglyceride concentration as a surrogate estimate of insulin action in nondiabetic subjects: triglycerides × glucose versus triglyceride/high-density lipoprotein cholesterol. Metabolism. 2011;60(12):1673–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.metabol.2011.04.006.

    Article  CAS  PubMed  Google Scholar 

  26. Galassetti P, Davis SN. Effects of insulin per se on neuroendocrine and metabolic counter-regulatory responses to hypoglycaemia. Clin Sci (Lond). 2000;99(5):351–62.

    Article  CAS  PubMed  Google Scholar 

  27. Shang J, Yu D, Cai Y, Wang Z, Zhao B, Zhao Z, et al. The triglyceride glucose index can predict newly diagnosed biopsy-proven diabetic nephropathy in type 2 diabetes: a nested case control study. Med (Baltim). 2019;98(46):e17995. https://doiorg.publicaciones.saludcastillayleon.es/10.1097/md.0000000000017995.

    Article  Google Scholar 

  28. Lee DY, Lee ES, Kim JH, Park SE, Park CY, Oh KW, et al. Predictive value of triglyceride glucose index for the risk of Incident Diabetes: a 4-Year retrospective longitudinal study. PLoS ONE. 2016;11(9):e0163465. https://doiorg.publicaciones.saludcastillayleon.es/10.1371/journal.pone.0163465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee EY, Yang HK, Lee J, Kang B, Yang Y, Lee SH, et al. Triglyceride glucose index, a marker of insulin resistance, is associated with coronary artery stenosis in asymptomatic subjects with type 2 diabetes. Lipids Health Dis. 2016;15(1):155. https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12944-016-0324-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang A, Li Y, Zhou L, Liu K, Li S, Song B, et al. Triglyceride-glucose index is related to Carotid Plaque and its Stability in nondiabetic adults: a cross-sectional study. Front Neurol. 2022;13:823611. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fneur.2022.823611.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cao J, Zhou D, Yao Z, Zeng Y, Zheng J, Tang Y, et al. Insulin resistance, vulnerable plaque and stroke risk in patients with carotid artery stenosis. Sci Rep. 2024;14(1):30453. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41598-024-81967-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Castañer O, Pintó X, Subirana I, Amor AJ, Ros E, Hernáez Á, et al. Remnant cholesterol, not LDL cholesterol, is Associated With Incident Cardiovascular Disease. J Am Coll Cardiol. 2020;76(23):2712–24. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2020.10.008.

    Article  CAS  PubMed  Google Scholar 

  33. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, et al. Association between lowering LDL-C and Cardiovascular Risk Reduction among different therapeutic interventions: a systematic review and Meta-analysis. JAMA. 2016;316(12):1289–97. https://doiorg.publicaciones.saludcastillayleon.es/10.1001/jama.2016.13985.

    Article  CAS  PubMed  Google Scholar 

  34. Jørgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjærg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J. 2013;34(24):1826–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/ehs431.

    Article  CAS  PubMed  Google Scholar 

  35. Boden WE, Bhatt DL, Toth PP, Ray KK, Chapman MJ, Lüscher TF. Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics. Eur Heart J. 2020;41(24):2304–12. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/ehz778.

    Article  CAS  PubMed  Google Scholar 

  36. Langsted A, Madsen CM, Nordestgaard BG. Contribution of remnant cholesterol to cardiovascular risk. J Intern Med. 2020;288(1):116–27. https://doiorg.publicaciones.saludcastillayleon.es/10.1111/joim.13059.

    Article  CAS  PubMed  Google Scholar 

  37. Qian S, You S, Sun Y, Wu Q, Wang X, Tang W, et al. Remnant cholesterol and common carotid artery intima-media thickness in patients with ischemic stroke. Circ Cardiovasc Imaging. 2021;14(4):e010953. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circimaging.120.010953.

    Article  PubMed  Google Scholar 

  38. Yuan L, Liu J, Huang Z, Zhao Y, Feng Y, Yang X, et al. Elevated remnant cholesterol increase 6-year type 2 diabetes mellitus onset risk. Clin Chim Acta. 2023;541:117253. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.cca.2023.117253.

    Article  CAS  PubMed  Google Scholar 

  39. Zeng N, Shen Y, Li Y, Wang Y. Association between remnant cholesterol and subclinical carotid atherosclerosis among Chinese general population in health examination. J Stroke Cerebrovasc Dis. 2023;32(8):107234. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jstrokecerebrovasdis.2023.107234.

    Article  PubMed  Google Scholar 

  40. Song Y, Zhao Y, Bai X, Cheng W, Wang L, Shu M, et al. Remnant cholesterol is independently asssociated with an increased risk of peripheral artery disease in type 2 diabetic patients. Front Endocrinol (Lausanne). 2023;14:1111152. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fendo.2023.1111152.

    Article  PubMed  Google Scholar 

  41. Li Q, Park K, Li C, Rask-Madsen C, Mima A, Qi W, et al. Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-β isoform in the endothelium. Circ Res. 2013;113(4):418–27. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circresaha.113.301074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, et al. Endothelial dysfunction in atherosclerotic Cardiovascular diseases and Beyond: from mechanism to Pharmacotherapies. Pharmacol Rev. 2021;73(3):924–67. https://doiorg.publicaciones.saludcastillayleon.es/10.1124/pharmrev.120.000096.

    Article  CAS  PubMed  Google Scholar 

  43. O’Hagan R, Gonzalez-Cantero A, Patel N, Hong CG, Berg AR, Li H, et al. Association of the triglyceride glucose index with insulin resistance and subclinical atherosclerosis in psoriasis: an observational cohort study. J Am Acad Dermatol. 2023;88(5):1131–4. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jaad.2022.08.027.

    Article  CAS  PubMed  Google Scholar 

  44. Reardon CA, Lingaraju A, Schoenfelt KQ, Zhou G, Cui C, Jacobs-El H, et al. Obesity and insulin resistance promote atherosclerosis through an IFNγ-Regulated macrophage protein network. Cell Rep. 2018;23(10):3021–30. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.celrep.2018.05.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sachs S, Zarini S, Kahn DE, Harrison KA, Perreault L, Phang T, et al. Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans. Am J Physiol Endocrinol Metab. 2019;316(5):E866–79. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpendo.00243.2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tada H, Nohara A, Inazu A, Mabuchi H, Kawashiri MA. Remnant lipoproteins and atherosclerotic cardiovascular disease. Clin Chim Acta. 2019;490:1–5. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.cca.2018.12.014.

    Article  CAS  PubMed  Google Scholar 

  47. Nakamura T, Takano H, Umetani K, Kawabata K, Obata JE, Kitta Y, et al. Remnant lipoproteinemia is a risk factor for endothelial vasomotor dysfunction and coronary artery disease in metabolic syndrome. Atherosclerosis. 2005;181(2):321–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.atherosclerosis.2005.01.012.

    Article  CAS  PubMed  Google Scholar 

  48. Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, et al. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation. 2000;102(6):670–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.cir.102.6.670.

    Article  CAS  PubMed  Google Scholar 

  49. Burnett JR, Hooper AJ, Hegele RA. Remnant cholesterol and atherosclerotic Cardiovascular Disease Risk. J Am Coll Cardiol. 2020;76(23):2736–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.jacc.2020.10.029.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by the 2022 Anhui Medical University Fund Project [grant number 2022xkj192].

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to the study conception and design. Writing - original draft preparation: [Xin Xu]; Writing - review and editing: [Yijun Du]; Conceptualization: [Deyuan Zhang]; Methodology: [Xing Zhong]; Formal analysis and investigation: [Xin Xu]; Funding acquisition: [Deyuan Zhang]; Resources: [Tianrong Pan]; Supervision: [Deyuan Zhang], and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Deyuan Zhang.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of The Second Affiliated Hospital of Anhui Medical University (YX2024-134). Informed consent was waived in this retrospective study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1: Figure S1 Sensitivity analysis in LASSO regression screening

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, X., Pan, T., Zhong, X. et al. Associations of the triglyceride-glucose index and remnant cholesterol levels with the prevalence of Carotid Plaque in patients with type 2 diabetes: a retrospective study. Lipids Health Dis 24, 26 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12944-025-02449-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12944-025-02449-1

Keywords