Angiology
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Beneficial Effects of Rosuvastatin Treatment in Patients With Metabolic Syndrome Cem Bostan, Ahmet Yildiz, Alev Arat Ozkan, Isil Uzunhasan, Aysem Kaya and Zerrin Yigit ANGIOLOGY published online 19 February 2014 DOI: 10.1177/0003319714522107 The online version of this article can be found at: http://ang.sagepub.com/content/early/2014/02/17/0003319714522107
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Article
Beneficial Effects of Rosuvastatin Treatment in Patients With Metabolic Syndrome
Angiology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319714522107 ang.sagepub.com
Cem Bostan, MD1, Ahmet Yildiz, MD1, Alev Arat Ozkan, MD1, Isil Uzunhasan, MD1, Aysem Kaya, PhD2, and Zerrin Yigit, MD1
Abstract We determined the effect of 6-month rosuvastatin treatment on blood lipids, oxidative parameters, apolipoproteins, highsensitivity C-reactive protein, lipoprotein(a), homocysteine, and glycated hemoglobin (HbA1c) in patients with metabolic syndrome (MetS). Healthy individuals (men aged >40 years and postmenopausal women) with a body mass index 30 (n ¼ 100) who fulfilled the National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria for MetS were included. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels decreased (P < .0001). The change in LDL 1 to 3 subgroups was significant (P ¼ .0007, P < .0001, and P ¼ .006, respectively). Changes in LDL 4 to 7 subgroups were not significant. There was a beneficial effect on oxidized LDL, fibrinogen, homocysteine, and HbA1c. Rosuvastatin significantly increased high-density lipoprotein levels (P ¼ .0003). The oxidant/antioxidant status and subclinical inflammatory state were also beneficially changed. Rosuvastatin had a significant beneficial effect on atherogenic dyslipidemia as well as on oxidative stress and inflammatory biomarkers in patients with MetS. Keywords metabolic syndrome, rosuvastatin, cholesterol subgroups, oxidative stress
Introduction Different diagnostic criteria are used in clinical practice to identify patients with metabolic syndrome (MetS). All the proposed classifications have 1 concept in common: MetS represents a constellation of interrelated risk factors for metabolic origin, which appear to directly promote the development of atherosclerotic cardiovascular (CV) disease. Such metabolic risk factors include central obesity, elevated blood pressure, elevated plasma glucose, and atherogenic dyslipidemia, which consists of lipoprotein abnormalities, including elevated plasma triglyceride levels, reduced high-density lipoprotein cholesterol (HDL-C) concentrations, and increased small, dense low-density lipoproteins (LDLs).1-4 In fact, the ‘‘quality,’’ rather than only the ‘‘quantity’’ of LDL, exerts a direct influence on the CV risk.5 Low-density lipoprotein consists of multiple distinct subclasses that differ in size, density, physicochemical composition, metabolic behavior, and atherogenicity.6 There are at least 4 major subspecies of LDL (eg, large LDL-1, medium LDL-2, small LDL-3, and very small LDL-4), and the predominance of small, dense LDL has been accepted as an emerging CV risk factor by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).1 Studies suggested that small, dense LDL may represent a valuable marker for diagnosis and severity of MetS but its predictive role remains to be established.7-9 Non-HDL-C and apolipoprotein (Apo) B may be better predictors of coronary heart disease (CHD) risk than LDL-C
levels.10 Non-HDL-C is a measure of the cholesterol carried by all atherogenic lipoproteins, such as that carried by LDL particles, as well as the cholesterol carried by very LDLs, intermediate-density lipoproteins, remnant lipoproteins, chylomicrons (and their remnants), and lipoprotein(a), Lp(a). Regarding particle number, 1 Apo B molecule is found in each non-HDL-C particle; thus, the Apo B level is often considered a surrogate marker for atherogenic lipoprotein particle concentration. An increase in atherogenic lipoprotein particle number is thought to increase CHD risk.10,11 Lipoprotein particle size is another lipid parameter that may influence CHD risk.11 A disproportionate increase in smaller LDL particles is often described as increasing CHD risk.12 However, it is unclear whether LDL particle size provides an additional predictive power for measuring CHD risk versus LDL particle number.13 High-density lipoprotein cholesterol is a highly heterogeneous lipoprotein that can be separated into 2 major subclasses (HDL-C2 and HDL-C3) and several minor subclasses based on
1
Department of Cardiology, Istanbul University Institute of Cardiology, Istanbul, Turkey 2 Department of Biochemistry, Istanbul University Institute of Cardiology, Istanbul, Turkey Corresponding Author: Cem Bostan, Department of Cardiology, Istanbul University Institute of Cardiology, Haseki, Aksaray 34350 Istanbul, Turkey. Email: [email protected]
Downloaded from ang.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 23, 2014
2
Angiology
Table 1. Characteristics of Patients Included in the Analysis. Male/female (M/F), n Age, years Waist circumference (M/F), cm Body mass index, kg/m2a Initial At 6 months Impaired OGTT, n Hypertension, n
49/51 55.4 + 12.5 111.9 + 6.1/99.7 + 13.3 32.7 + 3.7 32.4 + 4.8 38 44
Abbreviations: M, male; F, female; OGTT, oral glucose tolerance test. a P ¼ .58.
density. Both major subclasses are inversely related to CHD risk14 and low HDL-C and low HDL particle concentrations are associated with increased CHD risk.15 The aim of this study was to determine the effect of 6-month rosuvastatin treatment on (1) blood lipids, (2) LDL and HDL sub groups, (3) oxidized LDL and antioxidized LDL antibody (OLAb), (4) Apo A, Apo B, and Apo E, (5) high-sensitivity C-reactive protein (hsCRP), Lp(a), and homocysteine, (6) total oxidant capacity, antioxidant capacity, and oxidant capacity index, and (7) hemoglobin A1c (HbA1c) in patients with MetS.
Material and Methods The study was conducted from January 2009 to January 2011.Turkish individuals (men aged >40 years and postmenopausal women) with a body mass index (BMI) 30 (n ¼ 100) who fulfilled the NCEP ATP III criteria for the diagnosis of MetS, but who were otherwise healthy, were included in the study.
cigarette smoking, height, weight, and waist and hip circumferences. Fasting blood samples were analyzed for baseline lipids, glucose, hemoglobin A1c (HbA1c), hsCRP, homocysteine, uric acid, fibrinogen, total antioxidant capacity (TAC), and total oxidant status (TOS). Serum samples were taken after fasting for 12 hours. Blood samples were centrifuged 3000 rpm 10 minutes. All samples were stored at 20 C. Blood serum samples were measured using a full automated biochemistry analyzer (Opera-Technicon Bayer Inst) with colorimetric methods. Antioxidants in the sample reduce dark blue–green-colored 2, 2’-azinobis 3-ethylbenzothiazoline-6-sulfonic acid diammonium (ABTS) radical to colorless reduced ABTS form. The change in absorbance at 660 nm is related to total antioxidant level of the sample. The assay is calibrated with a stable antioxidant standard solution that is traditionally named as Trolox Equivalent (a vitamin E analog). Oxidants present in the sample oxidize the ferrous ion–chelator complex to ferric ion. The oxidation reaction is prolonged by enhancer molecules that are abundantly present in the reaction medium. The ferric ion makes a colored complex with chromogen in an acidic medium. The color intensity, which can be measured spectrophotometrically, is related to the total amount of oxidant molecules present in the sample. The assay is calibrated with hydrogen peroxide and the results are expressed in terms of mmol/L of hydrogen peroxide equivalent per liter (mmol H2O2 equivalent/L). Oxidative stress index (OSI) was calculated. OSI (arbitrary unit) ¼ (TOS [mmol H2O2 equiv/L]/TAC [mmol Trolox equiv/L]) 100.
Study Medication
Exclusion Criteria
Rosuvastatin 20 mg per day was administered for 6 months.
Individuals were excluded if they had type 2 diabetes mellitus (fasting glucose levels >126 mg/dL) or a history of cerebrovascular disease. In addition, patients with thyroid function abnormalities, abnormal hepatic function, impaired renal function, and those receiving drugs that may interfere with glucose or lipid metabolism were excluded.
Follow-Up Data
Anthropometric and Metabolic Variables Body weight was determined to the nearest 0.1 kg with a calibrated beam balance and standing height was measured to the nearest 1 cm. Body mass index was calculated as weight (kg) divided by height squared (m2). Waist circumference was measured midway between the lower ribs and the iliac crest. Blood pressure measurements were obtained at the same time (morning) in the sitting position, in duplicate, using the right arm, following a 10-minute rest and using a validated mercury sphygmomanometer.
Baseline Data Patient demographic information was collected, including age, sex, qualifying criterion, self-reported race, current medications,
Patients were followed-up for 6 months after recruitment. We did not aim to change diet or lifestyle of patients. Patients underwent further fasting blood testing for fasting lipids and hsCRP. Patient adherence was assessed by the number of tablets left over. Patients with >4 days of tablets left over were deemed nonadherent. All patients were counseled about the benefits of cholesterol lowering and were asked specifically about muscular and gastrointestinal symptoms.
Results We enrolled 100 patients (49 men and 51 women). The mean age was 55.4 + 12.5 years. The mean BMI was 32.7 + 3.7 kg/m2. The mean waist circumference was 99.7 +13.3 cm for women and 111.9 + 6.1 cm for men. In all, 44 patients had hypertension and 38 had an impaired oral glucose tolerance test (Table 1). The 6-month course of rosuvastatin produced significant reductions in plasma total cholesterol and LDL-C levels relative to baseline (P < .0001). There was also a significant
Downloaded from ang.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 23, 2014
Bostan et al
3
Table 2. Lipid Profiles at Baseline and After a 6-Month Course of Rosuvastatin. Baseline
At 6 months
213 + 37 40 + 7 138 + 33 176 + 103 1.6 + 2.2 1.1 + 0.3 0.61 (0.01–1.69) 0.11 (0.06–1.34)
Total cholesterol, mg/dL HDL cholesterol, mg/dL LDL cholesterol, mg/dL Triglyceride, mg/dL Apo A, g/L Apo B, g/L Apo E, g/L Lipoprotein(a), g/L
173 47 100 159 1.6 1.0 0.25 0.10
+ 42 + 15 + 31 + 110 + 0.3 + 0.3 (0.01–1.47) (0.01–0.85)
P
http://ang.sagepub.com/
Beneficial Effects of Rosuvastatin Treatment in Patients With Metabolic Syndrome Cem Bostan, Ahmet Yildiz, Alev Arat Ozkan, Isil Uzunhasan, Aysem Kaya and Zerrin Yigit ANGIOLOGY published online 19 February 2014 DOI: 10.1177/0003319714522107 The online version of this article can be found at: http://ang.sagepub.com/content/early/2014/02/17/0003319714522107
Published by: http://www.sagepublications.com
Additional services and information for Angiology can be found at: Email Alerts: http://ang.sagepub.com/cgi/alerts Subscriptions: http://ang.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Feb 19, 2014 What is This?
Downloaded from ang.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 23, 2014
Article
Beneficial Effects of Rosuvastatin Treatment in Patients With Metabolic Syndrome
Angiology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319714522107 ang.sagepub.com
Cem Bostan, MD1, Ahmet Yildiz, MD1, Alev Arat Ozkan, MD1, Isil Uzunhasan, MD1, Aysem Kaya, PhD2, and Zerrin Yigit, MD1
Abstract We determined the effect of 6-month rosuvastatin treatment on blood lipids, oxidative parameters, apolipoproteins, highsensitivity C-reactive protein, lipoprotein(a), homocysteine, and glycated hemoglobin (HbA1c) in patients with metabolic syndrome (MetS). Healthy individuals (men aged >40 years and postmenopausal women) with a body mass index 30 (n ¼ 100) who fulfilled the National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria for MetS were included. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels decreased (P < .0001). The change in LDL 1 to 3 subgroups was significant (P ¼ .0007, P < .0001, and P ¼ .006, respectively). Changes in LDL 4 to 7 subgroups were not significant. There was a beneficial effect on oxidized LDL, fibrinogen, homocysteine, and HbA1c. Rosuvastatin significantly increased high-density lipoprotein levels (P ¼ .0003). The oxidant/antioxidant status and subclinical inflammatory state were also beneficially changed. Rosuvastatin had a significant beneficial effect on atherogenic dyslipidemia as well as on oxidative stress and inflammatory biomarkers in patients with MetS. Keywords metabolic syndrome, rosuvastatin, cholesterol subgroups, oxidative stress
Introduction Different diagnostic criteria are used in clinical practice to identify patients with metabolic syndrome (MetS). All the proposed classifications have 1 concept in common: MetS represents a constellation of interrelated risk factors for metabolic origin, which appear to directly promote the development of atherosclerotic cardiovascular (CV) disease. Such metabolic risk factors include central obesity, elevated blood pressure, elevated plasma glucose, and atherogenic dyslipidemia, which consists of lipoprotein abnormalities, including elevated plasma triglyceride levels, reduced high-density lipoprotein cholesterol (HDL-C) concentrations, and increased small, dense low-density lipoproteins (LDLs).1-4 In fact, the ‘‘quality,’’ rather than only the ‘‘quantity’’ of LDL, exerts a direct influence on the CV risk.5 Low-density lipoprotein consists of multiple distinct subclasses that differ in size, density, physicochemical composition, metabolic behavior, and atherogenicity.6 There are at least 4 major subspecies of LDL (eg, large LDL-1, medium LDL-2, small LDL-3, and very small LDL-4), and the predominance of small, dense LDL has been accepted as an emerging CV risk factor by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III).1 Studies suggested that small, dense LDL may represent a valuable marker for diagnosis and severity of MetS but its predictive role remains to be established.7-9 Non-HDL-C and apolipoprotein (Apo) B may be better predictors of coronary heart disease (CHD) risk than LDL-C
levels.10 Non-HDL-C is a measure of the cholesterol carried by all atherogenic lipoproteins, such as that carried by LDL particles, as well as the cholesterol carried by very LDLs, intermediate-density lipoproteins, remnant lipoproteins, chylomicrons (and their remnants), and lipoprotein(a), Lp(a). Regarding particle number, 1 Apo B molecule is found in each non-HDL-C particle; thus, the Apo B level is often considered a surrogate marker for atherogenic lipoprotein particle concentration. An increase in atherogenic lipoprotein particle number is thought to increase CHD risk.10,11 Lipoprotein particle size is another lipid parameter that may influence CHD risk.11 A disproportionate increase in smaller LDL particles is often described as increasing CHD risk.12 However, it is unclear whether LDL particle size provides an additional predictive power for measuring CHD risk versus LDL particle number.13 High-density lipoprotein cholesterol is a highly heterogeneous lipoprotein that can be separated into 2 major subclasses (HDL-C2 and HDL-C3) and several minor subclasses based on
1
Department of Cardiology, Istanbul University Institute of Cardiology, Istanbul, Turkey 2 Department of Biochemistry, Istanbul University Institute of Cardiology, Istanbul, Turkey Corresponding Author: Cem Bostan, Department of Cardiology, Istanbul University Institute of Cardiology, Haseki, Aksaray 34350 Istanbul, Turkey. Email: [email protected]
Downloaded from ang.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 23, 2014
2
Angiology
Table 1. Characteristics of Patients Included in the Analysis. Male/female (M/F), n Age, years Waist circumference (M/F), cm Body mass index, kg/m2a Initial At 6 months Impaired OGTT, n Hypertension, n
49/51 55.4 + 12.5 111.9 + 6.1/99.7 + 13.3 32.7 + 3.7 32.4 + 4.8 38 44
Abbreviations: M, male; F, female; OGTT, oral glucose tolerance test. a P ¼ .58.
density. Both major subclasses are inversely related to CHD risk14 and low HDL-C and low HDL particle concentrations are associated with increased CHD risk.15 The aim of this study was to determine the effect of 6-month rosuvastatin treatment on (1) blood lipids, (2) LDL and HDL sub groups, (3) oxidized LDL and antioxidized LDL antibody (OLAb), (4) Apo A, Apo B, and Apo E, (5) high-sensitivity C-reactive protein (hsCRP), Lp(a), and homocysteine, (6) total oxidant capacity, antioxidant capacity, and oxidant capacity index, and (7) hemoglobin A1c (HbA1c) in patients with MetS.
Material and Methods The study was conducted from January 2009 to January 2011.Turkish individuals (men aged >40 years and postmenopausal women) with a body mass index (BMI) 30 (n ¼ 100) who fulfilled the NCEP ATP III criteria for the diagnosis of MetS, but who were otherwise healthy, were included in the study.
cigarette smoking, height, weight, and waist and hip circumferences. Fasting blood samples were analyzed for baseline lipids, glucose, hemoglobin A1c (HbA1c), hsCRP, homocysteine, uric acid, fibrinogen, total antioxidant capacity (TAC), and total oxidant status (TOS). Serum samples were taken after fasting for 12 hours. Blood samples were centrifuged 3000 rpm 10 minutes. All samples were stored at 20 C. Blood serum samples were measured using a full automated biochemistry analyzer (Opera-Technicon Bayer Inst) with colorimetric methods. Antioxidants in the sample reduce dark blue–green-colored 2, 2’-azinobis 3-ethylbenzothiazoline-6-sulfonic acid diammonium (ABTS) radical to colorless reduced ABTS form. The change in absorbance at 660 nm is related to total antioxidant level of the sample. The assay is calibrated with a stable antioxidant standard solution that is traditionally named as Trolox Equivalent (a vitamin E analog). Oxidants present in the sample oxidize the ferrous ion–chelator complex to ferric ion. The oxidation reaction is prolonged by enhancer molecules that are abundantly present in the reaction medium. The ferric ion makes a colored complex with chromogen in an acidic medium. The color intensity, which can be measured spectrophotometrically, is related to the total amount of oxidant molecules present in the sample. The assay is calibrated with hydrogen peroxide and the results are expressed in terms of mmol/L of hydrogen peroxide equivalent per liter (mmol H2O2 equivalent/L). Oxidative stress index (OSI) was calculated. OSI (arbitrary unit) ¼ (TOS [mmol H2O2 equiv/L]/TAC [mmol Trolox equiv/L]) 100.
Study Medication
Exclusion Criteria
Rosuvastatin 20 mg per day was administered for 6 months.
Individuals were excluded if they had type 2 diabetes mellitus (fasting glucose levels >126 mg/dL) or a history of cerebrovascular disease. In addition, patients with thyroid function abnormalities, abnormal hepatic function, impaired renal function, and those receiving drugs that may interfere with glucose or lipid metabolism were excluded.
Follow-Up Data
Anthropometric and Metabolic Variables Body weight was determined to the nearest 0.1 kg with a calibrated beam balance and standing height was measured to the nearest 1 cm. Body mass index was calculated as weight (kg) divided by height squared (m2). Waist circumference was measured midway between the lower ribs and the iliac crest. Blood pressure measurements were obtained at the same time (morning) in the sitting position, in duplicate, using the right arm, following a 10-minute rest and using a validated mercury sphygmomanometer.
Baseline Data Patient demographic information was collected, including age, sex, qualifying criterion, self-reported race, current medications,
Patients were followed-up for 6 months after recruitment. We did not aim to change diet or lifestyle of patients. Patients underwent further fasting blood testing for fasting lipids and hsCRP. Patient adherence was assessed by the number of tablets left over. Patients with >4 days of tablets left over were deemed nonadherent. All patients were counseled about the benefits of cholesterol lowering and were asked specifically about muscular and gastrointestinal symptoms.
Results We enrolled 100 patients (49 men and 51 women). The mean age was 55.4 + 12.5 years. The mean BMI was 32.7 + 3.7 kg/m2. The mean waist circumference was 99.7 +13.3 cm for women and 111.9 + 6.1 cm for men. In all, 44 patients had hypertension and 38 had an impaired oral glucose tolerance test (Table 1). The 6-month course of rosuvastatin produced significant reductions in plasma total cholesterol and LDL-C levels relative to baseline (P < .0001). There was also a significant
Downloaded from ang.sagepub.com at Nat. Taichung Univ. of Sci. & Tech. on April 23, 2014
Bostan et al
3
Table 2. Lipid Profiles at Baseline and After a 6-Month Course of Rosuvastatin. Baseline
At 6 months
213 + 37 40 + 7 138 + 33 176 + 103 1.6 + 2.2 1.1 + 0.3 0.61 (0.01–1.69) 0.11 (0.06–1.34)
Total cholesterol, mg/dL HDL cholesterol, mg/dL LDL cholesterol, mg/dL Triglyceride, mg/dL Apo A, g/L Apo B, g/L Apo E, g/L Lipoprotein(a), g/L
173 47 100 159 1.6 1.0 0.25 0.10
+ 42 + 15 + 31 + 110 + 0.3 + 0.3 (0.01–1.47) (0.01–0.85)
P
