Original Research Received: October 3, 2014 Accepted after revision: February 13, 2015 Published online: May 12, 2015
Cardiology 2015;131:228–235 DOI: 10.1159/000380941
Serum Triglyceride Levels and Cardiovascular Disease Events in Koreans Eun Hee Kim a Jung Bok Lee b Seon Ha Kim c Min-Woo Jo c Jenie Yoonoo Hwang a Sung Jin Bae a Chang Hee Jung d Woo Je Lee d Joong-Yeol Park d Gyung-Min Park f Young-Hak Kim e Hong-Kyu Kim a Jaewon Choe a
a
Health Screening and Promotion Center, b Department of Clinical Epidemiology and Biostatistics, c Department of Preventive Medicine, d Division of Endocrinology and Metabolism, and e Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, and f Division of Cardiology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, Daejeon, Korea
For editorial comment see p. 225
Abstract Objectives: Hypercholesterolemia, especially elevated levels of LDL-cholesterol, is a well-known risk factor for cardiovascular disease (CVD). However, the role of triglycerides in CVD risk remains controversial. Methods: We enrolled 86,476 individuals who had undergone a general health checkup at Asan Medical Center between January 2007 and June 2011. After exclusion criteria were applied to the total cohort, 76,434 participants were included. CVD events and death were gathered from the nationwide health insurance claims database and death certificates using ICD-10 codes. Results: Age- and sex-adjusted odds ratios (ORs) of the higher triglyceride group were significantly increased: 1.52 (95% CI: 1.27– 1.82) for major CVD events, 1.53 (95% CI: 1.24–1.88) for major ischemic heart disease events, and 1.49 (95% CI: 1.37–1.63) for overall CVD events. After adjustment for multiple risk factors including HDL-cholesterol, ORs for overall CVD events were significantly increased in the higher triglyceride group. When the analysis was stratified according to BMI, hypertension, and glycemic status at baseline, age- and sex-adjusted ORs for the outcomes were significantly increased in the
© 2015 S. Karger AG, Basel 0008–6312/15/1314–0228$39.50/0 E-Mail [email protected] www.karger.com/crd
higher triglyceride group with nonobese, normotensive, or nondiabetic subjects. Conclusions: Hypertriglyceridemia is independently associated with an increased risk for CVD, especially in nonobese, normotensive, or nondiabetic individuals. © 2015 S. Karger AG, Basel
Introduction
Cardiovascular disease (CVD) is one of the leading worldwide causes of death and disability [1]. Hypertension, diabetes mellitus, smoking, and dyslipidemia are well-established major risk factors for CVD [2]. After the introduction of statins, treatment for dyslipidemia focused on LDL-cholesterol as the primary lipid target [3]. However, a residual risk remains despite achieving LDLcholesterol targets by statin therapy [4, 5]. The residual risk is mainly due to low HDL-cholesterol and elevated triglycerides [4, 5]. Triglyceride has long been relatively underestimated compared with LDL- and HDL-cholesterol. With a growing population with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of hypertriglyceridemia has increased and become a major concern [6]. Triglyceride is now getting attention as a risk factor for CVD or mediator of atherosclerosis. Hong-Kyu Kim, MD, PhD Health Screening and Promotion Center Asan Medical Center, 388-1 Poongnap-dong Songpa-gu, Seoul 138-736 (Korea) E-Mail hkkim0801 @ amc.seoul.kr
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 6:20:38 AM
Key Words Triglyceride · Cardiovascular disease · Ischemic heart disease
Methods Study Population We enrolled 114,698 individuals who had undergone a general health examination in the Health Screening and Promotion Center at Asan Medical Center, Seoul, Korea, between January 2007 and June 2011. Of these individuals, 86,476 subjects (85%) consented to participate in our study. Information on medication, previous medical or surgical diseases, family history of CVD in first-degree relatives, and smoking and drinking habits were obtained from each subject using a standard questionnaire. Drinking habits were categorized as never and rarely or more than two times a week. Smoking habits were categorized as never and previous or current. We excluded 10,042 subjects with a previous history of CVD before the index day in the Health Insurance Review and Assessment Service (HIRA) database (codes I00–99 in the International Classification of Diseases, 10th Revision) or whose data were not available in the HIRA database. Subjects who had angina, myocardial infarction (MI), stroke, or malignancy based on the questionnaire and subjects under 20 years of age were also excluded. As a result, a total of 76,434 subjects were finally enrolled (fig. 1). Hypertriglyceridemia is a common form of dyslipidemia that is frequently seen in clinical practice. Blood samples for measurements of triglyceride levels are usually obtained in the fasting state and current classifications define triglyceride levels as normal when they are below 150 mg/dl, borderline high from 150 to 199 mg/dl, high from 200 to 499 mg/dl, and very high when these levels are higher than 500 mg/dl after a 12-hour fast [22]. Thus, we divided the participants into two groups by using a cutoff value of 150 mg/dl and tested the associations of triglyceride levels with
Triglyceride and CVD
Fig. 1. Study population.
incident CVD events in a large Korean population who were free of CVD at baseline. This study was approved by the Institutional Review Board of Asan Medical Center. Measurements Height and weight were measured by trained nurses with subjects wearing light clothing without shoes. BMI was calculated as weight in kilograms divided by the square of height in meters. Waist circumference (cm) was measured at the midway point between the inferior margin of the last rib and the superior iliac crest in a horizontal plane. Blood pressure was measured with an electronic sphygmomanometer on the right arm with subjects in a sitting position after a 5-min rest. Blood samples were collected in the morning after an overnight fast of at least 12 h. Fasting triglyceride, total cholesterol, LDL-cholesterol, and HDL-cholesterol levels were measured using an autoanalyzer (Toshiba, Tokyo, Japan). Fasting glucose was measured by the hexokinase method using an autoanalyzer (Toshiba). Serum insulin concentrations were obtained via an immunoradiometric assay (TFB, Tokyo, Japan). The homeostasis model assessment of insulin resistance (HOMA-IR), an index of insulin resistance, was calculated as fasting plasma glucose (mg/dl) multiplied by fasting insulin (μIU/ml) divided by 405. Outcomes The overall CVD event was defined as a composite of cardiovascular death, MI, stroke (hemorrhagic and ischemic), coronary revascularization, and hospitalization and outpatient visit due to ischemic heart disease (IHD), other vascular disease, or congestive heart failure. Cardiovascular death, MI, revascularization, and hospitalization with IHD were classified as major IHD events. A major CVD event was also defined as a composite of cardiovascular death, MI, stroke (hemorrhagic and ischemic), coronary revascularization. In subjects with multiple events, the first event was considered to be the component of the composite outcome. Deaths up to December 31, 2011 were confirmed by matching the information to the death records. For this process, death certificates in the National Statistical Office were identified using personal identification numbers that were assigned to the subjects at birth. The abstractors coded the causes of death according to the
Cardiology 2015;131:228–235 DOI: 10.1159/000380941
229
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 6:20:38 AM
Although an association exists between triglyceride levels and CVD or death and elevated triglyceride levels have been shown to be an independent risk factor for CVD in previous studies [7–14], this relationship is attenuated or nonsignificant after adjustment for major CVD risk factors [15–17]. The independent relationship between triglycerides and risk of CVD has long been debated. Because of this, different guidelines, for example ESC/EAS guidelines for the management of dyslipidemias as well as European guidelines on CVD prevention in clinical practice (version 2012), do not recommend any specific target value for triglyceride levels [18, 19]. Most studies of triglyceride levels and risk of CVD have examined populations that are composed largely or entirely of Western participants [7–12, 15–17, 20, 21] and there have been few Asian population studies [13, 14]. Several studies have analyzed the risk of CVD and triglyceride levels stratified for age at study entry, hypertension, BMI, drinking status, and diabetes status [8, 9, 14]. We thus wished to determine if hypertriglyceridemia is associated with increased CVD risk and also which patients with various metabolic conditions show an independent association between hypertriglyceridemia and CVD in Koreans.
eride level
Subjects, n Female, n (%) Age, years Smoking Current smoker Ex-smoker Alcohol ≥2/week Exercise ≥3–5/week BMI, kg/m2 Waist circumference, cm Hypertension SBP, mm Hg DBP, mm Hg Type 2 diabetes mellitus Family history of CVD Total cholesterol, mg/dl HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl Triglyceride, mg/dl Fasting glucose, mg/dl HbA1c HOMA-IR
TG
Cardiology 2015;131:228–235 DOI: 10.1159/000380941
Serum Triglyceride Levels and Cardiovascular Disease Events in Koreans Eun Hee Kim a Jung Bok Lee b Seon Ha Kim c Min-Woo Jo c Jenie Yoonoo Hwang a Sung Jin Bae a Chang Hee Jung d Woo Je Lee d Joong-Yeol Park d Gyung-Min Park f Young-Hak Kim e Hong-Kyu Kim a Jaewon Choe a
a
Health Screening and Promotion Center, b Department of Clinical Epidemiology and Biostatistics, c Department of Preventive Medicine, d Division of Endocrinology and Metabolism, and e Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, and f Division of Cardiology, Department of Internal Medicine, Daejeon St. Mary’s Hospital, Daejeon, Korea
For editorial comment see p. 225
Abstract Objectives: Hypercholesterolemia, especially elevated levels of LDL-cholesterol, is a well-known risk factor for cardiovascular disease (CVD). However, the role of triglycerides in CVD risk remains controversial. Methods: We enrolled 86,476 individuals who had undergone a general health checkup at Asan Medical Center between January 2007 and June 2011. After exclusion criteria were applied to the total cohort, 76,434 participants were included. CVD events and death were gathered from the nationwide health insurance claims database and death certificates using ICD-10 codes. Results: Age- and sex-adjusted odds ratios (ORs) of the higher triglyceride group were significantly increased: 1.52 (95% CI: 1.27– 1.82) for major CVD events, 1.53 (95% CI: 1.24–1.88) for major ischemic heart disease events, and 1.49 (95% CI: 1.37–1.63) for overall CVD events. After adjustment for multiple risk factors including HDL-cholesterol, ORs for overall CVD events were significantly increased in the higher triglyceride group. When the analysis was stratified according to BMI, hypertension, and glycemic status at baseline, age- and sex-adjusted ORs for the outcomes were significantly increased in the
© 2015 S. Karger AG, Basel 0008–6312/15/1314–0228$39.50/0 E-Mail [email protected] www.karger.com/crd
higher triglyceride group with nonobese, normotensive, or nondiabetic subjects. Conclusions: Hypertriglyceridemia is independently associated with an increased risk for CVD, especially in nonobese, normotensive, or nondiabetic individuals. © 2015 S. Karger AG, Basel
Introduction
Cardiovascular disease (CVD) is one of the leading worldwide causes of death and disability [1]. Hypertension, diabetes mellitus, smoking, and dyslipidemia are well-established major risk factors for CVD [2]. After the introduction of statins, treatment for dyslipidemia focused on LDL-cholesterol as the primary lipid target [3]. However, a residual risk remains despite achieving LDLcholesterol targets by statin therapy [4, 5]. The residual risk is mainly due to low HDL-cholesterol and elevated triglycerides [4, 5]. Triglyceride has long been relatively underestimated compared with LDL- and HDL-cholesterol. With a growing population with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of hypertriglyceridemia has increased and become a major concern [6]. Triglyceride is now getting attention as a risk factor for CVD or mediator of atherosclerosis. Hong-Kyu Kim, MD, PhD Health Screening and Promotion Center Asan Medical Center, 388-1 Poongnap-dong Songpa-gu, Seoul 138-736 (Korea) E-Mail hkkim0801 @ amc.seoul.kr
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 6:20:38 AM
Key Words Triglyceride · Cardiovascular disease · Ischemic heart disease
Methods Study Population We enrolled 114,698 individuals who had undergone a general health examination in the Health Screening and Promotion Center at Asan Medical Center, Seoul, Korea, between January 2007 and June 2011. Of these individuals, 86,476 subjects (85%) consented to participate in our study. Information on medication, previous medical or surgical diseases, family history of CVD in first-degree relatives, and smoking and drinking habits were obtained from each subject using a standard questionnaire. Drinking habits were categorized as never and rarely or more than two times a week. Smoking habits were categorized as never and previous or current. We excluded 10,042 subjects with a previous history of CVD before the index day in the Health Insurance Review and Assessment Service (HIRA) database (codes I00–99 in the International Classification of Diseases, 10th Revision) or whose data were not available in the HIRA database. Subjects who had angina, myocardial infarction (MI), stroke, or malignancy based on the questionnaire and subjects under 20 years of age were also excluded. As a result, a total of 76,434 subjects were finally enrolled (fig. 1). Hypertriglyceridemia is a common form of dyslipidemia that is frequently seen in clinical practice. Blood samples for measurements of triglyceride levels are usually obtained in the fasting state and current classifications define triglyceride levels as normal when they are below 150 mg/dl, borderline high from 150 to 199 mg/dl, high from 200 to 499 mg/dl, and very high when these levels are higher than 500 mg/dl after a 12-hour fast [22]. Thus, we divided the participants into two groups by using a cutoff value of 150 mg/dl and tested the associations of triglyceride levels with
Triglyceride and CVD
Fig. 1. Study population.
incident CVD events in a large Korean population who were free of CVD at baseline. This study was approved by the Institutional Review Board of Asan Medical Center. Measurements Height and weight were measured by trained nurses with subjects wearing light clothing without shoes. BMI was calculated as weight in kilograms divided by the square of height in meters. Waist circumference (cm) was measured at the midway point between the inferior margin of the last rib and the superior iliac crest in a horizontal plane. Blood pressure was measured with an electronic sphygmomanometer on the right arm with subjects in a sitting position after a 5-min rest. Blood samples were collected in the morning after an overnight fast of at least 12 h. Fasting triglyceride, total cholesterol, LDL-cholesterol, and HDL-cholesterol levels were measured using an autoanalyzer (Toshiba, Tokyo, Japan). Fasting glucose was measured by the hexokinase method using an autoanalyzer (Toshiba). Serum insulin concentrations were obtained via an immunoradiometric assay (TFB, Tokyo, Japan). The homeostasis model assessment of insulin resistance (HOMA-IR), an index of insulin resistance, was calculated as fasting plasma glucose (mg/dl) multiplied by fasting insulin (μIU/ml) divided by 405. Outcomes The overall CVD event was defined as a composite of cardiovascular death, MI, stroke (hemorrhagic and ischemic), coronary revascularization, and hospitalization and outpatient visit due to ischemic heart disease (IHD), other vascular disease, or congestive heart failure. Cardiovascular death, MI, revascularization, and hospitalization with IHD were classified as major IHD events. A major CVD event was also defined as a composite of cardiovascular death, MI, stroke (hemorrhagic and ischemic), coronary revascularization. In subjects with multiple events, the first event was considered to be the component of the composite outcome. Deaths up to December 31, 2011 were confirmed by matching the information to the death records. For this process, death certificates in the National Statistical Office were identified using personal identification numbers that were assigned to the subjects at birth. The abstractors coded the causes of death according to the
Cardiology 2015;131:228–235 DOI: 10.1159/000380941
229
Downloaded by: University of Pittsburgh 198.143.32.65 - 1/27/2016 6:20:38 AM
Although an association exists between triglyceride levels and CVD or death and elevated triglyceride levels have been shown to be an independent risk factor for CVD in previous studies [7–14], this relationship is attenuated or nonsignificant after adjustment for major CVD risk factors [15–17]. The independent relationship between triglycerides and risk of CVD has long been debated. Because of this, different guidelines, for example ESC/EAS guidelines for the management of dyslipidemias as well as European guidelines on CVD prevention in clinical practice (version 2012), do not recommend any specific target value for triglyceride levels [18, 19]. Most studies of triglyceride levels and risk of CVD have examined populations that are composed largely or entirely of Western participants [7–12, 15–17, 20, 21] and there have been few Asian population studies [13, 14]. Several studies have analyzed the risk of CVD and triglyceride levels stratified for age at study entry, hypertension, BMI, drinking status, and diabetes status [8, 9, 14]. We thus wished to determine if hypertriglyceridemia is associated with increased CVD risk and also which patients with various metabolic conditions show an independent association between hypertriglyceridemia and CVD in Koreans.
eride level
Subjects, n Female, n (%) Age, years Smoking Current smoker Ex-smoker Alcohol ≥2/week Exercise ≥3–5/week BMI, kg/m2 Waist circumference, cm Hypertension SBP, mm Hg DBP, mm Hg Type 2 diabetes mellitus Family history of CVD Total cholesterol, mg/dl HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl Triglyceride, mg/dl Fasting glucose, mg/dl HbA1c HOMA-IR
TG
