Association of the cumulative triglyceride-glucose index with major adverse cardiovascular events in patients with type 2 diabetes

Cardiovascular disease (CVD), including coronary heart disease, cerebrovascular disease, and peripheral arterial disease, is the leading cause of morbidity and mortality in individuals with diabetes [1]. Recent cardiovascular outcome event trials in type 2 diabetes mellitus (T2DM) patients showed that the rate of major adverse cardiovascular events (MACEs), including myocardial infarction (MI), stroke, and cardiovascular death, ranges from 9.4 to 12.1% [2‐4] and results in an estimated $37.3 billion in cardiovascular-related spending per year associated with diabetes [5]. Thus, assessing and controlling individual cardiovascular risk factors to prevent or slow CVD in people with diabetes is important. Insulin resistance (IR), underpinning the pathophysiology of T2DM, is commonly associated with hypertension, dyslipidemia, and dysglycemia [6]. Additionally, inflammatory and thrombotic markers are associated with IR thereby creating an inflammatory atherothrombotic syndrome [7]. Therefore, long-term IR not only causes hyperglycemia and hypertension, but it also results in abnormal blood lipid metabolism and anticoagulant mechanisms, which increases the risk of thrombosis. Furthermore, several studies have demonstrated that coronary atherosclerotic disease in diabetes is associated with more atheroma and increased macrophage infiltration and intraplaque thrombi [8]; this indicates that IR in diabetes is a biomarker of an inflammatory atherothrombotic process linking MACEs to the underlying mechanism in T2DM. Therefore, long-lasting monitoring and control of IR may contribute to the prevention of MACEs in patients with T2DM.

In clinical settings or large population-based studies, IR measurements can be challenging owing to some limitations in the current gold-standard methods (the euglycemic clamp and homeostasis model assessment for insulin resistance [HOMA-IR]) [9, 10]. The triglyceride-glucose (TyG) index, as a parameter derived from fasting blood glucose (FBG) and triglyceride (TG) levels first proposed in 2008, has been proposed as a convincing indicator of IR [11, 12]. The TyG index has been proven to correlate with the euglycemic-hyperinsulinemic clamp formation and thus has a validity similar to HOMA-IR [11]. Moreover, the TyG index has the advantage of being easily accessible in any clinical setting, thereby making our findings widely applicable. Thus, the TyG index was used as a biomarker of IR in this post-hoc analysis to study its relationship with the risk of MACEs in patients with T2DM. Recently, a considerable number of studies have provided robust statistical evidence suggesting that the TyG index may help identify individuals at risk of developing T2DM [13, 14] and that it is associated with the development and prognosis of CVD [15]. A cohort study (6078 participants > 60 years old) suggested that participants in the highest TyG index quartile were at a 72% higher risk of CVD events [16]. Using data from the National Health Information Database with a median follow-up period of 8.2 years, Hong et al. further confirmed that participants in the highest TyG index quartile were at a higher risk of stroke and MI, independently of other traditional cardiovascular risk factors [17]. The relationship between the TyG index and different types of CVD has been consecutively revealed thereafter [18]. However, most observational studies on the association between a high TyG index and cardiovascular outcomes have focused on TyG index values measured at a single timepoint, and few studies have characterized the long-term TyG index and its implications for MACEs in patients with T2DM [19‐21].

More importantly, poorly controlled lipid and glucose levels influence the slow progression of cardiovascular events. Long-term versus contemporary lipid and glucose levels may more significantly impact the development of cardiovascular events [22]. Moreover, cumulative exposure in cardiovascular risk factors has been shown to predict the risk of adverse long-term cardiovascular outcomes and mortality, independent of baseline risk factors levels over [19]. Previous study showed that the longer duration of higher TyG index exposure was significantly associated with increased CVD risk [23]. Although our previous study has also shown that high long-term trajectories of the TyG index were significantly associated with the occurrence of MACEs [24], it remains unclear whether the cumulative TyG index is a stronger risk factor for future MACEs in patients with T2DM. In the present study, we hypothesized that long-term exposure to a high TyG index during follow-up may influence the development of MACEs in T2DM. Using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) [25] and ACCORD Follow-On (ACCORDION) studies [26], we evaluated the association between cumulative TyG index exposure during early follow-up and the incidence of MACEs later in life.

In the present post-hoc analysis of the ACCORD cohort, we found that the cumulative TyG index was significantly associated with the risk of MACEs. Notably, the risk of MACEs and TyG index over time were directly proportional. Similar patterns were observed for CVD-related death and non-fatal MI. These trends remained when subjected to sensitivity analyses and analyses of stratified data. Furthermore, the addition of the cumulative TyG index to the baseline risk model, including traditional risk factors, significantly improved its predictive value.

The comparisons conducted on baseline characteristics across the quartiles in present study found that participants with a very high cumulative TyG index were associated with high cardiovascular risk when comprised with those with a low cumulative TyG index. However, diabetes duration is longer in the lower cumulative TyG index group indicating patients with longer diabetes duration would be likely to better control of blood glucose and lipid levels. Notably, the causality relationship needs to be further clarified by prospective study. Regarding cardiovascular events, the incidence of MACEs increased substantially with the magnitude of cumulative TyG index, which is consistent with previous studies [29]. Nevertheless, cumulative TyG index is not significantly associated with non-fatal stroke when analyzing the relationship between cumulative index and individual events. Despite previous studies showing that high cumulative TyG index is associated with a higher risk of ischemic stroke by using data from the Kailuan cohort [21], we found that cumulative TyG was not related to non-fatal stroke in patients with T2DM. One major reason for this difference could be the inclusion criteria of participants; previous studies have focused primarily on general population, while we concentrated on participants who had T2DM.

Previous observational studies on the association between the TyG index and cardiovascular outcomes focused on the TyG index at a single timepoint and ignored changes in the TyG index over time, which could result in potential regression dilution bias and subsequently affect the accuracy of results. Recently, the association between cumulative exposure in various biological measures (e.g., blood pressure and cholesterol) and incident CVD have been examined [30, 31]. Cui et al. described the cumulative effect of TyG on the risk of cardiovascular disease [23]. The risk of developing CVD increased with the cumulative TyG index, after adjustment for multiple potential confounders. Moreover, this study proposed that the causal effect of the cumulative TyG index on the risk of CVD is determined by both the magnitude and the cumulative duration of exposure to a high TyG index. While cardiovascular damage evolves over prolonged periods, current prediction models use only a ‘snapshot’ of baseline data as a proxy for actual long-term exposure to risk factors. Furthermore, within person variability and measurement errors bias risk prediction may occur if based on a single measurement. This suggests a need to consider both the magnitude and the cumulative duration of exposure to risk factors. Therefore, evaluation of the TyG index at baseline alone does not reflect the longitudinal association between the cumulative exposure to high TyG index and cardiovascular outcomes over time. It is feasible that the participant's electronic medical record allows the rapid integration of data across multiple time points, allowing the calculation of a cumulative exposure index. Using the cumulative TyG index in the present study, we found that a higher cumulative TyG index resulted in an increased risk of developing MACEs in T2DM patients. The risk of MACE development was highest in individuals in the highest quartile group, with a multivariate-adjusted HR of 1.72 (95% CI 1.28–2.30). In addition, this risk was not attenuated after adjusting for traditional risk factors and clinical variables. The cumulative effect seems to be independent of the pathogenesis of MACEs. Likewise, the longest exposure time was associated with the highest risk of MACEs. Nowadays, handheld and mobile technology essentially place a continuous monitoring device in the entire population’s pocket, and many health systems record all information electronically [32], making a compelling case for using routinely collected electronic health information to furthers assess the utility of repeated and cumulative measurements of risk factors.

The current study extends the findings of these previous reports and the cumulative TyG index to the conventional risk model, which had an incremental effect on the predictive value for incidence of MACEs. The predictive utility of a single TyG index value for the prediction of MACEs has shown that the TyG index is a useful parameter and a stronger predictive factor than HbA1c and TG levels for cardiovascular events; therefore, it may offer an additional prognostic benefit in patients with T2DM [33]. Recently, an observational study that included 1932 patients with acute coronary syndrome (ACS) and T2DM further confirmed that the TyG index was an independent predictor of MACEs in patients with T2DM and ACS (OR, 2.32; 95% CI 1.92–2.80) [34]. Additionally, a study that enrolled 776 patients with ACS and T2DM collected percutaneous coronary intervention evidence that the TyG index was also an independent predictor of MACEs (HR, 2.17; 95% CI 1.45–3.24) [35]. Importantly, a study showed that the addition of the TyG index to the traditional Framingham predictors improved the predictive accuracy of coronary heart disease by using data from the Vascular Metabolic CUN (Clinica Universidad de Navarra) cohort [15]. By using data from the Kailuan study with a median follow-up period of 7.01 years, Wang et al. further confirmed that substantial changes in the TyG index independently predicted the risk of CVD in the general population [20]. In the present study, the findings further imply that the cumulative TyG index is associated with a high risk of incidence of MACEs and that this higher risk can be predicted more accurately with the addition of the cumulative TyG index than with models that only included a single TyG index value. This highlights the importance of monitoring longitudinal patterns of the cumulative TyG index in clinical practice for patients with T2DM.

The pathophysiological processes of atherosclerosis suggest a mechanistic association between MACEs and the cumulative TyG index. TyG is an index consisting of two risk factors for CVD: lipid- and glucose-related factors, which are reflective of IR in the human body. Numerous studies have confirmed the TyG index as a reliable marker of IR, which may explain this association [12]. IR can induce glucose metabolism imbalance, which contributes to hyperglycemia and in turn induces inflammation, oxidative stress, and excessive glycosylation; this ultimately promotes smooth muscle cell proliferation, collagen crosslinking, and collagen deposition. These pathological events contribute to increased vascular stiffness and aging [7]. Additionally, systemic lipid disturbances induced by IR may cause the initiation and progression of atherosclerosis [36]. Furthermore, IR mitigates nitric oxide bioavailability and promotes oxidative stress in endothelial cells [37‐39], and it increases adhesion-induced and thromboxane A2-dependent tissue factor expression in platelets [40], which have been implicated in the occurrence of both thrombosis and cardiovascular events. Thus, an increase in the TyG index over time may accelerate the development of arterial stiffness, thereby leading to the development of MACEs in patients with T2DM.

These findings have substantial clinical implications. IR, a well-established hallmark of metabolic disorders and systemic inflammation, is not only a substantial risk factor for CVD but also contributes to a worse prognosis. Current studies have confirmed that the TyG index can be used as a reliable and convenient surrogate for IR, and it may be more optimized for risk stratification and outcome prediction for MACEs in patients with T2DM. Additionally, a recent systematic review found moderate-to-low quality evidence about the usefulness of the TyG index as a surrogate biochemical marker of IR [41]. Due to the lack of a standardized IR definition and heterogeneity between studies, further validation and standardized cut-off values are needed in clinical practice. Clinical practice is currently guided by contemporary FBG and TG values, whereas our findings suggest that incorporating cumulative exposure to IR into clinical practice may further refine risk assessment of cardiovascular outcomes and help inform strategies for secondary prevention of MACEs in patients with T2DM. Additionally, the TG/HDL-C ratio was considered a potential predictive marker of IR and β-cell dysfunction [42]. It is closely associated with T2DM as well as CVD development. The possible mechanisms could be referenced to that high TG levels reflect the abundance of TG-rich lipoproteins particles containing apo B and in essence, highly atherogenic, that it may help to explain the pathophysiological processes of atherosclerosis. Moreover, given that the risk of developing MACEs is associated with the cumulative TyG index, it is plausible that improving IR and maintaining optimal FBG and TG levels may prevent the development of MACEs better than the current paradigm of deferring IR improvement to later, when MACEs have likely to already have occurred.

The strengths of this study include its large cohort size and its complete follow-up of MACEs and repeat assessment of FBG and TG measurements, which allowed us to model the long-term cumulative TyG index and assess associations between the cumulative TyG index and MACEs. These advantages not only permitted us to reliably estimate the cumulative TyG index beyond conventional risk in patients with T2DM with high cardiovascular risk, but they also demonstrated that patients with T2DM with a high cumulative TyG index had a greater risk of MACEs. This suggests that this population may benefit from earlier and more frequent screening for adverse cardiovascular events, aggressive risk factor management, and maintenance of metabolic health.

This study had some limitations. First, our findings were observational, and the causal role of the TyG index on cardiovascular event risk should be verified in further prospective intervention studies. Second, despite adjustments for potential known confounding variables in the multivariable Cox regression analysis, we cannot exclude a possible residual bias because of the post-hoc nature of this study, nor can we assess all metabolic factors and parameters related to IR. Finally, the population of the ACCORD trial included only high-risk patients with T2DM. Additional studies are necessary to increase the generalizability of the results.

In T2DM, long exposure to a high TyG index may increase the risk of MACEs. These findings indicate that monitoring the longitudinal TyG index may assist with optimized-for-risk stratification, as well as outcome prediction for MACEs in patients with T2DM.