Triglyceride to HDL-Cholesterol Ratio and the Incident Risk of Ischemic Heart Disease Among Koreans Without Diabetes: A Prospective Study Using National Health Insurance Data


 Background

Early insulin resistance without diabetes can cause cardiovascular disease, which is a public health challenge. This study aimed to investigate the longitudinal effects of the triglyceride to high-density lipid (HDL)-cholesterol ratio (TG/HDL-C), which could reflect insulin resistance from the beginning, on the incident risk of ischemic heart disease (IHD).
Methods

We assessed 16,455 individuals (8,426 men and 8,029 women) without diabetes in a community-dwelling Korean cohort using National Health Insurance data. Participants were classified based on the TG/HDL-C quartiles. Using multivariate Cox proportional-hazards regression models, we prospectively examined the hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD over 50 months after baseline enrolment.
Results

During the follow-up period, 321 (2.0%) participants developed IHD. After adjusting for potential confounding variables, the HRs of IHD for TG/HDL-C quartiles were 1.00, 1.61 (95% CI, 1.05–2.48), 1.85 (95% CI, 1.21–2.81), and 2.29 (95% CI, 1.50–3.51), respectively. Compared with men, women showed higher HRs for the risk of incident IHD in the fourth quartile [HR (95% CI) = 2.98 [1.50–5.88] and 1.80 [1.02–3.17], respectively). Compared with metabolic syndrome, TG/HDL-C had a more powerful predictive value for IHD.
Conclusions

In Koreans without diabetes, an increased TG/HDL-C precedes future IHD. Additionally, sex differences may merit serious consideration when interpreting TG/HDL-C for assessing cardiovascular risks in clinical practice.


Conclusions
In Koreans without diabetes, an increased TG/HDL-C precedes future IHD. Additionally, sex differences may merit serious consideration when interpreting TG/HDL-C for assessing cardiovascular risks in clinical practice.

Background
Ischemic heart disease (IHD) is a signi cant challenge among middle-aged individuals without diabetes.
From an epidemiological perspective, patients without diabetes who have IHD can have a poorer prognosis than patients with diabetes [1][2][3]. There may be a signi cant decline in insulin sensitivity over approximately 5 years as a natural course of β-cell function, even among individuals with normal glucose tolerance or in a pre-diabetic state [4]. Additionally, coronary heart disease can begin in early-stage insulin resistance [5], which may be overlooked in clinical settings. Therefore, management of IHD risk factors in the preclinical stage is important from a public health perspective, which facilitates disease prevention and delays IHD progression.
Individuals with early insulin resistance often have increased and decreased triglyceride (TG) and highdensity lipoprotein cholesterol (HDL-C) levels, respectively [6]. Epidemiological studies have reported the predictive utility of the TG to HDL-C ratio (TG/HDL-C) for type 2 diabetes, which suggests that it is a simple and more accessible marker of insulin resistance from onset compared with homeostasis model assessment of insulin resistance or hyperinsulinemic-euglycemic clamp testing [7,8]. Furthermore, TG/HDL-C is closely associated with small dense low-density lipoprotein cholesterol (LDL-C) levels, which have atherogenic properties [9,10].
A recent study reported that a higher TG/HDL-C ratio is associated with the subclinical burden of coronary atherosclerosis [11]. Previous prospective studies have primarily focused on cardiovascular mortality or individuals with some cardiovascular risks [12][13][14][15]. Additionally, sex differences in these relationships remain unclear. This prospective study aimed to investigate the relationship between the TG/HDL-C ratio and incident IHD in a large-scale, community-dwelling, Korean cohort without diabetes, using National Health Insurance Service data.

Study population
This study is a derivative of the Health Risk Assessment Study (HERAS), which was designed to identify and explore surrogate indicators for cardiometabolic diseases among Korean adults. The HERAS cohort is comprised of 20,530 participants who sequentially visited the Health Promotion Center, Yonsei University Gangnam Severance Hospital, for health examination between November 1, 2006, and June 8, 2010. Among the participants identi ed at baseline, we excluded 1,590 individuals previously diagnosed with angina pectoris, myocardial infarction, ischemic stroke, diabetes mellitus, or newly developed type 2 diabetes (de ned as a fasting plasma glucose level ≥ 126 mg/dL). Additionally, we excluded participants according to the following criteria: aged < 30 years, current use of dyslipidemia medication or aspirin, and high-sensitivity C-reactive protein (hsCRP) level ≥ 10 mg/L (n = 2,485). Consequently, 16,455 individuals were included in the nal analysis (Fig. 1).

Data collection
Each participant completed a lifestyle behavior and medical history questionnaire, which included information regarding cigarette smoking, alcohol intake, and physical activity. Smoking status was de ned using the following categories: non-smoker, ex-smoker, and current smoker. Regular alcohol intake was de ned as an alcohol consumption rate of ≥ 140 g/week. Regular exercise was de ned as moderate physical activity ≥ thrice per week. Bodyweight and height were measured to the nearest 0.1 kg and 0.1 cm, respectively, in light indoor clothing without footwear. The body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters (kg/m 2 ). Systolic and diastolic blood pressures were measured on the patient's right arm using a standard mercury sphygmomanometer in the sitting position after 10 min of rest (Baumanometer, W.A. Baum Co., Inc., Copiague, NY, USA). The mean arterial pressure was calculated from the systolic and diastolic blood pressures and weighted as 1/3 systolic and 2/3 diastolic blood pressure [16]. Blood samples were obtained from the antecubital vein after overnight 12-h fasting. Fasting plasma glucose, total cholesterol, triglyceride, and HDL-C levels were measured through enzymatic methods using a Hitachi 7600 automated chemistry analyzer (Hitachi Co., Tokyo, Japan). Serum hsCRP levels were measured with a Roche/Hitachi 912 System using a latex-enhanced immunoturbidimetric method (Roche Diagnostics, Indianapolis, IN, USA). Hypertension was de ned as a systolic and diastolic blood pressure ≥ 140 mmHg and ≥ 90 mmHg, respectively, or current hypertension medication use [17]. Impaired fasting glucose was de ned as a fasting plasma glucose level of 100-126 mg/dL [18]. Metabolic syndrome was de ned using the modi ed National Cholesterol Education Program Adult Treatment Panel III. Since we did not measure the waist circumference, obesity was de ned as BMI ≥ 25 kg/m 2 , as suggested by the position statement of the American College of Endocrinology [19]. Metabolic syndrome was de ned as the presence of ≥ 3 of the following risk factors: obesity with BMI ≥ 25.0 kg/m 2 , elevated systolic blood pressure ≥ 130 mmHg, elevated diastolic blood pressure ≥ 85 mmHg, or using an antihypertensive medication; high fasting plasma glucose levels ≥ 100 mg/dL or using diabetes medication; triglyceride levels ≥ 150 mg/dL; and HDL cholesterol levels < 40 mg/dL and < 50 mg/dL for men and women, respectively. TG/HDL-C was calculated as TG (mg/dL) divided by HDL-C level (mg/dL). TG/HDL-C values were categorized into quartiles as follows: Q1 (≤ 1.25), Q2 (1.26-1.98), Q3 (1.99-3.24), and Q4 (≥ 3.25).

Outcomes
The primary outcome was IHD, which comprised of angina pectoris (ICD-10 code I20) or acute myocardial infarction (ICD-10 code I21) occurring after study enrolment. To de ne baseline and post-survey outcomes, we linked a personal 13-digit identi cation number for each participant that was assigned using the Health Insurance Review and Assessment Data (HIRA) in Korea, which is a repository of claims data collected while reimbursing healthcare providers, from November 1, 2006, to December 31, 2010. We excluded participants with angina pectoris, myocardial infarction, or ischemic stroke (ICD-10 codes I20, I21, and I63, respectively) at baseline.

Statistical analysis
Baseline characteristics were compared among the TG/HDL-C quartiles using analysis of variance (ANOVA) and the chi-squared test for continuous and categorical variables, respectively. Moreover, we performed sex-based comparisons of the clinical and biochemical characteristics using independent twosample t-tests and a chi-square test. Kaplan-Meier curves were used to assess the cumulative incidence of IHD. The log-rank test was used for among-group comparisons of the distribution of the cumulative IHD incidence. In multivariate analysis, after setting the lowest TG/HDL-C quartile as a reference group, the hazard ratios (HRs) and 95% con dence intervals (CIs) for incident IHD were calculated using the Cox proportional hazards regression model after adjusting for potential confounding variables. Pairwise comparisons of receiver-operating characteristic (ROC) curves were used to compare the areas under ROC curves (AUC) for IHD incidence based on TG/HDL-C, presence of metabolic syndrome, and the number of metabolic syndrome components. Furthermore, we used AUC values to test the sensitivity and speci city of the biomarkers for predicting IHD. All statistical analyses were performed using SAS version 9.4 software (; SAS Institute Inc., Cary, NC, USA) and all statistical tests were two-sided. Statistical signi cance was set at p < 0.05.

Results
Baseline characteristics of the study population Table 1 shows the baseline characteristics of the study population (n = 16,455; 8,426 men and 8,029 women) based on the TG/HDL-C quartiles. The mean age, BMI, TG levels, HDL-C levels, and TG/HDL-C were 46.1 ± 9.5 years, 23.4 ± 3.0 kg/m 2 , 124.2 ± 84.9 mg/dl, 53.2 ± 12.6 mg/dl, and 2.64 ± 2.42 mg/dl, respectively. The group with the highest TG/HDL-C quartile showed the highest mean values of BMI, mean arterial pressure, fasting plasma glucose, total cholesterol, and hsCRP levels, as well as the lowest mean HDL-C levels. Moreover, this group showed the highest proportions of current smokers and alcohol drinkers, as well as the lowest proportion of individuals involved in regular exercise. The prevalence of hypertension, impaired fasting glucose, and metabolic syndrome were 20.3%, 18.0%, and 12.1%, respectively, which gradually increased according to TG/HDL-C quartiles. There was no sex difference in the age distribution; however, men showed a higher TG/HDL-C than women (3.33 ± 2.91 vs 1.91 ± 1.44; Table 2). Cumulative ischemic heart disease incidence During the follow-up period, 321 (2.0%, 321/16,455) individuals developed IHD. The IHD incidence rate (per 1000 person-years) was positively correlated with the TG/HDL-C quartiles. The higher TG/HDL-C groups showed a signi cantly increased cumulative IHD incidence over 50 months following the baseline survey (log-rank test, P < 0.001) (Fig. 2).
Hazard ratios for incident ischemic heart diseases  Fig. 3). Model 2: adjusted for age, sex, body mass index, smoking status, alcohol intake, physical activity, mean arterial blood pressure, fasting plasma glucose, and high sensitivity C-reactive protein.
Model 3: adjusted for age, sex, body mass index, smoking status, alcohol intake, physical activity, mean arterial blood pressure, fasting plasma glucose, high sensitivity C-reactive protein, and hypertension medication.
Pairwise comparison with metabolic syndrome parameters Pairwise comparison of receiver operating characteristic (ROC) analysis for incident IHD revealed that the AUC of TG/HDL-C was signi cantly higher than that of metabolic syndrome (P < 0.001), which was similar to that of the number of metabolic syndrome components (P = 0.929). In the longitudinal model, the AUC, sensitivity, and speci city of TG/HDL-C were 0.607, 64.2%, and 52.1%, respectively (Table 4).

Discussion
This large-scale cohort study on community-dwelling Koreans without diabetes over a 50-month period found that higher TG/HDL-C values were associated with IHD incidence, which remained after adjustment for lifestyle factors, in ammation, and hypertension medication. Moreover, compared with metabolic syndrome, TG/HDL-C had a more powerful predictive value for IHD.
The association between TG/HDL-C and incident IHD was more prominent in women than in men. Additionally, the HRs of incident IHD in women signi cantly increased according to the TG/HDL-C quartiles; contrastingly, those in men did not exhibit signi cant trends. Cheng et al. conducted a prospective study on 11,946 Chinese individuals without diabetes found that the risk for type 2 diabetes increased by approximately 30% with 1-unit of the TG/HDL-C increment [8]. Moreover, they observed a clearer dose-response relationship in women than in men. Regarding cardiovascular disease (CVD), studies conducted in men and women separately have established this relationship. Hadaegh et al.
showed that Iranian men in the highest TG/HDL-C quartile had a 1.75-fold higher risk of coronary heart disease over a median follow-up period of 6.5 years compared with the reference low quartile [20]. Another longitudinal study conducted by Bittner et al. reported a positive relationship between the TG/HDL-C and suspected CVD mortality in 554 US women over a median period of 6 years [15]. The former and latter studies on men and women, respectively, reported a fourth quartile cut point of 6.9 and 2.8, respectively. Recent studies on TG/HDL-C have reported that it is associated with long-term mortality in high-risk individuals who have undergone percutaneous coronary angiography [21], as well as the relevance of subclinical coronary arterial calci cation in low-risk individuals without diabetes [11].
However, these studies did not address sex differences. Another study reported that TG/HDL-C, but not the LDL-C to HDL-C ratio, in women has a signi cant predictive value for CVD in a population-based cross-sectional study, unlike in men [22]. Therefore, it may be advantageous for assessing and managing TG/HDL-C differently in men and women.
There was a noticeable increase and decrease in TG and HDL-C, respectively, with insulin resistance progression; moreover, the TG/HDL-c ratio is useful for assessing early insulin resistance [6,23]. High TG and low HDL-C are the two most common lipid abnormalities among Korean adults aged > 20 years, with a prevalence of approximately 28.7% and 41.2%, respectively [24]. The Korea National Health and Nutrition Examination Survey indicated an increase in both high TG and low HDL-C by > 30% in 2010 compared with 2007. In the United States, approximately 30% and 40% of adult men /women in their 20s and 30s, respectively, have high TG and/or low HDL-C [25]. Individuals with insulin resistance are more susceptible to atherosclerosis; moreover, coronary arterial disease can develop and progress from early insulin resistance [5,26]. The atherogenic link between TG/HDL-C and IHD, besides insulin resistance, is associated with the generation of small, dense LDL particles, which can cause vascular compromise [9,27]. The NCEP guidelines for metabolic syndrome indicate well-established sex differences in the HDL-C level [28]. In the same context, the TG/HDL-C ratio was signi cantly higher in men; however, its association with IHD was more pronounced in women.
A major strength of our study was that this was a longitudinal large-scale study linked to HIRA data, which are based on the universal coverage system in Korea. This decreases the chance of missing data.
This study has several limitations. First, given that the study cohort comprised volunteers for health promotion screenings conducted at a single hospital, the participants could have been slightly healthier than the general Korean population. Moreover, some confounding variables, including dietary data, may have not been initially assessed. Second, some individuals with diabetes may have been included in the nal analysis since hemoglobin A1c assessment and oral glucose tolerance tests were not performed at the beginning of the study. Figure 1 Flowchart for the selection of study participants.

Figure 2
Kaplan-Meier plots indicating the cumulative probability of being diagnosed with ischemic heart disease after the baseline survey.