This study demonstrated that there was a positive association between the TyG index primary outcomes (CCVDs or all-cause mortality) in men, but not in women. After stratifying the primary outcomes into CVDs, CbVDs, CCVD-related death, and all-cause death, a higher TyG index predicted a higher risk of CVDs in both sexes while it was not significantly associated with CbVDs, CCVD-related death, and all-cause death.
Insulin stimulates glucose metabolism and suppresses fatty acid utilization and lipolysis as an energy source. Insulin resistance is defined as an impaired tissue response to insulin stimulation, resulting in the dysfunction of glucose and lipid metabolism [3]. These metabolic alterations lead to chronic hyperglycemia, dyslipidemia (in particular, increased free fatty acid release in adipose tissue and hepatic TG production), oxidative stress, and inflammation that induce endothelial dysfunction and atherosclerotic change. Eventually, insulin resistance increases CCVDs and premature death through these pathophysiologic mechanisms [3-5]. Thus, early detection and a more intensive management of insulin resistance are very important in reducing the likelihood of these events. Even though several methods to measure insulin resistance have been proposed, the hyperinsulinemic-euglycemic glucose clamp is considered the standard [6]. However, the hyperinsulinemic-euglycemic glucose clamp is not practical for use in real-world clinics because of complex and invasive measurements. Another reliable surrogate marker of insulin resistance is HOMA-IR. However, the disadvantage is that blood insulin levels are not routinely checked for patients without diabetes in the primary clinical setting [7].
The TyG index is newly proposed as a marker to measure insulin resistance. TG and glucose levels, which are used as variables to calculate the TyG index, are widely and commonly measured in clinics. The Korean Society of Lipid and Atherosclerosis recommends that the lipid profile (total cholesterol, TG, HDL-C, and LDL-C) be checked every 4‒6 years for adults to screen for dyslipidemia and CCVD risk [13]. Many guidelines recommend the annual measurement of fasting glucose levels to screen for diabetes or prediabetes [14, 15], while there are few recommendations for the measurement of fasting insulin levels to screen for them. Furthermore, Asian populations may consume more foods with a higher carbohydrate content than Western populations, which increases their blood TG and glucose levels [16]. Carbohydrate-rich diets raise the possibility of developing hypertriglyceridemia and impaired fasting glucose, which are related to the risk of CCVDs [17, 18]. Epidemiological studies support the proposal that the TyG index is a better indicator of insulin resistance in Asian populations than HOMA-IR [10, 19]. In addition, a lot of studies report that the TyG index was more closely associated with atherosclerosis, arterial stiffness, subclinical cerebral vessel diseases, and coronary arterial diseases than HOMA-IR [20-23].
The primary outcome of this study is CCVDs and all-cause mortality. CCVDs are composed of CVDs (such as angina pectoris, myocardial infarctions) and CbVDs (such as non-traumatic cerebral hemorrhage, cerebral infarction, and cerebral arterial diseases, etc.). The statistical significance between the TyG index and primary outcomes are different according to statistical methods (significant only in women from the log-rank test and only in men from Cox proportional hazards model). Here we observed a very interesting result. In terms of the association between the incidence of the primary outcomes and TyG index in men, there was no significance from the log-rank test (Figure 2). However, it began to be significant after adjusting for age in the Cox proportional hazards regression model (Supplementary Table). This phenomenon is the opposite in women. That is, the log-rank test showed a significant association, but the result from the fully adjusted Cox proportional hazards regression model showed non-significance. This might be explained by the different age distribution over TyG index by sex. As the TyG quartile increases, the mean age decreases in men but increases in women. Because the log-rank test does not take any confounding factors into account, the significance in women might include the compounded effect of age and TyG index. An investigation into the conflicting relationship between age and the TyG index by sex is worthwhile. However, the elevated TyG index increased CVDs in both sexes, while it was not independently associated with individual events such as CbVDs, CCVD-related deaths, and all-cause deaths. These findings signify that the TyG index may be a good indicator in predicting CVDs such as ischemic heart diseases. Results from this study are consistent with a previous study by Park et. al. who reported that an elevated TyG index forecasted the risk of ischemic heart disease in Korean population [24]. Zhao et al. reported that the TyG index is an independent marker for cardiovascular events [25]. However, these studies have a smaller population size and did not stratify the study population according to sex. Our study supports the previous studies but more clearly clarifies the association between the TyG index and individual events. The TyG index was significantly associated with the primary outcomes (CCVDs and all-cause mortality) in men, but not in women. However, further statistical analyses demonstrated that an elevated TyG index was an independent indicator of CVD development in both sexes while there was a null association between TyG index and other outcomes (CbVDs, CCVD-related death, and all-cause death).
This study has several strengths to distinguish it from previous studies. First, the NHIS-HEALS cohort represents the entire Korean adult population. The NHIS provides reliable information on individual medical history (diagnostic code, laboratory results from national health screening program, lifestyle factors, anthropometric data, and death information based on a death certificate) and socioeconomic data (based on insurance premiums and self-reported questionnaires). The data from the NHIS-HEALS cohort were based on real-world measurements in a clinical setting. The real-world data showed the true relationship reflecting many variables and environments that we did not expect. Second, an apparently healthy population aged 40 years or older who received a national health screening examination was enrolled in this study, while patients who were diagnosed with diabetes, cancers, or CCVDs were excluded from the analysis. In addition, to control the effects of medications, such as glucose-lowering and lipid-lowering drugs, individuals who had taken these drugs between 2002 and 2010 were excluded. However, individuals treated with these drugs after 2010 were not excluded in the final analyses because the aim of this study was to investigate the association between the initial TyG index and CCVDs or all-cause mortality regardless of medication during the follow-up period. In other words, we just tried to examine whether the elevated TyG index at baseline increases the CCVDs and all-cause mortality. These strict exclusion criteria may minimize the effects of underlying conditions on the primary outcome. Despite strict exclusion, many subjects (144,000 or more) were included in the final analyses. Third, the follow-up duration (median 5.97 years) was relatively long. In the case of apparently healthy individuals, large population size and longer study duration allowed a more accurate relationship to be explored than those from previous studies. Fourth, we widely examined the outcomes, which were related to the TyG index. The primary outcomes were stratified to several individual outcomes and sequentially investigated the relationships between them and the TyG index. In addition, many conventional risk factors including health behaviors, SBP, LDL-C, and economic status for CCVDs were adjusted in the Cox proportional hazards regression models. This conservative approach provides a reliable association between the TyG index and outcomes to minimize the function of these conventional risk factors as confounders.
There are several limitations that should be interpreted cautiously. We could not validate whether the TyG index directly correlated with insulin resistance because the NHIS-HEALS cohort did not contain information on serum insulin levels. However, the TyG index was already validated to indicate insulin resistance in previous studies [26, 27]. The outcomes such as CVDs, CbVDs, and CCVD-related deaths were not directly collected by our research team. There is the possibility of misclassification or a different definition of outcome events. The Korean health insurance system is uniquely different from other countries because all Koreans should subscribe to the NHIS and the Korean government collects and controls health information, insurance claim information, and reimbursement. For example, the NHIS assesses the coverage of insurance and determines the cost of the individual medical service, while Health Insurance Review and Assessment Service (HIRAS), another national agency, reviews the claim data and reimburses the hospital fees. Special diseases such as CCVDs, cancers, and rare diseases are more strictly monitored by these two national agencies because patients with special diseases pay 5% of their hospital fee and the NHIS pays the remaining medical cost. These strict monitoring systems minimize inaccurate diagnosis. In addition, to minimize the misclassification, we more conservatively defined the CCVDs. CCVDs were defined when the relevant diagnostic codes (I20-I25 or I60-I69) as the main diagnostic code were recorded more than once at hospitalization or at least twice at the outpatient visit. Even if there are misclassifications, we believe that there would be very few.
In conclusion, men with an elevated TyG index were at higher risk for CCVDs or all-cause mortality. Individuals with a higher TyG index were more likely to develop CVDs in both sexes while the TyG index was not significantly associated with CbVDs, CCVD-related death, and all-cause death.