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Prevalence of metabolic syndrome and cardiovascular disease in a hypertriglyceridemic population
European Journal of Internal Medicine 22 (2011) 177–181
Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Original article
Prevalence of metabolic syndrome and cardiovascular disease in a hypertriglyceridemic population Juan F. Ascaso a,⁎, Jesús Millán b, Rocio Mateo-Gallego c, Antonio Ruiz d, M. Suarez-Tembra e, Rosa M. Borrallo f, Daniel Zambon g, Pedro Gonzalez-Santos h, Miguel Peres-de-Juan i, Emili Ros g and On behalf of the Hypertriglyceridemia Registry of the Spanish Arteriosclerosis Society a
Clinic-University Hospital, University of Valencia, Spain University Hospital Gregorio Marañon, Madrid, Spain c Miguel Servet Hospital, Zaragoza, Spain d CS Pinto, Madrid, Spain e San Rafael Hospital, Madrid, Spain f Terrasa Hospital, Terrasa, Spain g Clinic Hospital, Barcelona, Barcelona, Spain h Clinic Hospital, Málaga, Spain i Santa Maria Nai Hospital, Ourense, Spain b
a r t i c l e
i n f o
Article history: Received 26 July 2010 Received in revised form 14 December 2010 Accepted 16 December 2010 Available online 14 January 2011 Keywords: Hypertriglyceridemia Metabolic syndrome Diabetes Cardiovascular disease
a b s t r a c t Background: We aim to study the prevalence of metabolic syndrome (MS), hypertension and diabetes, and their relationship to cardiovascular disease in subjects with hypertriglyceridemia. Methods: This is an observational cross-sectional study, uncontrolled and multicentre study. Selected subjects were patients with hypertriglyceridemia (triglycerides, TG, ≥ 200 mg/dl) visited in the Lipid Units of the Spanish Arteriosclerosis Society who met the inclusion criteria. Prevalence of MS (ATPIII and IDF criteria, MS-ATPIII or MS-IDF), hypertension and diabetes were studied. The presence of cardiovascular disease (CVD) was also determined. Results: The results showed that individuals referred for hypertriglyceridemia had a high prevalence of MS-ATPIII 79.6% and MS-IDF 75.2%. The prevalence of MS was independent of plasma triglyceride levels. The prevalence of hypertension and diabetes were 50.9% and 33.5%, respectively. The prevalence of diabetes was double than in the general population. The prevalence of CVD was 14.6%. 95.9% of CVD events were found in patients with MS-ATPIII and only 4.1% in the group without MS-ATPIII, significant differences. Conclusions: Hypertriglyceridemia is associated to the metabolic syndrome and diabetes, as well as the risk of CVD, independently of the levels of triglycerides. Hypertriglyceridemia may be an important marker in the screening of these severe metabolic and vascular abnormalities. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Hypertriglyceridemias are metabolic diseases characterized by increasing levels of very-low density lipoproteins (VLDL), chylomicrons or remnant particles of both. Its wide aetiology is a clear example of the interaction of genetic and external factors [1–3]. Hypertriglyceridemias are often associated with prevalent diseases, such as obesity, hypertension, diabetes mellitus, alcohol intake and metabolic syndrome. Metabolic Syndrome is characterized by the association of metabolic and vascular abnormalities that can be progressively shown in patients who are overweight and have insulin-resistance. Hypertriglyceridemia is the most frequent and ⁎ Corresponding author. Department of Medicine, University of Valencia, Blasco Ibanez 15, 46010, Valencia, Spain. Tel.: +34 963862665; fax: +34 963864767. E-mail address: [email protected] (J.F. Ascaso).
earliest alteration in the MS and it is due to the increase in the hepatic synthesis of VLDL, along with an alteration in its catabolism due to a decrease in the activity of lipoprotein lipase. This also leads to a decrease in the catabolism of chylomicrons. As a consequence, levels of triglyceride-rich proteins, and ultimately levels of triglycerides, increase in plasma [4,5]. Subjects with a well-established MS (i.e. with the presence of 4 to 5 of the MS components) have a higher risk of developing diabetes and cardiovascular disease[6]. Hypertriglyceridemia has also been considered by others [7,8] as an independent factor for cardiovascular risk. However, other authors consider hypertriglyceridemia indirectly related to cardiovascular risk, and also that this relationship would be rather related to alterations in lipid metabolism: changes in size and composition of LDL and reduction in HDL concentration. However, in favour of the atherogenic effect of TG, and independently of triglyceride-rich lipoproteins (chylomicron remnants and VLDL),
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J.F. Ascaso et al. / European Journal of Internal Medicine 22 (2011) 177–181
there are well-known mechanisms (such as deposition of cholesterol within the arterial wall, stimulation of the synthesis and secretion of PA-1 and VIIa factor) that are involved in the atherogenic process [9]. With this premises, our aim were to determine the prevalence of cardiovascular risk factors such as hypertension and diabetes mellitus, the prevalence of metabolic syndrome and the association between metabolic syndrome and cardiovascular disease in patients with hypertriglyceridemia. 2. Materials and methods A detailed description of the study has been published previously [10]. Briefly, the study was design as an observational cross-sectional study, uncontrolled and multicentre study. Data were obtained from the Spanish Hypertriglyceridemia Registry of the Spanish Arteriosclerosis Society (SEA). The primary objective of the study was to determine the prevalence of metabolic syndrome in patients with hypertriglyceridemia who have been referred to different lipid units in Spain for the screening of hypertriglyceridemia. 2.1. Inclusion criteria Patients of both genders and any age, referred to the Lipid Units of SEA for the screening and treatment of hypertriglyceridemia. Hypertriglyceridemia was defined as plasma levels of TG ≥ 200 mg/ dL (it corresponds to a high hypertriglyceridemia according to the ATPIII; Table 1) in the first blood sample tested in the Lipid Unit, independently of the level of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) or high-density lipoprotein-cholesterol (HDL-C). Eligible subjects were consecutively enrolled after the informed consent was signed. 2.2. Exclusion criteria Patients' unwillingness to collaborate in the study, patients with severe diseases that may interfere with the ability to comply with study protocol or may shorten their life expectancy or quality of life. Patients diagnosed with neoplasia or cardiovascular disease in the 3 months before the study. Sample size calculation was performed according to the primary objective of the study. The minimal sample size to estimate a proportion of 50%, with a confidence interval of 95% and a precision of 4% was 601 subjects. For this calculation a non-finite population was considered. To adjust for an expected 20% drop-out or noncompliance rate, the number was increased to 750 subjects. Thirty Lipid Units recruiting a minimum of 25 patients per unit were considered necessary to achieve the sample size. Eventually, 1524 patients participated in the registry. The study was approved by the Ethics Committee of the Carlos III Hospital (Madrid, Spain) and by the other selected hospitals in the study. For this study a total of 1182 patients were considered eligible, including criteria for metabolic syndrome; 868 men and 314 women.
Table 1 Definition of hypertriglyceridemia (NCEP-ATPIII). Category
Plasma triglycerides in mg/dl
Normal Upper-limit High (hypertriglyceridemia) Very high (severe hypertriglyceridemia)
b 150 150–199 200–499 ≥ 500
Expert panel on detection. Evaluation and treatment of high blood cholesterol in adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection. Evaluation and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486-97.
Demographic data, personal and family background (coronary disease, cerebrovascular disease, peripheral artery disease, hypertension, diabetes, smoking habits, hypothyroidism, pancreatitis and biliary, lithiasis), smoking habits, alcohol consumption, physical activity and diet were registered in the baseline visit. Physical examination included the presence of xanthomas, xanthelasmas and hepatomegaly. The weight measures were given in kg, the size in cm, the waist circumference in cm and the blood pressure in mmHg. The body mass index (BMI) was also calculated. Diagnosis of cardiovascular disease was established by the presence of coronary heart disease (myocardial infarction, angor or revascularization), cerebrovascular disease (stroke or transient cerebral ischemia) or peripheral artery disease. Laboratory analyses were performed in the Lipid Units in accordance with the standardized methods of each unit. Analyses of total cholesterol, triglycerides, HDL-C, glycaemia, alanine aminotransferase (ALT), aspartate transaminase (AST), uric acid, creatinine, gamma-glutamyl transpeptidase, alkaline phosphatase, TSH, haemoglobin A1c (HbA1c) and total bilirubin were performed. When plasma triglycerides were b 400 mg/dL, LDL-C was calculated by using the Friedewald formula [11]. The presence of metabolic syndrome was registered, according to modified NCEP-APTIII (MS-ATPIII) criteria [12] by the presence of three of the following parameters: waist circumference N102 cm in men or N88 cm in women; systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg or subjects treated with antihypertensive drugs, plasma glucose≥ 100 mg/dl; plasma TG ≥ 150 mg/dl; HDL-C b40 mg/dL (men) or b50 mg/dL (women). Prevalence of metabolic syndrome was also calculated according to the definition of the IDF [13] (MS-IDF), by the presence of abdominal obesity (waist circumference N94 cm in men or N80 cm in women) plus 2 of the following criteria: TG≥ 150 mg/dl (or under specific hypolipidemic treatment), HDL-C ≤ 40 mg/dl (men) or ≤ 50 mg/dl (women) (or under specific hypolipidemic treatment), systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg or subjects treated with antihypertensive drugs, fasting plasma glucose ≥ 100 mg/dl. 2.2.1. Statistical analysis Statistical analysis was conducted using the SPSS software, version 15.0 (Chicago, Illinois, EEUU). Discrete variables are shown as number of cases (in %), quantitative variables are shown as mean and standard deviation (SD) or median and interquartile range (triglycerides concentration), according to their symmetry. Comparison between groups was performed by the Chi-squared test (χ2). Mean comparison was performed by the Student t-test or non-parametric Mann– Whitney test, according to the normality of variables. 3. Results Anthropometric and analytical variables (N = 1182) are shown in Table 2. Prevalence of metabolic syndrome according to ATPIII criteria was 79.6% (77.5% men and 85.4% women) and according to IDF criteria of 75.2% (71.3% and 87.3% in men and women respectively) with no significant differences between both methods. In subjects with MS-ATPIII, the percentage of patients that showed 4–5 criteria was 66.0% while for the MS-IDF was 76.0%. Prevalence of metabolic syndrome increased with the age of the patients (with statistical differences among age groups, see Fig. 1) regardless of the criteria used to define the metabolic syndrome. Prevalence of metabolic syndrome was similar when patients were stratified according to their level of plasma triglycerides (200–499, 500–999 and ≥ 1000 mg/dL); 51.3%, 49.5% and 51.9%, respectively (p = 0.88846) (Fig. 2). The prevalence of hypertension, (defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or
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Table 2 General characteristics. Anthropometric and analytical data in the group studied.
N Age (years) BMI WC (cm) SBP (mm Hg) DBP (mm Hg) TC (mg/dl) TG (mg/dl) HDL-C (mg/dl) FPG (mg/dl) Uric Acid (mg/dl)
Total
Women
Men
p
1182 50.8 ± 12.3 29.2 4.1 99.7 ± 11.5 135.5 ± 16.6 82.6 ± 10.5 249.6 ± 71.1 327 (254–520) 40.7 ± 13.0 116.0 ± 42.2 6.2 ± 1.7
314 55.5 ± 13.1 29.2 4.0 95.2 ± 11.6 135.8 ± 15.8 80.6 ± 41.3 247.0 ± 73.5 303 (245–435) 45.8 ± 14.5 118.5 ± 41.3 5.3 ± 1.5
868 49.2 ± 16.6 29.3 4.6 101.3 ± 11.0 134.9 ± 18.3 83.4 ± 10.2 256.5 ± 63.7 337 (258–548) 38.8 ± 11.8 115.0 ± 42.5 6.5 ± 1.6
b0.0001 0.7921 b0.0001 0.1932 0.0002 0.0022 0.0003 b0.0001 0.2918 b0.0001
Variables are shown as mean ± standard deviation (SD) or median (interquartile range). BMI = body mass index; WC = Waist circumference. SBP = systolic blood pressure and DBP = diastolic blood pressure. TC = Total cholesterol; TG = plasma triglycerides; HDL-C = HDL cholesterol. FPG = fasting plasma glucose.
subjects previously diagnosed or treated with antihypertensive drugs) was 50.9%. The prevalence of diabetes in this hypertriglyceridemic population was 33.5%. We did not find differences in the percentage of diabetic subjects considering their plasma level of triglycerides; 30.1%, 32.4% and 38.0% (p = 0,3080) in patients with triglycerides 200–499, 500– 999 and ≥1000 mg/dL respectively. The prevalence of hypertension, diabetes, and both together were not statistical different according to the definition of MS (59.7% vs 57% for hypertension, 40.9% vs. 35.7% for diabetes, and 28.6 vs. 25.1% for both; ATP-III and IDF criteria respectively). The prevalence of cardiovascular disease in this population was 7.6% (7.8% coronary heart disease, 2.6% cerebrovascular disease (CD), 4.8% peripheral artery disease (PAD) and 2.4% for the combination of CD and PAD) in subjects with metabolic syndrome according to ATPIII criteria and 2.9% (2.1% coronary heart disease, 0.8% cerebrovascular disease) in subjects without metabolic syndrome (according to ATPIII). Those differences between groups were statistically significant; (p = 0.0040, Fig. 3). On the other hand, we did not find differences when comparing the prevalence of cardiovascular disease in subjects according to the presence of metabolic syndrome following IDF criteria (p = 0.6500). Subject distribution in percentage of patients with cardiovascular disease, with or without metabolic syndrome was statistically different (p b 0.0001) and is shown in Fig. 3. 95.9% of patients with cardiovascular disease also had metabolic syndrome, according to
Fig. 1. MS-ATPIII = metabolic syndrome according to NCEP-ATPIII (“National Cholesterol Education Program — Adults Treatment Program-III”) criteria; MS-IDF = metabolic syndrome according to the “International Diabetes Federation” criteria.
Fig. 2. MS-ATPIII = metabolic syndrome according to NCEP-ATPIII (“National Cholesterol Education Program — Adults Treatment Program-III”) criteria; MS-IDF = metabolic syndrome according to the “International Diabetes Federation” criteria.
ATP-III criteria, whereas only a 79.5% with cardiovascular disease were diagnosed with metabolic syndrome according to IDF criteria. 4. Discussion Hypertriglyceridemia, or the elevation of plasma triglycerides, is a frequent and complex abnormality in lipid the metabolism. Hypertriglyceridemia is also the lipid disorder most commonly found in patients with non-fatal myocardial infarction. The majority of consensus and guidelines published in the last decade have established the upper limit of normality in plasma triglycerides at 200 mg/dl (2.3 mmol/l). This cut-off value of triglycerides has also been used in this study (Table 2) [14]. In the clinical practice, hypertriglyceridemia is often found in patients with abdominal obesity, insulin resistance and metabolic syndrome [14,15]. In our study, the relationship with metabolic syndrome is highly evident; 79.6% of hypertriglyceridemic patients with MS-ATPIII and 75.2% with MS-IDF (no statistical difference). It is well-known that the prevalence of metabolic syndrome increases with the age of the patients; from 5% in patients aged 20–30 to 50% in patients aged 50 [16,17]. We found the same tendency of elevation in the prevalence of metabolic syndrome with the age. However, this
Fig. 3. MS-ATPIII = metabolic syndrome according to NCEP-ATPIII (“National Cholesterol Education Program — Adults Treatment Program-III”) criteria; MS-IDF = metabolic syndrome according to the “International Diabetes Federation” criteria; MS = metabolic syndrome; NO MS = No metabolic syndrome; N = number of subjects; CVD = cardiovascular disease (coronary heart disease. cerebrovascular disease of peripheral artery disease or a combination of them). Data calculated over the total of patients with data of all the components of metabolic syndrome (N = 1182) and had metabolic syndrome (N ATPIII = 941. N IDF = 893).
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association was even higher than in the general population, reaching a prevalence of 60.0% in patients aged under 40. and of 92.0% in patients aged 60 or above (Fig. 1). These data pointed out the importance of hypertriglyceridemia as a marker for metabolic syndrome. Although controversial results have been published, several studies have shown that, adjusted by age and other classic cardiovascular risk factors, the cardiovascular risk is double in subjects with an elevated number of components of metabolic syndrome, which leads into the conclusion that metabolic syndrome is an independent risk factor for cardiovascular disease [18,19]. This relationship has been described both for coronary heart disease and for ischemic cerebral disease [20]. In this study, a correlation between the presence of metabolic syndrome (mainly in MS-ATPIII) and cardiovascular disease was also observed. Thus, 95.0% of patients with cardiovascular disease also showed MS-ATPIII and only a 4.1% of patients with cardiovascular disease did not show MS-ATPIII (Fig. 3). Similar results were found when the metabolic syndrome was defined by IDF criteria. Another prospective study has shown that subjects with MS-ATPIII had a relative risk for cardiovascular disease of 2.88 in men and 2.25 in women [21] and a risk for type 2 diabetes of 6.92 and 6.90, in men and women respectively. The presence of metabolic syndrome (using both criteria) was followed by an increase in the prevalence of diabetes, being 25–30% in the group of subjects with metabolic syndrome [22], and it predicts the development of diabetes with a HR of 4.1 (2.8–6.0 CI95%) and 3.5 (2.3–5.2 CI95%), for MS-ATPII and MS-IDF respectively. The Verona study showed that the presence of metabolic syndrome is an independent factor that increases the risk of diabetes 5 times [23]. Recent data indicate that metabolic syndrome is a better predictor than glucose intolerance for the development of diabetes [24,25]. In this study we also found that hypertriglyceridemic patients have an elevated prevalence of diabetes (33.0%), with no significant differences with respect to the level of triglycerides (the prevalence of diabetes was of 30.1%, 32.4% and 38.0% in patients with triglycerides levels of 200–499, 500–999 and ≥ 1000 mg/dL respectively, p = 0,3080). This fact is in contrast with the data on prevalence of diabetes in Spain in recent years, which ranged between 8.0 and 12.0% [26]. Hypertriglyceridemia, regardless of the levels of triglycerides, is a marker for risk of diabetes, since the data found in this study doubled the risk found in the general population. On the other hand, the presence of diabetes associated with hypertriglyceridemia also increases the risk of cardiovascular disease and cardiovascular mortality. Finally, in conclusion, hypertriglyceridemia, independently of plasma levels of triglycerides could be clinically useful to detect subjects with metabolic syndrome and diabetes, as well as the risk of cardiovascular disease. Therefore, it might be used as a marker for the screening of these metabolic and cardiovascular alterations. Learning points “Prevalence of metabolic syndrome and cardiovascular disease in a hypertriglyceridemic population” • The hypertriglyceridemia (TG 200 mg/dl is, independently of plasma levels of triglycerides, able to predict the development of metabolic syndrome and diabetes. • The hypertriglyceridemia predicts the risk of cardiovascular disease. • Hypertriglyceridemia is a good marker for the screening metabolic and cardiovascular alterations. Acknowledgements * Hypertriglyceridemia Registry of the Spanish Arteriosclerosis Society: Almagro Múgica F, Álvarez-Sala Walther LA, Aranda Arcas JL,
Argimón Pallas J, Becerra Fernández A, Brea Hernando A, Borrallo Almansa RM, Carrasco Miras F, Civeira Murillo F, Eloy Moreno Bandera FJ, Fabiani Romero F, Fahades Enrich A, Fernández-Miranda Parra C, Ferrando Vela J, Fuentes Jiménez FJ, Galiana López Del Pulgar J, García Arias C, Godoy Rocati D, González Santos P , Gordo Fraile P, Hernández Anguera JM, Hernández Mijares A, Irigoyen Cucalon L, Jansen Chaparro S, Jarauta Simón E, Jiménez Morales JL, Laguna F, Lahoz Rallo C , López Chozas JM, Martínez Hervas S, Mari Solivellas B, Martis Sueiro A, Masana Marín L, Mateo Gallego R, Mediavilla García JD, Merino Ribas J, Morales Coca C, Morillas Ariño C, Mosquera Lozano D, Mostaza Prieto J, Panisello Royo J, Pérez De Juan Romero M, Pérez Silvestre J, Pia Iglesias G, Plana Gil N, Recarte Andrade C, Ros Rahola E, Ruiz García A, Saenz Aranzubia P, Sánchez Muñoz Torrero JF, Sanclemente Anso C, Sarasa Corral I, Sevilla Moya JC, Sola Izquierdo E, Suarez Tembra M, Toro Santos JM, Trias Vilaguta F, Valdivielso Felices P, Vives Almandoz A, Pinto Sala X, Zambón Rados D. 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Contents lists available at ScienceDirect
European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m
Original article
Prevalence of metabolic syndrome and cardiovascular disease in a hypertriglyceridemic population Juan F. Ascaso a,⁎, Jesús Millán b, Rocio Mateo-Gallego c, Antonio Ruiz d, M. Suarez-Tembra e, Rosa M. Borrallo f, Daniel Zambon g, Pedro Gonzalez-Santos h, Miguel Peres-de-Juan i, Emili Ros g and On behalf of the Hypertriglyceridemia Registry of the Spanish Arteriosclerosis Society a
Clinic-University Hospital, University of Valencia, Spain University Hospital Gregorio Marañon, Madrid, Spain c Miguel Servet Hospital, Zaragoza, Spain d CS Pinto, Madrid, Spain e San Rafael Hospital, Madrid, Spain f Terrasa Hospital, Terrasa, Spain g Clinic Hospital, Barcelona, Barcelona, Spain h Clinic Hospital, Málaga, Spain i Santa Maria Nai Hospital, Ourense, Spain b
a r t i c l e
i n f o
Article history: Received 26 July 2010 Received in revised form 14 December 2010 Accepted 16 December 2010 Available online 14 January 2011 Keywords: Hypertriglyceridemia Metabolic syndrome Diabetes Cardiovascular disease
a b s t r a c t Background: We aim to study the prevalence of metabolic syndrome (MS), hypertension and diabetes, and their relationship to cardiovascular disease in subjects with hypertriglyceridemia. Methods: This is an observational cross-sectional study, uncontrolled and multicentre study. Selected subjects were patients with hypertriglyceridemia (triglycerides, TG, ≥ 200 mg/dl) visited in the Lipid Units of the Spanish Arteriosclerosis Society who met the inclusion criteria. Prevalence of MS (ATPIII and IDF criteria, MS-ATPIII or MS-IDF), hypertension and diabetes were studied. The presence of cardiovascular disease (CVD) was also determined. Results: The results showed that individuals referred for hypertriglyceridemia had a high prevalence of MS-ATPIII 79.6% and MS-IDF 75.2%. The prevalence of MS was independent of plasma triglyceride levels. The prevalence of hypertension and diabetes were 50.9% and 33.5%, respectively. The prevalence of diabetes was double than in the general population. The prevalence of CVD was 14.6%. 95.9% of CVD events were found in patients with MS-ATPIII and only 4.1% in the group without MS-ATPIII, significant differences. Conclusions: Hypertriglyceridemia is associated to the metabolic syndrome and diabetes, as well as the risk of CVD, independently of the levels of triglycerides. Hypertriglyceridemia may be an important marker in the screening of these severe metabolic and vascular abnormalities. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Hypertriglyceridemias are metabolic diseases characterized by increasing levels of very-low density lipoproteins (VLDL), chylomicrons or remnant particles of both. Its wide aetiology is a clear example of the interaction of genetic and external factors [1–3]. Hypertriglyceridemias are often associated with prevalent diseases, such as obesity, hypertension, diabetes mellitus, alcohol intake and metabolic syndrome. Metabolic Syndrome is characterized by the association of metabolic and vascular abnormalities that can be progressively shown in patients who are overweight and have insulin-resistance. Hypertriglyceridemia is the most frequent and ⁎ Corresponding author. Department of Medicine, University of Valencia, Blasco Ibanez 15, 46010, Valencia, Spain. Tel.: +34 963862665; fax: +34 963864767. E-mail address: [email protected] (J.F. Ascaso).
earliest alteration in the MS and it is due to the increase in the hepatic synthesis of VLDL, along with an alteration in its catabolism due to a decrease in the activity of lipoprotein lipase. This also leads to a decrease in the catabolism of chylomicrons. As a consequence, levels of triglyceride-rich proteins, and ultimately levels of triglycerides, increase in plasma [4,5]. Subjects with a well-established MS (i.e. with the presence of 4 to 5 of the MS components) have a higher risk of developing diabetes and cardiovascular disease[6]. Hypertriglyceridemia has also been considered by others [7,8] as an independent factor for cardiovascular risk. However, other authors consider hypertriglyceridemia indirectly related to cardiovascular risk, and also that this relationship would be rather related to alterations in lipid metabolism: changes in size and composition of LDL and reduction in HDL concentration. However, in favour of the atherogenic effect of TG, and independently of triglyceride-rich lipoproteins (chylomicron remnants and VLDL),
0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2010.12.011
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there are well-known mechanisms (such as deposition of cholesterol within the arterial wall, stimulation of the synthesis and secretion of PA-1 and VIIa factor) that are involved in the atherogenic process [9]. With this premises, our aim were to determine the prevalence of cardiovascular risk factors such as hypertension and diabetes mellitus, the prevalence of metabolic syndrome and the association between metabolic syndrome and cardiovascular disease in patients with hypertriglyceridemia. 2. Materials and methods A detailed description of the study has been published previously [10]. Briefly, the study was design as an observational cross-sectional study, uncontrolled and multicentre study. Data were obtained from the Spanish Hypertriglyceridemia Registry of the Spanish Arteriosclerosis Society (SEA). The primary objective of the study was to determine the prevalence of metabolic syndrome in patients with hypertriglyceridemia who have been referred to different lipid units in Spain for the screening of hypertriglyceridemia. 2.1. Inclusion criteria Patients of both genders and any age, referred to the Lipid Units of SEA for the screening and treatment of hypertriglyceridemia. Hypertriglyceridemia was defined as plasma levels of TG ≥ 200 mg/ dL (it corresponds to a high hypertriglyceridemia according to the ATPIII; Table 1) in the first blood sample tested in the Lipid Unit, independently of the level of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) or high-density lipoprotein-cholesterol (HDL-C). Eligible subjects were consecutively enrolled after the informed consent was signed. 2.2. Exclusion criteria Patients' unwillingness to collaborate in the study, patients with severe diseases that may interfere with the ability to comply with study protocol or may shorten their life expectancy or quality of life. Patients diagnosed with neoplasia or cardiovascular disease in the 3 months before the study. Sample size calculation was performed according to the primary objective of the study. The minimal sample size to estimate a proportion of 50%, with a confidence interval of 95% and a precision of 4% was 601 subjects. For this calculation a non-finite population was considered. To adjust for an expected 20% drop-out or noncompliance rate, the number was increased to 750 subjects. Thirty Lipid Units recruiting a minimum of 25 patients per unit were considered necessary to achieve the sample size. Eventually, 1524 patients participated in the registry. The study was approved by the Ethics Committee of the Carlos III Hospital (Madrid, Spain) and by the other selected hospitals in the study. For this study a total of 1182 patients were considered eligible, including criteria for metabolic syndrome; 868 men and 314 women.
Table 1 Definition of hypertriglyceridemia (NCEP-ATPIII). Category
Plasma triglycerides in mg/dl
Normal Upper-limit High (hypertriglyceridemia) Very high (severe hypertriglyceridemia)
b 150 150–199 200–499 ≥ 500
Expert panel on detection. Evaluation and treatment of high blood cholesterol in adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection. Evaluation and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486-97.
Demographic data, personal and family background (coronary disease, cerebrovascular disease, peripheral artery disease, hypertension, diabetes, smoking habits, hypothyroidism, pancreatitis and biliary, lithiasis), smoking habits, alcohol consumption, physical activity and diet were registered in the baseline visit. Physical examination included the presence of xanthomas, xanthelasmas and hepatomegaly. The weight measures were given in kg, the size in cm, the waist circumference in cm and the blood pressure in mmHg. The body mass index (BMI) was also calculated. Diagnosis of cardiovascular disease was established by the presence of coronary heart disease (myocardial infarction, angor or revascularization), cerebrovascular disease (stroke or transient cerebral ischemia) or peripheral artery disease. Laboratory analyses were performed in the Lipid Units in accordance with the standardized methods of each unit. Analyses of total cholesterol, triglycerides, HDL-C, glycaemia, alanine aminotransferase (ALT), aspartate transaminase (AST), uric acid, creatinine, gamma-glutamyl transpeptidase, alkaline phosphatase, TSH, haemoglobin A1c (HbA1c) and total bilirubin were performed. When plasma triglycerides were b 400 mg/dL, LDL-C was calculated by using the Friedewald formula [11]. The presence of metabolic syndrome was registered, according to modified NCEP-APTIII (MS-ATPIII) criteria [12] by the presence of three of the following parameters: waist circumference N102 cm in men or N88 cm in women; systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg or subjects treated with antihypertensive drugs, plasma glucose≥ 100 mg/dl; plasma TG ≥ 150 mg/dl; HDL-C b40 mg/dL (men) or b50 mg/dL (women). Prevalence of metabolic syndrome was also calculated according to the definition of the IDF [13] (MS-IDF), by the presence of abdominal obesity (waist circumference N94 cm in men or N80 cm in women) plus 2 of the following criteria: TG≥ 150 mg/dl (or under specific hypolipidemic treatment), HDL-C ≤ 40 mg/dl (men) or ≤ 50 mg/dl (women) (or under specific hypolipidemic treatment), systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg or subjects treated with antihypertensive drugs, fasting plasma glucose ≥ 100 mg/dl. 2.2.1. Statistical analysis Statistical analysis was conducted using the SPSS software, version 15.0 (Chicago, Illinois, EEUU). Discrete variables are shown as number of cases (in %), quantitative variables are shown as mean and standard deviation (SD) or median and interquartile range (triglycerides concentration), according to their symmetry. Comparison between groups was performed by the Chi-squared test (χ2). Mean comparison was performed by the Student t-test or non-parametric Mann– Whitney test, according to the normality of variables. 3. Results Anthropometric and analytical variables (N = 1182) are shown in Table 2. Prevalence of metabolic syndrome according to ATPIII criteria was 79.6% (77.5% men and 85.4% women) and according to IDF criteria of 75.2% (71.3% and 87.3% in men and women respectively) with no significant differences between both methods. In subjects with MS-ATPIII, the percentage of patients that showed 4–5 criteria was 66.0% while for the MS-IDF was 76.0%. Prevalence of metabolic syndrome increased with the age of the patients (with statistical differences among age groups, see Fig. 1) regardless of the criteria used to define the metabolic syndrome. Prevalence of metabolic syndrome was similar when patients were stratified according to their level of plasma triglycerides (200–499, 500–999 and ≥ 1000 mg/dL); 51.3%, 49.5% and 51.9%, respectively (p = 0.88846) (Fig. 2). The prevalence of hypertension, (defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or
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Table 2 General characteristics. Anthropometric and analytical data in the group studied.
N Age (years) BMI WC (cm) SBP (mm Hg) DBP (mm Hg) TC (mg/dl) TG (mg/dl) HDL-C (mg/dl) FPG (mg/dl) Uric Acid (mg/dl)
Total
Women
Men
p
1182 50.8 ± 12.3 29.2 4.1 99.7 ± 11.5 135.5 ± 16.6 82.6 ± 10.5 249.6 ± 71.1 327 (254–520) 40.7 ± 13.0 116.0 ± 42.2 6.2 ± 1.7
314 55.5 ± 13.1 29.2 4.0 95.2 ± 11.6 135.8 ± 15.8 80.6 ± 41.3 247.0 ± 73.5 303 (245–435) 45.8 ± 14.5 118.5 ± 41.3 5.3 ± 1.5
868 49.2 ± 16.6 29.3 4.6 101.3 ± 11.0 134.9 ± 18.3 83.4 ± 10.2 256.5 ± 63.7 337 (258–548) 38.8 ± 11.8 115.0 ± 42.5 6.5 ± 1.6
b0.0001 0.7921 b0.0001 0.1932 0.0002 0.0022 0.0003 b0.0001 0.2918 b0.0001
Variables are shown as mean ± standard deviation (SD) or median (interquartile range). BMI = body mass index; WC = Waist circumference. SBP = systolic blood pressure and DBP = diastolic blood pressure. TC = Total cholesterol; TG = plasma triglycerides; HDL-C = HDL cholesterol. FPG = fasting plasma glucose.
subjects previously diagnosed or treated with antihypertensive drugs) was 50.9%. The prevalence of diabetes in this hypertriglyceridemic population was 33.5%. We did not find differences in the percentage of diabetic subjects considering their plasma level of triglycerides; 30.1%, 32.4% and 38.0% (p = 0,3080) in patients with triglycerides 200–499, 500– 999 and ≥1000 mg/dL respectively. The prevalence of hypertension, diabetes, and both together were not statistical different according to the definition of MS (59.7% vs 57% for hypertension, 40.9% vs. 35.7% for diabetes, and 28.6 vs. 25.1% for both; ATP-III and IDF criteria respectively). The prevalence of cardiovascular disease in this population was 7.6% (7.8% coronary heart disease, 2.6% cerebrovascular disease (CD), 4.8% peripheral artery disease (PAD) and 2.4% for the combination of CD and PAD) in subjects with metabolic syndrome according to ATPIII criteria and 2.9% (2.1% coronary heart disease, 0.8% cerebrovascular disease) in subjects without metabolic syndrome (according to ATPIII). Those differences between groups were statistically significant; (p = 0.0040, Fig. 3). On the other hand, we did not find differences when comparing the prevalence of cardiovascular disease in subjects according to the presence of metabolic syndrome following IDF criteria (p = 0.6500). Subject distribution in percentage of patients with cardiovascular disease, with or without metabolic syndrome was statistically different (p b 0.0001) and is shown in Fig. 3. 95.9% of patients with cardiovascular disease also had metabolic syndrome, according to
Fig. 1. MS-ATPIII = metabolic syndrome according to NCEP-ATPIII (“National Cholesterol Education Program — Adults Treatment Program-III”) criteria; MS-IDF = metabolic syndrome according to the “International Diabetes Federation” criteria.
Fig. 2. MS-ATPIII = metabolic syndrome according to NCEP-ATPIII (“National Cholesterol Education Program — Adults Treatment Program-III”) criteria; MS-IDF = metabolic syndrome according to the “International Diabetes Federation” criteria.
ATP-III criteria, whereas only a 79.5% with cardiovascular disease were diagnosed with metabolic syndrome according to IDF criteria. 4. Discussion Hypertriglyceridemia, or the elevation of plasma triglycerides, is a frequent and complex abnormality in lipid the metabolism. Hypertriglyceridemia is also the lipid disorder most commonly found in patients with non-fatal myocardial infarction. The majority of consensus and guidelines published in the last decade have established the upper limit of normality in plasma triglycerides at 200 mg/dl (2.3 mmol/l). This cut-off value of triglycerides has also been used in this study (Table 2) [14]. In the clinical practice, hypertriglyceridemia is often found in patients with abdominal obesity, insulin resistance and metabolic syndrome [14,15]. In our study, the relationship with metabolic syndrome is highly evident; 79.6% of hypertriglyceridemic patients with MS-ATPIII and 75.2% with MS-IDF (no statistical difference). It is well-known that the prevalence of metabolic syndrome increases with the age of the patients; from 5% in patients aged 20–30 to 50% in patients aged 50 [16,17]. We found the same tendency of elevation in the prevalence of metabolic syndrome with the age. However, this
Fig. 3. MS-ATPIII = metabolic syndrome according to NCEP-ATPIII (“National Cholesterol Education Program — Adults Treatment Program-III”) criteria; MS-IDF = metabolic syndrome according to the “International Diabetes Federation” criteria; MS = metabolic syndrome; NO MS = No metabolic syndrome; N = number of subjects; CVD = cardiovascular disease (coronary heart disease. cerebrovascular disease of peripheral artery disease or a combination of them). Data calculated over the total of patients with data of all the components of metabolic syndrome (N = 1182) and had metabolic syndrome (N ATPIII = 941. N IDF = 893).
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association was even higher than in the general population, reaching a prevalence of 60.0% in patients aged under 40. and of 92.0% in patients aged 60 or above (Fig. 1). These data pointed out the importance of hypertriglyceridemia as a marker for metabolic syndrome. Although controversial results have been published, several studies have shown that, adjusted by age and other classic cardiovascular risk factors, the cardiovascular risk is double in subjects with an elevated number of components of metabolic syndrome, which leads into the conclusion that metabolic syndrome is an independent risk factor for cardiovascular disease [18,19]. This relationship has been described both for coronary heart disease and for ischemic cerebral disease [20]. In this study, a correlation between the presence of metabolic syndrome (mainly in MS-ATPIII) and cardiovascular disease was also observed. Thus, 95.0% of patients with cardiovascular disease also showed MS-ATPIII and only a 4.1% of patients with cardiovascular disease did not show MS-ATPIII (Fig. 3). Similar results were found when the metabolic syndrome was defined by IDF criteria. Another prospective study has shown that subjects with MS-ATPIII had a relative risk for cardiovascular disease of 2.88 in men and 2.25 in women [21] and a risk for type 2 diabetes of 6.92 and 6.90, in men and women respectively. The presence of metabolic syndrome (using both criteria) was followed by an increase in the prevalence of diabetes, being 25–30% in the group of subjects with metabolic syndrome [22], and it predicts the development of diabetes with a HR of 4.1 (2.8–6.0 CI95%) and 3.5 (2.3–5.2 CI95%), for MS-ATPII and MS-IDF respectively. The Verona study showed that the presence of metabolic syndrome is an independent factor that increases the risk of diabetes 5 times [23]. Recent data indicate that metabolic syndrome is a better predictor than glucose intolerance for the development of diabetes [24,25]. In this study we also found that hypertriglyceridemic patients have an elevated prevalence of diabetes (33.0%), with no significant differences with respect to the level of triglycerides (the prevalence of diabetes was of 30.1%, 32.4% and 38.0% in patients with triglycerides levels of 200–499, 500–999 and ≥ 1000 mg/dL respectively, p = 0,3080). This fact is in contrast with the data on prevalence of diabetes in Spain in recent years, which ranged between 8.0 and 12.0% [26]. Hypertriglyceridemia, regardless of the levels of triglycerides, is a marker for risk of diabetes, since the data found in this study doubled the risk found in the general population. On the other hand, the presence of diabetes associated with hypertriglyceridemia also increases the risk of cardiovascular disease and cardiovascular mortality. Finally, in conclusion, hypertriglyceridemia, independently of plasma levels of triglycerides could be clinically useful to detect subjects with metabolic syndrome and diabetes, as well as the risk of cardiovascular disease. Therefore, it might be used as a marker for the screening of these metabolic and cardiovascular alterations. Learning points “Prevalence of metabolic syndrome and cardiovascular disease in a hypertriglyceridemic population” • The hypertriglyceridemia (TG 200 mg/dl is, independently of plasma levels of triglycerides, able to predict the development of metabolic syndrome and diabetes. • The hypertriglyceridemia predicts the risk of cardiovascular disease. • Hypertriglyceridemia is a good marker for the screening metabolic and cardiovascular alterations. Acknowledgements * Hypertriglyceridemia Registry of the Spanish Arteriosclerosis Society: Almagro Múgica F, Álvarez-Sala Walther LA, Aranda Arcas JL,
Argimón Pallas J, Becerra Fernández A, Brea Hernando A, Borrallo Almansa RM, Carrasco Miras F, Civeira Murillo F, Eloy Moreno Bandera FJ, Fabiani Romero F, Fahades Enrich A, Fernández-Miranda Parra C, Ferrando Vela J, Fuentes Jiménez FJ, Galiana López Del Pulgar J, García Arias C, Godoy Rocati D, González Santos P , Gordo Fraile P, Hernández Anguera JM, Hernández Mijares A, Irigoyen Cucalon L, Jansen Chaparro S, Jarauta Simón E, Jiménez Morales JL, Laguna F, Lahoz Rallo C , López Chozas JM, Martínez Hervas S, Mari Solivellas B, Martis Sueiro A, Masana Marín L, Mateo Gallego R, Mediavilla García JD, Merino Ribas J, Morales Coca C, Morillas Ariño C, Mosquera Lozano D, Mostaza Prieto J, Panisello Royo J, Pérez De Juan Romero M, Pérez Silvestre J, Pia Iglesias G, Plana Gil N, Recarte Andrade C, Ros Rahola E, Ruiz García A, Saenz Aranzubia P, Sánchez Muñoz Torrero JF, Sanclemente Anso C, Sarasa Corral I, Sevilla Moya JC, Sola Izquierdo E, Suarez Tembra M, Toro Santos JM, Trias Vilaguta F, Valdivielso Felices P, Vives Almandoz A, Pinto Sala X, Zambón Rados D. 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