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Risk factors associated with atherogenic dyslipidemia in the presence of optimal statin therapy
Risk factors associated with atherogenic dyslipidemia in the presence of optimal statin therapy Wang Zhao, Xi-Long Zheng, Ze-Nan Jiang, Xiao-Bo Liao, Shui-Ping Zhao PII: DOI: Reference:
S0167-5273(16)32843-1 doi:10.1016/j.ijcard.2017.06.105 IJCA 25197
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
6 October 2016 8 June 2017 26 June 2017
Please cite this article as: Zhao Wang, Zheng Xi-Long, Jiang Ze-Nan, Liao Xiao-Bo, Zhao Shui-Ping, Risk factors associated with atherogenic dyslipidemia in the presence of optimal statin therapy, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.06.105
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ACCEPTED MANUSCRIPT Risk factors associated with atherogenic dyslipidemia in the
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presence of optimal statin therapy
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Wang Zhao,1 Xi-Long Zheng,2 Ze-Nan Jiang,3 Xiao-Bo Liao,3 Shui-Ping Zhao,1 * Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central
South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, China Department of Biochemistry and Molecular Biology, The Libin Cardiovascular
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Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South
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*
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University, No.139 Middle Renmin Road, Changsha, Hunan 410011, China
Corresponding Author:
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Name: Shui-Ping Zhao
Address: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, China Phone: 0086-731-85295806 Fax: 0086-731-85360309 Email: [email protected]
Running title: Risk factors of AD in statin therapy 1
ACCEPTED MANUSCRIPT ABSTRACT Background: This study investigated the prevalence of atherogenic dyslipidemia
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(AD) in Chinese outpatients whose low-density lipoprotein cholesterol (LDL-C)
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levels reached the goals with statin monotherapy and evaluated the characteristics of these patients.
Methods: An analysis of the Dyslipidemia International Survey-China study that was
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carried out at 122 hospitals in China. Among patients reaching their LDL-C goals, the
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presence of AD was defined as triglycerides levels ≥1.7 mmol/L and/or low levels of high-density lipoprotein cholesterol (men: <1.0 mmol/L; women:<1.3 mmol/L).
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Results: 22,039 patients receiving statin monotherapy were analyzed. According to
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the American National Cholesterol Education Program Adult Treatment Panel-III,
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13,088 patients reached LDL-C goals, and 7134 patients of them had AD. Age, male gender, BMI, sedentary lifestyle, diabetes mellitus, ischemic cerebrovascular disease,
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serum uric acid levels, and fasting plasma glucose (all P<0.05) were independently associated with AD. Based on the Chinese guideline for the management of dyslipidemia, 13,551 patients reached LDL-C goals, and 7719 patients of them had AD. Age, male gender, BMI, sedentary lifestyle, coronary heart disease, serum uric acid levels, and fasting plasma glucose (all P<0.05) were independently associated with AD. The intensity of statin therapy did not affect the prevalence of AD. Conclusion: There was a high prevalence of AD in Chinese patients with optimal statin treatment. Some risk factors associated with AD were identified, but these factors were slightly different according to two criteria/guidelines. The intensity of 2
ACCEPTED MANUSCRIPT statin therapy did not reduce the prevalence of AD. A combination lipid therapy may
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be more suitable for Chinese patients.
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Keywords: cardiovascular disease; risk factor; hypercholesterolemia; atherogenic
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dyslipidemia; statin.
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ACCEPTED MANUSCRIPT INTRODUCTION Increased levels of low-density lipoprotein cholesterol (LDL-C) are usually
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associated with increased cardiovascular disease (CVD) risk [1]. In recent decades,
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the prevalence of hypercholesterolemia has dramatically increased in China, because the new life habits become more similar to those in Western countries, leading to an increased in CVD mortality [2-4]. About 230 million people suffer from CVD in
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China, leading to a significant social and economic burden [4].
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Statins, a class of drugs effectively reducing the cholesterol, are currently often used in China without significant side effects [5]. However, some patients who use
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statins and whose LDL-C levels reach the goals still have atherogenic
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dyslipidemia (AD), which has defined as elevated levels of triglycerides (TG) (≥1.7
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mmol/L) with or without decreased levels of high-density lipoprotein cholesterol (HDL-C) (male <1.0 mmol/L, female <1.3 mmol/L) [6]. Studies have shown that AD
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is closely related to residual cardiovascular risk despite statin therapy [7-9]. Among the patients of the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials (patients with stroke or transient ischemic attack), 9-10% of patients still had AD despite optimal statin management [7]. A Chinese study showed that the residual cardiovascular risk could be higher in some patient populations, such as those with metabolic syndrome [9]. The international Dyslipidemia International Survey (DYSIS) trial showed that a 4
ACCEPTED MANUSCRIPT significant proportion of patients at high and very high cardiovascular risk still had some manifestations of AD despite optimal treatment [10]. Nevertheless, these studies
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were carried out in a variety of different populations. More studies are still necessary
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to examine comprehensively the residual cardiovascular risk in some populations. Therefore, this study aimed to investigate and assess the prevalence of AD in Chinese outpatients whose LDL-C levels reached the goals after statin monotherapy
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and also evaluate the characteristics of these patients. These results may help
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Study design and subjects
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SUBJECTS AND METHODS
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adequately manage the overall residual cardiovascular risk of CVD patients.
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This was an analysis of the Dyslipidemia International Survey-China (DYSIS-China) study that was carried out from April 2012 to October 2012 at 122
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Chinese hospitals in different cities in China [10]. The study was approved by the ethics committee of the Peking University People's Hospital (Approval number: [2010] Clinical medicine No.95). Inclusion criteria were: 1) patients in the DYSIS-China study who received a single-agent treatment of statin; and 2) LDL-C reached the goals. The LDL-C goals were determined according to the American National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (Table 1) or Chinese guideline for the management of dyslipidemia (2007 Chinese guideline) (Table 2) [2,11]. In the NCEP-ATP III criteria [11], CVD risk equivalent refers to that the risk of 5
ACCEPTED MANUSCRIPT major coronary events within 10 years in patients without CVD equivalent to the risk of patients with coronary heart disease (including peripheral arterial disease,
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abdominal aortic aneurysm, carotid artery disease, other clinical forms of
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atherosclerotic diseases, such as renal artery disease, diabetes, and multiple risk factors combined with a 10-year risk >20%). Risk factors were cigarette smoking, hypertension (blood pressure ≥140/90 mmHg or on antihypertensive medication), low
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HDL-C levels (<40 mg/dL), family history of premature coronary heart disease (CHD)
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(CHD in male first-degree relative <55 years; CHD in female first-degree relative <65 years), and age (men ≥45 years; women ≥55 years). The 10-year risk was determined
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from the Framingham risk score [11,12].
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In the 2007 Chinese guidelines, CHD risk equivalent refers to that of the risk of
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major coronary events within 10 years in patients without coronary heart disease equivalent to the risk of coronary heart disease patients. They included the following
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diseases: peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, other clinical forms of atherosclerotic disease (such as renal artery disease), diabetes, and multiple risk factors combined with a 10-year risk >20%. Risk factors included hypertension (blood pressure ≥140/90 mmHg or on antihypertensive medication), smoking, low HDL-C level (<1.0 mmol/L or <40 mg/dL), obesity [body mass index (BMI) ≥28 kg/m2], family history of premature ischemic cerebrovascular disease (disease in male first-degree relative <55 years; disease in female first-degree relative <65 years), and age (men ≥45 years; women ≥55 years). The 10-year risk was determined from the Framingham risk score [11,12]. 6
ACCEPTED MANUSCRIPT Grouping Patients were grouped according to the presence or absence of AD. For patients
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whose LDL-C levels reached the goals after treatment, the presence of AD was
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defined by the presence of TG levels ≥1.7 mmol/L and/or low levels of HDL-C (men: <1.0 mmol/L; women: <1.3 mmol/L). Data collection
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The following data were collected: Gender, age, history of CHD, history of
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hypertension (blood pressure), diabetes (fasting blood glucose and glycosylated hemoglobin), smoking history, drinking history, physical activity, obesity, family
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history of the premature disease, and statin monotherapy.
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"Current smokers" were defined as currently smoking or smoking cessation for
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less than one year. "Former smokers" were defined as smoking cessation for more than one year. "Non-smokers" were defined as never having smoked.
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Drinking was defined as the average daily drinking of >50 ml of liquor, the average daily drinking of >150 ml of wine, or average daily drinking of >500 ml of beer. "Abstinence from alcohol" was defined as non-consumption of alcohol for more than one year. If the patient had no routine physical activity (less than 20-30 minutes of walking, 3-4 days a week; or equivalent amount of activity), it was considered as a sedentary lifestyle. Obesity was defined by BMI ≥28 kg/m2. Intensity of statin therapy was classified into high-intensity, moderate-intensity, and low-intensity, according to the 2013 ACC/AHA guidelines [6]: low-intensity 7
ACCEPTED MANUSCRIPT statin (daily; simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg, and pitavastatin 1 mg), moderate-intensity statin (daily; atorvastatin 10-20
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mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40
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mg, fluvastatin sustained-release tablets 80 mg, fluvastatin 40 mg (twice a day), and pitavastatin 2-4 mg), and high-intensity statin (daily; atorvastatin 40-80 mg and rosuvastatin 20-40 mg).
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Statistical analysis
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Continuous data with a normal distribution were presented as mean ± standard deviation. Continuous data with a non-normal distribution were presented as median
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(range). Continuous data were presented as frequencies. Logistic regression analysis
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was used for multivariate analysis (enter method). SAS 9.2 (SAS Institute Inc., Cary,
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NC, USA) was used for data analysis. Two-sided P-values<0.05 were considered
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statistically significant.
RESULTS
Characteristics of the patients reaching the LDL-C goals In the DYSIS-China study, 22,039 patients received a statin monotherapy. Among them, 13,088 (59.4%) patients reached the LDL-C goals according to the NCEP ATP-III criteria and 13,551 (61.5%) patients reached the LDL-C goals according to the 2007 Chinese guidelines [11,12]. Table 3 presents the characteristics of the patients reaching the LDL-C goals according to the NCEP-ATP III criteria or the 2007 Chinese guidelines. Majority of 8
ACCEPTED MANUSCRIPT patients were aged between 45-64 years (50.3% and 51.0%) and male (54.5% and 54.9%). Mean BMI was 24.5±3.2 kg/m2. About 12.1% of patients were smokers,
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8.5-8.8% consumed alcohol, 19.2-19.3% had a sedentary lifestyle, 65.1-65.8% had
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hypertension, 23.5-25.2% had diabetes, 30.1-37.1% had CAD, and 14.1-16.0% had cerebrovascular diseases. In both classifications, the majority of patients were at high
Univariate and multivariate analyses
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risk (45.1% and 54.8%).
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According to the NCEP ATP-III criteria, 7134 patients (54.5%) reaching the LDL-C goals still had AD compared with 7719 patients (57.0%) according to the
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2007 Chinese guidelines.
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Table 4 presents the univariate analyses of the risk factors associated with or
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without the prevalence of AD according to the NCEP-ATP III criteria or the 2007 Chinese guidelines. According to the NCEP-ATP III criteria, patients with risk factors
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of AD were characterized by younger age (P<0.0001), lower proportion of males (P<0.0001), larger waist circumference (P<0.0001), higher BMI (P<0.0001), higher proportion of sedentary lifestyle (P=0.04), higher proportion of diabetes (P<0.0001), higher proportion of CAD (P<0.0001), lower proportion of ischemic cerebrovascular disease (P=0.03), higher proportion of patients with very high risk (P<0.0001), higher SBP (P=0.002), higher DBP (P<0.0001), higher serum uric acid (P<0.0001), higher fasting plasma glucose (P<0.0001), higher 2-h postprandial glucose (P=0.006), higher HbA1c (P<0.0001), lower HDL-C levels (P<0.0001), higher TG levels (P<0.0001), and higher non-HDL-C levels (P<0.0001). Similar univariate associations were 9
ACCEPTED MANUSCRIPT observed according to the 2007 Chinese guidelines (Table 4), except for CAD (P=0.30) and alcohol (P=0.03).
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Table 5 presents the multivariate analyses. Variables that were associated with
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risk factors of AD in univariate analyses (P<0.05) were included in the multivariate model (enter method). Risk classification could not be included because it was a covariate of risk factors of AD; 2-h postprandial plasma glucose and HbA1c were
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covariates of fasting plasma glucose FPG and had to be removed. Finally, because
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HDL-C and TG were included in the indicators for the determination of the risk factors of AD, they were removed from the analysis.
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According to the NCEP-ATP III definition, age (OR=0.98, 95%CI: 0.97-0.99,
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P<0.0001), male gender (OR=0.47, 95%CI: 0.41-0.54, P<0.0001), BMI (OR=1.08,
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95%CI: 1.06-1.11, P<0.0001), sedentary lifestyle (OR=1.24, 95%CI: 1.07-1.44, P=0.004), diabetes mellitus (OR=1.36, 95%CI: 1.17-1.58, P<0.0001), ischemic
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cerebrovascular disease (OR=1.20, 95%CI: 1.02-1.41, P=0.03), serum uric acid levels (OR=1.00, 95%CI: 1.00-1.00, P<0.0001), and fasting plasma glucose (OR=1.08, 95%CI: 1.04-1.12, P<0.0001) were independently associated with a residual AD despite optimal statin therapy. According to the 2007 Chinese guidelines, age (OR=0.98, 95%CI: 0.97-0.99, P<0.0001), male gender (OR=0.44, 95%CI: 0.39-0.50, P<0.0001), BMI (OR=1.09, 95%CI: 1.06-1.11, P<0.0001), sedentary lifestyle (OR=1.26, 95%CI: 1.09-1.45, P=0.002), CHD (OR=1.15, 95%CI: 1.00-1.32, P=0.03), serum uric acid levels (OR=1.00, 95%CI: 1.00-1.00, P<0.0001), and fasting plasma glucose (OR=1.09, 10
ACCEPTED MANUSCRIPT 95%CI: 1.05-1.13, P<0.0001) were independently associated with a residual AD
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despite optimal statin therapy.
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DISCUSSION
Many patients still display AD despite optimal statin treatment, which helps in the assessment of the residual cardiovascular risk in statin-treated patients [13]. This
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study has investigated and assessed the prevalence of AD in Chinese outpatients
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whose LDL-C levels reached the goals after statin monotherapy and also evaluated the characteristics of these patients. The analysis of our article was based on
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DYSIS-China study which was carried out on Chinese population. For this reason,
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we chose the 2007 Chinese guidelines. Given that the NCEP ATP-III criteria has been
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widely used by doctors in China, we analyzed the data according the different criteria/guidelines to confirm whether different criteria/guidelines could result in
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similar conclusions. As expected, our results showed the similar conclusion that the high prevalence of AD in Chinese patients with optimal statin treatment were 54.5% (according to the NCEP ATP-III criteria) and 57.0% (according to the 2007 Chinese guidelines). Interestingly, the rate to reach the LDL-C goals in Chinese patients was higher than those observed in other countries participating in the DYSIS study. For instance, 51.8% of statin-treated patients in Canada and 11 European countries (Austria, Denmark, France, Germany, Ireland, the Netherlands, Norway, Portugal, Spain, Sweden, and the United Kingdom) reached their LDL-C goals [14]. 49.7% of South 11
ACCEPTED MANUSCRIPT African patients achieved the target LDL-C [15]. 43.8% of the statin-treated Belgian patients reached the goals of LDL-C [16]. In the DYSIS-Middle East study, 38.2% of
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Middle Eastern (the United Arab Emirates, Saudi Arabia, Lebanon and Jordan)
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patients reached their LDL-C targets [17]. In the DYSIS-Egypt study, 32.8% of the Egyptian patients reached their LDL-C targets [18]. Only 19.3% of patients in the Baltic states (Estonia, Latvia, and Lithuania) were at the target LDL-C level (Figure 1)
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[19]. However, the prevalence of AD in Chinese patients who reached their LDL-C
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goals was higher than that in Canada and 11 European countries’ patients (50.0%) [14], Baltic states patients (43.8%) [19], Belgian patients (33.8%) [16], lower than
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that of Middle Eastern patients (62.5%) [17], South African patients (58.7%) [15], and
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similar with that of Egyptian patients (54.8%) (Figure 2) [18]. These differences
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among different countries participating in the DYSIS study could be due to several factors, such as genetics, clinical factors (DM, hypertension, history of CVD) and
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environmental factors (smoking, stress, diet, sedentary lifestyle, pollution, etc.). These factors were not all available in the present study. Additional studies will be necessary to increase the generalizability of these results. In the present study, age, male gender, BMI, sedentary lifestyle, diabetes mellitus, CVD, serum uric acid levels, and fasting plasma glucose were independently associated with AD despite optimal statin therapy. These factors are well-known risk factors for CVD [11]. Therefore, their association with AD could be predicted. Previous studies on AD after statin therapy have shown similar factors [9,10]. The intensity of statin therapy was not associated with AD. AD has been noted in 12
ACCEPTED MANUSCRIPT most large-scale trials of statin therapy [20-26]. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE
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IT-TIMI 22), The Incremental Decrease in Endpoints Through Aggressive Lipid
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Lowering (IDEAL), and Treat to New Target (TNT) trials showed that targeting LDL-C levels of 100 or 70 mg/dL using different intensities of statin therapy led to similar of proportions of patients with AD in each group [27-29]. In these three trials,
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atorvastatin 80 mg led to a higher reduction in the CVD risk, but AD was still present.
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In the Aggrastat to Zocor (A to Z) trial, early initiation of intensive simvastatin therapy in patients with acute coronary syndrome did not lead to a reduction in
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subsequent endpoints compared with less aggressive regimens [30]. Nevertheless, a
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meta-analysis in patients in secondary prevention showed that more aggressive
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therapy could lower the risk of secondary cardiovascular events [31]. In the present study, about half of the patients were in primary prevention, which could explain, at
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least in part, some discrepancies with previous studies. In addition, it may be because low HDL levels and high TG levels are two major types of dyslipidemia in Chinese adults [32], and stain has little influence on TG and HDL, inducing no effect on the AD in Chinese patients. In the multivariate analysis, age, gender, BMI, serum uric acid levels, and fasting plasma glucose were common between the two criteria/guidelines, but not diabetes mellitus, coronary artery disease, and ischemic cerebrovascular disease. These differences could be explained by the different criteria used to define the very-high risk group. Such a discrepancy was shown in a study of Chinese patients with 13
ACCEPTED MANUSCRIPT metabolic syndrome [9]. Nevertheless, despite these differences, all these patients need a pharmacological
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treatment to lower their risk of CVD. Indeed, the associations among diabetes mellitus,
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coronary artery disease, ischemic cerebrovascular disease, and dyslipidemia are well known [11,33]. However, as shown in the present study and previous trials [27-29], aggressive statin therapy could not be suitable for all patients. Therefore, some
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authors suggest that other methods should be sought to decrease AD [34]. Even if
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they are generally well-tolerated, statins may have some side effects, and this should be balanced with the optimal benefits of the treatment. Fibrates or nicotinic acid could
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be used to manage AD, but trials are necessary to address these treatments [35]. In the
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Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, subgroup
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analyses suggested a benefit of the fenofibrate and simvastatin combination therapy for type 2 diabetic patients with both TG levels ≥2.3 mmol/L and HDL-C levels ≤0.9
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mmol/L [36]. Based on the high prevalence of AD and special dyslipidemia in Chinese adults, a combination lipid therapy may be more suitable for Chinese patients.
Despite some differences in the definition of lipid target values and AD between the two criteria/guidelines, a similar proportion of patients still had AD after optimal statin treatment according to the LDL-C levels. These results suggest that the two criteria/guidelines are roughly equivalent to determine AD. Nevertheless, the 2007 Chinese guidelines were specifically tailored to Chinese individuals [12], and it could be more appropriate to use these guidelines when assessing Chinese patients. 14
ACCEPTED MANUSCRIPT There were some limitations in the present study. Some data were missing for some patients, which could introduce a bias. In addition, this was a cross-sectional
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study, without any follow-up of the eventual cardiovascular events. Only traditional
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risk factors were examined, and the emerging risk factors, such as LDL size, oxidative stress, and levels of metalloproteinases, could be examined. Additional studies are necessary to address the actual cardiovascular risk in relation to AD after optimal
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statin therapy.
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In conclusion, there was a high prevalence of AD in Chinese patients with optimal statin treatment. Some risk factors associated with AD were found in the
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current study, and these factors were slightly different according to two different
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criteria/guidelines. The intensity of statin therapy did not reduce the prevalence of AD
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despite optimal statin therapy. A combination lipid therapy may be more suitable for
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Chinese patients.
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ACCEPTED MANUSCRIPT COMPETING INTERESTS
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All authors declare that they have no competing interests.
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20. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 2012;14:1-10. 21. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57. 22. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised 20
ACCEPTED MANUSCRIPT placebo-controlled trial. Lancet 2002;360:7-22. 23. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA,
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Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute
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coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-22.
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24. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L,
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Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol
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1996;335:1001-9.
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levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med
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25. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with
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hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7. 26. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol 2005;46:1225-8. 27. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504. 21
ACCEPTED MANUSCRIPT 28. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT)
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coronary disease. N Engl J Med 2005;352:1425-35.
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Investigators. Intensive lipid lowering with atorvastatin in patients with stable
29. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End
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Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose
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atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-45.
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30. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau
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JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer
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DW, Pfeffer MA, Califf RM, Braunwald E; Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z
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of the A to Z trial. JAMA 2004;292:1307-16. 31. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48:438-45. 32. Pan L, Yang Z, Wu Y, Yin RX, Liao Y, Wang J, Gao B, Zhang L; China National Survey of Chronic Kidney Disease Working Group. The prevalence, awareness, treatment and control of dyslipidemia among adults in China. Atherosclerosis 2016;248:2-9. 33. Soler EP, Ruiz VC. Epidemiology and risk factors of cerebral ischemia and 22
ACCEPTED MANUSCRIPT ischemic heart diseases: similarities and differences. Curr Cardiol Rev 2010;6:138-49. 34. Sazonov V, Beetsch J, Phatak H, Wentworth C, Evans M. Association between
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dyslipidemia and vascular events in patients treated with statins: report from the UK
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General Practice Research Database. Atherosclerosis 2010;208:210-6. 35. Reiner Z. Managing the residual cardiovascular disease risk associated with
Metab Cardiovasc Dis 2013;23:799-807.
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HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. Nutr
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36. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH,
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Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington
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2010;362:1563-74.
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RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med
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ACCEPTED MANUSCRIPT Table 1. Risk stratification and LDL-C goals according to the NCEP-ATP III Risk
Definition
LDL-C goals
History of coronary heart disease, combined with:
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Very-high risk
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stratification
(1) diabetes (2) smoking
<1.8
mmol/L
(70 mg/dL)
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(3) multiple risk factors of metabolic syndrome
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(especially when TG ≥200 mg/dL combined with non-HDL-C ≥130 mg/dL and low level of HDL-C
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[<40 mg/dL])
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(4) acute coronary artery syndrome History of coronary heart disease or coronary <2.6
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High risk
risk
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Moderate-high
Moderate risk
mmol/L
heart disease risk equivalent
(100 mg/dL)
≥2 risk factors with 10-year risk of 10-20%
<3.4
mmol/L
(130 mg/dL) ≥2 risk factors with 10-year risk <10%
<3.4
mmol/L
(130 mg/dL) Low risk
0-1 risk factor
<4.1
mmol/L
(160 mg/dL)
24
ACCEPTED MANUSCRIPT Table 2. Risk stratification and LDL-C goals of the 2007 Chinese guideline Risk
Definition
LDL-C value
Acute coronary artery syndrome or ischemic <2.0
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Very-high risk
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stratification
cerebrovascular disease combined with diabetes High risk
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5-10%
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0-1 risk factor combined with 10-year risk <5%
mmol/L
(100 mg/dL)
≥2 risk factors combined with 10-year risk of <3.4
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Moderate risk
mmol/L
(80 mg/dL)
Coronary heart disease or coronary heart disease <2.6 risk equivalent, or 10-year risk of 10-15%
Low risk
target
mmol/L
(130 mg/dL) <4.1
mmol/L
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(160 mg/dL)
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ACCEPTED MANUSCRIPT Table 3. Characteristics of the patients who reached the LDL-C goals NCEP-ATP III criteria 2007 Chinese guidelines Variable
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65.4±10.6
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65.6±10.6 6584 (50.3)
65-74, n (%)
3849 (29.4)
>75, n (%)
2655 (20.3)
2685 (19.8)
Male, n (%)
7134 (54.5)
7446 (54.9)
Waist circumference (cm)
86.5±11.2
86.8±11.3
BMI (kg/m2)
24.5±3.2
24.5±3.2
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45-64, n (%)
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Age (years), mean±SD
(n=13,551)
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(n=13,088)
3949 (29.1)
1579 (12.1)
1636 (12.1)
1146 (8.8)
1157 (8.5)
Sedentary life style, n (%)
2514 (19.2)
2617 (19.3)
Hypertension, n (%)
8520 (65.1)
8911 (65.8)
Diabetes mellitus, n (%)
3070 (23.5)
3415 (25.2)
Coronary heart disease, n (%)
3936 (30.1)
5031 (37.1)
1980 (15.1)
2169 (16.0)
124 (0.9)
145 (1.1)
1104 (8.4)
1195 (8.8)
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Smoking, n (%)
6917 (51.0)
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Alcohol consumption, n (%)
Ischemic
cerebrovascular
disease, n (%) Peripheral arterial disease, n (%) Family history of CAD, n (%) Risk classification, n (%) 26
ACCEPTED MANUSCRIPT 1369 (10.5)
1163 (8.6)
High risk
5908 (45.1)
7423 (54.8)
Moderate-high risk
201 (1.5)
-
Moderate risk
194 (1.5)
Low risk
5416 (41.4) blood
pressure 129.6±15.0
blood
pressure
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329.5±98.3
331.7±98.8
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80.2±31.3
80.4±31.8
5.9±2.0
6.0±2.0
11.7±5.5
11.9±5.5
HbA1c (%)
6.8±1.6
6.9±1.6
Total cholesterol (mmol/L)
4.11±1.05
4.03±0.99
2.15±0.73
2.09±0.65
1.28±0.37
1.26±0.37
1.35(0.97-1.95)
1.36(0.97-1.98)
plasma
(mmol/L)
postprandial
plasma
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2-h
glucose
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Fasting
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Serum creatinine (mmol/L)
129.4±14.9
77.3±9.5
(mmHg) Serum uric acid (mmol/L)
3302 (24.4)
77.4±9.5
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Diastolic
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(mmHg)
1663 (12.3)
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Systolic
T
Very high risk
glucose (mmol/L)
Low-density
lipoprotein
cholesterol (mmol/L) High-density
lipoprotein
cholesterol (mmol/L) Triglyceride (mmol/L)
27
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2.83±0.97
2.77±0.91
High-intensity
1070 (8.3)
1140 (8.5)
Moderate-intensity
10,132 (78.3)
Low-intensity
1738 (13.4)
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Statin therapy, n (%)
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NU
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10,561 (78.8)
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1704 (12.7)
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Table 4. Univariate analyses of the risk factors associated with the prevalence of AD or not,
n=7134 64.5±10.4
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Age (years), mean±SD
Without AD
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With AD
With AD
Without AD
P
n=5954
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Variables
2007 Chinese guidelines
CR
NCEP-ATP III criteria
P n=7719
n=5832
67.0±10.5
<0.0001
64.4±10.4
66.8±10.6
<0.0001
<0.0001
4273 (55.4)
2644 (45.3)
< 0.0001
3939 (55.2)
2645 (44.4)
65-74, n (%)
1976 (27.7)
1873 (31.5)
2135 (27.7)
1814 (31.1)
1311 (17.0)
1374 (23.6)
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45-64, n (%)
1436 (24.1)
3458 (48.5)
3676 (61.7)
<0.0001
3803 (49.3)
3643 (62.5)
<0.0001
Waist circumference, n (%)
87.1±11.3
85.9±11.0
<0.0001
87.5±11.5
86.0±11.0
<0.0001
BMI (kg/m2)
24.9±3.2
24.0±3.2
<0.0001
24.9±3.2
24.0±3.2
<0.0001
Smoking, n (%)
870 (12.2)
709 (11.9)
0.6315
945 (12.2)
691 (11.8)
0.4857
Male, n (%)
1219 (17.1)
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>75, n (%)
29
Sedentariness, n (%)
1418 (19.9)
1096 (18.4)
Hypertension, n (%)
4662 (65.3)
3858 (64.8)
Diabetes mellitus, n (%)
1882 (26.4)
1188 (20.0)
Coronary heart disease, n (%)
1926 (27.0)
Ischemic cerebrovascular disease, n (%)
1034 (14.5)
Peripheral arterial disease, n (%)
65 (0.9)
Family history of CAD, n (%)
646 (9.1)
532 (9.1)
0.0345
0.0355
1548 (20.1)
1069 (18.3)
0.0118
0.522
5120 (66.3)
3791 (65.0)
0.1072
<0.0001
2093 (27.1)
1322 (22.7)
<0.0001
2010 (33.8)
<0.0001
2837 (36.8)
2194 (37.6)
0.3012
946 (15.9)
0.0283
1180 (15.3)
989 (17.0)
0.0086
59 (1.0)
0.7083
84 (1.1)
61 (1.0)
0.8128
458 (7.7)
0.0057
734 (9.5)
461 (7.9)
0.0011
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AC
Very high risk
625 (8.1)
T
553 (9.3)
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593 (8.3)
CR
Alcohol consumption, n (%)
Risk classification, n (%)
0.0531
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<0.0001
<0.0001
1035 (14.5)
334 (5.6)
734 (9.5)
429 (7.4)
High risk
2873 (40.3)
3035 (51.0)
4139 (53.6)
3284 (56.3)
Moderate-high risk
191 (2.7)
10 (0.2)
-
-
Moderate risk
194 (2.7)
0
933 (12.1)
730 (12.5)
30
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130.0±14.9
129.1±150
Diastolic blood pressure (mmHg)
77.9±9.5
76.9±9.4
Serum uric acid (mmol/L)
338.2±102.3
319.7±92.6
Serum creatinine (mmol/L)
79.9±31.6
Fasting plasma glucose (mmol/L)
6.1±2.1
2-h postprandial plasma glucose (mmol/L)
12.3±5.4
HbA1c (%) Total cholesterol (mmol/L)
0.0015
129.9±15.0
128.7±14.7
<0.0001
<0.0001
77.8±9.6
76.6±9.3
<0.0001
<0.0001
340.9±102.2
320.1±93.0
<0.0001
80.5±30.9
0.3596
80.3±32.6
80.6±30.9
0.6586
5.7±1.7
<0.0001
6.1±2.1
5.8±1.8
<0.0001
10.7±5.4
0.0062
12.5±5.4
10.9±5.5
0.0059
7.0±1.7
6.7±1.5
<0.0001
7.0±1.7
6.7±1.5
<0.0001
4.12±1.15
4.10±0.93
0.1748
4.04±1.07
4.01±0.87
0.1493
2.15±0.76
2.15±0.69
0.8288
2.09±0.67
2.08±0.62
0.3237
1.12±0.33
1.47±0.33
<0.0001
1.10±0.32
1.46±0.33
<0.0001
1.87(1.30,
1.04(0.81,
US
MA N
CE P
AC
High-density lipoprotein cholesterol (mmol/L)
Triglycerides (mmol/L)
1389 (23.8)
T
Systolic blood pressure (mmHg)
Low-density lipoprotein cholesterol (mmol/L)
1913 (24.8)
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2575 (43.2)
CR
28741 (39.8)
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Low risk
1.87(1.30, 2.51)
1.05(0.81, 1.32)
<0.0001
<0.0001 2.50)
31
1.31)
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2.62±0.84
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3.00±1.03
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Non-HDL-C (mmol/L)
CR
Statin therapy, n (%) 583 (8.4)
477 (8.1)
Moderate-intensity
5563 (78.6)
4569 (77.9)
Low-intensity
919 (13.0)
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US
High-intensity
AC
CE P
TE D
819 (14.0)
32
<0.0001
2.93±0.97
2.55±0.78
0.2561
<0.0001 0.5323
933 (12.2)
771 (13.4)
6061 (79.1)
4500 (78.3)
665 (8.7)
475 (8.3)
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Table 5. Multivariate analyses of the risk factors associated with the prevalence of AD or not 2007 Chinese guidelines
CR
NCEP-ATP III criteria Variables p
Age
0.979 (0.973, 0.985)
<0.0001
Male
0.473 (0.414, 0.540)
<0.0001
0.438 (0.385, 0.498)
<0.0001
Waist circumference
1.001 (0.995, 1.007)
0.7790
1.002 (0.996, 1.008)
0.5780
BMI
1.082 (1.058, 1.106)
<0.0001
1.085 (1.061, 1.109)
<0.0001
Alcohol consumption
0.822 (0.670, 1.008)
0.0590
0.844 (0.691, 1.031)
0.1450
Sedentary lifestyle
1.241 (1.073, 1.436)
0.0040
1.259 (1.092, 1.451)
0.0020
Diabetes mellitus
1.361 (1.174, 1.577)
<0.0001
1.147 (0.996, 1.321)
0.0730
Coronary heart disease
0.934 (0.822, 1.062)
0.2980
1.153 (1.023, 1.300)
0.0300
Ischemic cerebrovascular disease
1.201 (1.021, 1.413)
0.0270
1.168 (0.999, 1.365)
0.0700
Family history of CAD
0.949 (0.765, 1.176)
0.6320
0.955 (0.778, 1.173)
0.6990
MA N
0.979 (0.974, 0.985)
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CE P
AC
OR (95%CI)
US
OR (95%CI)
33
p <0.0001
1.000 (0.996, 1.005)
0.9200
1.003 (0.998, 1.007)
0.4390
Diastolic blood pressure
1.005 (0.997, 1.013)
0.2120
1.005 (0.998, 1.013)
0.0720
Serum uric acid
1.003 (1.002, 1.004)
<0.0001
1.003 (1.003, 1.004)
<0.0001
Fasting plasma glucose
1.076 (1.037, 1.116)
<0.0001
US
CR
T
Systolic blood pressure
IP
ACCEPTED MANUSCRIPT
AC
CE P
TE D
MA N
1.088 (1.051, 1.127)
34
<0.0001
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CR
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Figure Legends
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Figure 1. The rates for the patients to reach the LDL-C goals
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LDL-C: low-density lipoprotein cholesterol; China (NCEP ATP-III criteria): Chinese patients according to the NCEP ATP-III criteria; China (2007 Chinese guidelines): Chinese patients according to the 2007 Chinese guidelines; Canada and 11 European countries: Canada and 11
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Egyptian patients; the Baltic states: Baltic states patients.
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European countries’ patients; South Africa: South African patients; Belgium: Belgian patients; the Middle East: Middle Eastern patients; Egypt:
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Figure 2. The prevalence of atherogenic dyslipidemia in patients who reached the LDL-C goals LDL-C: low-density lipoprotein cholesterol; China (NCEP ATP-III criteria): Chinese patients according to the NCEP ATP-III criteria; China (2007 Chinese guidelines): Chinese patients according to the 2007 Chinese guidelines; Canada and 11 European countries: Canada and 11 European countries’ patients; South Africa: South African patients; Belgium: Belgian patients; the Middle East: Middle Eastern patients; Egypt: Egyptian patients; the Baltic states: Baltic states patients.
35
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Figure 1
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MA N
US
CR
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ACCEPTED MANUSCRIPT
36
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Figure 2
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MA N
US
CR
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S0167-5273(16)32843-1 doi:10.1016/j.ijcard.2017.06.105 IJCA 25197
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
6 October 2016 8 June 2017 26 June 2017
Please cite this article as: Zhao Wang, Zheng Xi-Long, Jiang Ze-Nan, Liao Xiao-Bo, Zhao Shui-Ping, Risk factors associated with atherogenic dyslipidemia in the presence of optimal statin therapy, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.06.105
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Risk factors associated with atherogenic dyslipidemia in the
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presence of optimal statin therapy
1
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Wang Zhao,1 Xi-Long Zheng,2 Ze-Nan Jiang,3 Xiao-Bo Liao,3 Shui-Ping Zhao,1 * Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central
South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, China Department of Biochemistry and Molecular Biology, The Libin Cardiovascular
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2
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Institute of Alberta, Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South
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3
*
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University, No.139 Middle Renmin Road, Changsha, Hunan 410011, China
Corresponding Author:
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Name: Shui-Ping Zhao
Address: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, China Phone: 0086-731-85295806 Fax: 0086-731-85360309 Email: [email protected]
Running title: Risk factors of AD in statin therapy 1
ACCEPTED MANUSCRIPT ABSTRACT Background: This study investigated the prevalence of atherogenic dyslipidemia
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(AD) in Chinese outpatients whose low-density lipoprotein cholesterol (LDL-C)
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levels reached the goals with statin monotherapy and evaluated the characteristics of these patients.
Methods: An analysis of the Dyslipidemia International Survey-China study that was
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carried out at 122 hospitals in China. Among patients reaching their LDL-C goals, the
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presence of AD was defined as triglycerides levels ≥1.7 mmol/L and/or low levels of high-density lipoprotein cholesterol (men: <1.0 mmol/L; women:<1.3 mmol/L).
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Results: 22,039 patients receiving statin monotherapy were analyzed. According to
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the American National Cholesterol Education Program Adult Treatment Panel-III,
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13,088 patients reached LDL-C goals, and 7134 patients of them had AD. Age, male gender, BMI, sedentary lifestyle, diabetes mellitus, ischemic cerebrovascular disease,
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serum uric acid levels, and fasting plasma glucose (all P<0.05) were independently associated with AD. Based on the Chinese guideline for the management of dyslipidemia, 13,551 patients reached LDL-C goals, and 7719 patients of them had AD. Age, male gender, BMI, sedentary lifestyle, coronary heart disease, serum uric acid levels, and fasting plasma glucose (all P<0.05) were independently associated with AD. The intensity of statin therapy did not affect the prevalence of AD. Conclusion: There was a high prevalence of AD in Chinese patients with optimal statin treatment. Some risk factors associated with AD were identified, but these factors were slightly different according to two criteria/guidelines. The intensity of 2
ACCEPTED MANUSCRIPT statin therapy did not reduce the prevalence of AD. A combination lipid therapy may
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be more suitable for Chinese patients.
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Keywords: cardiovascular disease; risk factor; hypercholesterolemia; atherogenic
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dyslipidemia; statin.
3
ACCEPTED MANUSCRIPT INTRODUCTION Increased levels of low-density lipoprotein cholesterol (LDL-C) are usually
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associated with increased cardiovascular disease (CVD) risk [1]. In recent decades,
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the prevalence of hypercholesterolemia has dramatically increased in China, because the new life habits become more similar to those in Western countries, leading to an increased in CVD mortality [2-4]. About 230 million people suffer from CVD in
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China, leading to a significant social and economic burden [4].
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Statins, a class of drugs effectively reducing the cholesterol, are currently often used in China without significant side effects [5]. However, some patients who use
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statins and whose LDL-C levels reach the goals still have atherogenic
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dyslipidemia (AD), which has defined as elevated levels of triglycerides (TG) (≥1.7
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mmol/L) with or without decreased levels of high-density lipoprotein cholesterol (HDL-C) (male <1.0 mmol/L, female <1.3 mmol/L) [6]. Studies have shown that AD
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is closely related to residual cardiovascular risk despite statin therapy [7-9]. Among the patients of the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials (patients with stroke or transient ischemic attack), 9-10% of patients still had AD despite optimal statin management [7]. A Chinese study showed that the residual cardiovascular risk could be higher in some patient populations, such as those with metabolic syndrome [9]. The international Dyslipidemia International Survey (DYSIS) trial showed that a 4
ACCEPTED MANUSCRIPT significant proportion of patients at high and very high cardiovascular risk still had some manifestations of AD despite optimal treatment [10]. Nevertheless, these studies
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were carried out in a variety of different populations. More studies are still necessary
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to examine comprehensively the residual cardiovascular risk in some populations. Therefore, this study aimed to investigate and assess the prevalence of AD in Chinese outpatients whose LDL-C levels reached the goals after statin monotherapy
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and also evaluate the characteristics of these patients. These results may help
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Study design and subjects
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SUBJECTS AND METHODS
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adequately manage the overall residual cardiovascular risk of CVD patients.
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This was an analysis of the Dyslipidemia International Survey-China (DYSIS-China) study that was carried out from April 2012 to October 2012 at 122
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Chinese hospitals in different cities in China [10]. The study was approved by the ethics committee of the Peking University People's Hospital (Approval number: [2010] Clinical medicine No.95). Inclusion criteria were: 1) patients in the DYSIS-China study who received a single-agent treatment of statin; and 2) LDL-C reached the goals. The LDL-C goals were determined according to the American National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (Table 1) or Chinese guideline for the management of dyslipidemia (2007 Chinese guideline) (Table 2) [2,11]. In the NCEP-ATP III criteria [11], CVD risk equivalent refers to that the risk of 5
ACCEPTED MANUSCRIPT major coronary events within 10 years in patients without CVD equivalent to the risk of patients with coronary heart disease (including peripheral arterial disease,
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abdominal aortic aneurysm, carotid artery disease, other clinical forms of
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atherosclerotic diseases, such as renal artery disease, diabetes, and multiple risk factors combined with a 10-year risk >20%). Risk factors were cigarette smoking, hypertension (blood pressure ≥140/90 mmHg or on antihypertensive medication), low
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HDL-C levels (<40 mg/dL), family history of premature coronary heart disease (CHD)
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(CHD in male first-degree relative <55 years; CHD in female first-degree relative <65 years), and age (men ≥45 years; women ≥55 years). The 10-year risk was determined
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from the Framingham risk score [11,12].
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In the 2007 Chinese guidelines, CHD risk equivalent refers to that of the risk of
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major coronary events within 10 years in patients without coronary heart disease equivalent to the risk of coronary heart disease patients. They included the following
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diseases: peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, other clinical forms of atherosclerotic disease (such as renal artery disease), diabetes, and multiple risk factors combined with a 10-year risk >20%. Risk factors included hypertension (blood pressure ≥140/90 mmHg or on antihypertensive medication), smoking, low HDL-C level (<1.0 mmol/L or <40 mg/dL), obesity [body mass index (BMI) ≥28 kg/m2], family history of premature ischemic cerebrovascular disease (disease in male first-degree relative <55 years; disease in female first-degree relative <65 years), and age (men ≥45 years; women ≥55 years). The 10-year risk was determined from the Framingham risk score [11,12]. 6
ACCEPTED MANUSCRIPT Grouping Patients were grouped according to the presence or absence of AD. For patients
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whose LDL-C levels reached the goals after treatment, the presence of AD was
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defined by the presence of TG levels ≥1.7 mmol/L and/or low levels of HDL-C (men: <1.0 mmol/L; women: <1.3 mmol/L). Data collection
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The following data were collected: Gender, age, history of CHD, history of
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hypertension (blood pressure), diabetes (fasting blood glucose and glycosylated hemoglobin), smoking history, drinking history, physical activity, obesity, family
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history of the premature disease, and statin monotherapy.
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"Current smokers" were defined as currently smoking or smoking cessation for
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less than one year. "Former smokers" were defined as smoking cessation for more than one year. "Non-smokers" were defined as never having smoked.
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Drinking was defined as the average daily drinking of >50 ml of liquor, the average daily drinking of >150 ml of wine, or average daily drinking of >500 ml of beer. "Abstinence from alcohol" was defined as non-consumption of alcohol for more than one year. If the patient had no routine physical activity (less than 20-30 minutes of walking, 3-4 days a week; or equivalent amount of activity), it was considered as a sedentary lifestyle. Obesity was defined by BMI ≥28 kg/m2. Intensity of statin therapy was classified into high-intensity, moderate-intensity, and low-intensity, according to the 2013 ACC/AHA guidelines [6]: low-intensity 7
ACCEPTED MANUSCRIPT statin (daily; simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg, and pitavastatin 1 mg), moderate-intensity statin (daily; atorvastatin 10-20
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mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40
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mg, fluvastatin sustained-release tablets 80 mg, fluvastatin 40 mg (twice a day), and pitavastatin 2-4 mg), and high-intensity statin (daily; atorvastatin 40-80 mg and rosuvastatin 20-40 mg).
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Statistical analysis
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Continuous data with a normal distribution were presented as mean ± standard deviation. Continuous data with a non-normal distribution were presented as median
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(range). Continuous data were presented as frequencies. Logistic regression analysis
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was used for multivariate analysis (enter method). SAS 9.2 (SAS Institute Inc., Cary,
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NC, USA) was used for data analysis. Two-sided P-values<0.05 were considered
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statistically significant.
RESULTS
Characteristics of the patients reaching the LDL-C goals In the DYSIS-China study, 22,039 patients received a statin monotherapy. Among them, 13,088 (59.4%) patients reached the LDL-C goals according to the NCEP ATP-III criteria and 13,551 (61.5%) patients reached the LDL-C goals according to the 2007 Chinese guidelines [11,12]. Table 3 presents the characteristics of the patients reaching the LDL-C goals according to the NCEP-ATP III criteria or the 2007 Chinese guidelines. Majority of 8
ACCEPTED MANUSCRIPT patients were aged between 45-64 years (50.3% and 51.0%) and male (54.5% and 54.9%). Mean BMI was 24.5±3.2 kg/m2. About 12.1% of patients were smokers,
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8.5-8.8% consumed alcohol, 19.2-19.3% had a sedentary lifestyle, 65.1-65.8% had
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hypertension, 23.5-25.2% had diabetes, 30.1-37.1% had CAD, and 14.1-16.0% had cerebrovascular diseases. In both classifications, the majority of patients were at high
Univariate and multivariate analyses
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risk (45.1% and 54.8%).
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According to the NCEP ATP-III criteria, 7134 patients (54.5%) reaching the LDL-C goals still had AD compared with 7719 patients (57.0%) according to the
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2007 Chinese guidelines.
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Table 4 presents the univariate analyses of the risk factors associated with or
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without the prevalence of AD according to the NCEP-ATP III criteria or the 2007 Chinese guidelines. According to the NCEP-ATP III criteria, patients with risk factors
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of AD were characterized by younger age (P<0.0001), lower proportion of males (P<0.0001), larger waist circumference (P<0.0001), higher BMI (P<0.0001), higher proportion of sedentary lifestyle (P=0.04), higher proportion of diabetes (P<0.0001), higher proportion of CAD (P<0.0001), lower proportion of ischemic cerebrovascular disease (P=0.03), higher proportion of patients with very high risk (P<0.0001), higher SBP (P=0.002), higher DBP (P<0.0001), higher serum uric acid (P<0.0001), higher fasting plasma glucose (P<0.0001), higher 2-h postprandial glucose (P=0.006), higher HbA1c (P<0.0001), lower HDL-C levels (P<0.0001), higher TG levels (P<0.0001), and higher non-HDL-C levels (P<0.0001). Similar univariate associations were 9
ACCEPTED MANUSCRIPT observed according to the 2007 Chinese guidelines (Table 4), except for CAD (P=0.30) and alcohol (P=0.03).
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Table 5 presents the multivariate analyses. Variables that were associated with
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risk factors of AD in univariate analyses (P<0.05) were included in the multivariate model (enter method). Risk classification could not be included because it was a covariate of risk factors of AD; 2-h postprandial plasma glucose and HbA1c were
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covariates of fasting plasma glucose FPG and had to be removed. Finally, because
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HDL-C and TG were included in the indicators for the determination of the risk factors of AD, they were removed from the analysis.
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According to the NCEP-ATP III definition, age (OR=0.98, 95%CI: 0.97-0.99,
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P<0.0001), male gender (OR=0.47, 95%CI: 0.41-0.54, P<0.0001), BMI (OR=1.08,
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95%CI: 1.06-1.11, P<0.0001), sedentary lifestyle (OR=1.24, 95%CI: 1.07-1.44, P=0.004), diabetes mellitus (OR=1.36, 95%CI: 1.17-1.58, P<0.0001), ischemic
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cerebrovascular disease (OR=1.20, 95%CI: 1.02-1.41, P=0.03), serum uric acid levels (OR=1.00, 95%CI: 1.00-1.00, P<0.0001), and fasting plasma glucose (OR=1.08, 95%CI: 1.04-1.12, P<0.0001) were independently associated with a residual AD despite optimal statin therapy. According to the 2007 Chinese guidelines, age (OR=0.98, 95%CI: 0.97-0.99, P<0.0001), male gender (OR=0.44, 95%CI: 0.39-0.50, P<0.0001), BMI (OR=1.09, 95%CI: 1.06-1.11, P<0.0001), sedentary lifestyle (OR=1.26, 95%CI: 1.09-1.45, P=0.002), CHD (OR=1.15, 95%CI: 1.00-1.32, P=0.03), serum uric acid levels (OR=1.00, 95%CI: 1.00-1.00, P<0.0001), and fasting plasma glucose (OR=1.09, 10
ACCEPTED MANUSCRIPT 95%CI: 1.05-1.13, P<0.0001) were independently associated with a residual AD
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despite optimal statin therapy.
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DISCUSSION
Many patients still display AD despite optimal statin treatment, which helps in the assessment of the residual cardiovascular risk in statin-treated patients [13]. This
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study has investigated and assessed the prevalence of AD in Chinese outpatients
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whose LDL-C levels reached the goals after statin monotherapy and also evaluated the characteristics of these patients. The analysis of our article was based on
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DYSIS-China study which was carried out on Chinese population. For this reason,
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we chose the 2007 Chinese guidelines. Given that the NCEP ATP-III criteria has been
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widely used by doctors in China, we analyzed the data according the different criteria/guidelines to confirm whether different criteria/guidelines could result in
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similar conclusions. As expected, our results showed the similar conclusion that the high prevalence of AD in Chinese patients with optimal statin treatment were 54.5% (according to the NCEP ATP-III criteria) and 57.0% (according to the 2007 Chinese guidelines). Interestingly, the rate to reach the LDL-C goals in Chinese patients was higher than those observed in other countries participating in the DYSIS study. For instance, 51.8% of statin-treated patients in Canada and 11 European countries (Austria, Denmark, France, Germany, Ireland, the Netherlands, Norway, Portugal, Spain, Sweden, and the United Kingdom) reached their LDL-C goals [14]. 49.7% of South 11
ACCEPTED MANUSCRIPT African patients achieved the target LDL-C [15]. 43.8% of the statin-treated Belgian patients reached the goals of LDL-C [16]. In the DYSIS-Middle East study, 38.2% of
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Middle Eastern (the United Arab Emirates, Saudi Arabia, Lebanon and Jordan)
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patients reached their LDL-C targets [17]. In the DYSIS-Egypt study, 32.8% of the Egyptian patients reached their LDL-C targets [18]. Only 19.3% of patients in the Baltic states (Estonia, Latvia, and Lithuania) were at the target LDL-C level (Figure 1)
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[19]. However, the prevalence of AD in Chinese patients who reached their LDL-C
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goals was higher than that in Canada and 11 European countries’ patients (50.0%) [14], Baltic states patients (43.8%) [19], Belgian patients (33.8%) [16], lower than
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that of Middle Eastern patients (62.5%) [17], South African patients (58.7%) [15], and
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similar with that of Egyptian patients (54.8%) (Figure 2) [18]. These differences
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among different countries participating in the DYSIS study could be due to several factors, such as genetics, clinical factors (DM, hypertension, history of CVD) and
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environmental factors (smoking, stress, diet, sedentary lifestyle, pollution, etc.). These factors were not all available in the present study. Additional studies will be necessary to increase the generalizability of these results. In the present study, age, male gender, BMI, sedentary lifestyle, diabetes mellitus, CVD, serum uric acid levels, and fasting plasma glucose were independently associated with AD despite optimal statin therapy. These factors are well-known risk factors for CVD [11]. Therefore, their association with AD could be predicted. Previous studies on AD after statin therapy have shown similar factors [9,10]. The intensity of statin therapy was not associated with AD. AD has been noted in 12
ACCEPTED MANUSCRIPT most large-scale trials of statin therapy [20-26]. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE
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IT-TIMI 22), The Incremental Decrease in Endpoints Through Aggressive Lipid
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Lowering (IDEAL), and Treat to New Target (TNT) trials showed that targeting LDL-C levels of 100 or 70 mg/dL using different intensities of statin therapy led to similar of proportions of patients with AD in each group [27-29]. In these three trials,
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atorvastatin 80 mg led to a higher reduction in the CVD risk, but AD was still present.
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In the Aggrastat to Zocor (A to Z) trial, early initiation of intensive simvastatin therapy in patients with acute coronary syndrome did not lead to a reduction in
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subsequent endpoints compared with less aggressive regimens [30]. Nevertheless, a
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meta-analysis in patients in secondary prevention showed that more aggressive
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therapy could lower the risk of secondary cardiovascular events [31]. In the present study, about half of the patients were in primary prevention, which could explain, at
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least in part, some discrepancies with previous studies. In addition, it may be because low HDL levels and high TG levels are two major types of dyslipidemia in Chinese adults [32], and stain has little influence on TG and HDL, inducing no effect on the AD in Chinese patients. In the multivariate analysis, age, gender, BMI, serum uric acid levels, and fasting plasma glucose were common between the two criteria/guidelines, but not diabetes mellitus, coronary artery disease, and ischemic cerebrovascular disease. These differences could be explained by the different criteria used to define the very-high risk group. Such a discrepancy was shown in a study of Chinese patients with 13
ACCEPTED MANUSCRIPT metabolic syndrome [9]. Nevertheless, despite these differences, all these patients need a pharmacological
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treatment to lower their risk of CVD. Indeed, the associations among diabetes mellitus,
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coronary artery disease, ischemic cerebrovascular disease, and dyslipidemia are well known [11,33]. However, as shown in the present study and previous trials [27-29], aggressive statin therapy could not be suitable for all patients. Therefore, some
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authors suggest that other methods should be sought to decrease AD [34]. Even if
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they are generally well-tolerated, statins may have some side effects, and this should be balanced with the optimal benefits of the treatment. Fibrates or nicotinic acid could
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be used to manage AD, but trials are necessary to address these treatments [35]. In the
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Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, subgroup
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analyses suggested a benefit of the fenofibrate and simvastatin combination therapy for type 2 diabetic patients with both TG levels ≥2.3 mmol/L and HDL-C levels ≤0.9
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mmol/L [36]. Based on the high prevalence of AD and special dyslipidemia in Chinese adults, a combination lipid therapy may be more suitable for Chinese patients.
Despite some differences in the definition of lipid target values and AD between the two criteria/guidelines, a similar proportion of patients still had AD after optimal statin treatment according to the LDL-C levels. These results suggest that the two criteria/guidelines are roughly equivalent to determine AD. Nevertheless, the 2007 Chinese guidelines were specifically tailored to Chinese individuals [12], and it could be more appropriate to use these guidelines when assessing Chinese patients. 14
ACCEPTED MANUSCRIPT There were some limitations in the present study. Some data were missing for some patients, which could introduce a bias. In addition, this was a cross-sectional
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study, without any follow-up of the eventual cardiovascular events. Only traditional
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risk factors were examined, and the emerging risk factors, such as LDL size, oxidative stress, and levels of metalloproteinases, could be examined. Additional studies are necessary to address the actual cardiovascular risk in relation to AD after optimal
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statin therapy.
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In conclusion, there was a high prevalence of AD in Chinese patients with optimal statin treatment. Some risk factors associated with AD were found in the
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current study, and these factors were slightly different according to two different
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criteria/guidelines. The intensity of statin therapy did not reduce the prevalence of AD
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despite optimal statin therapy. A combination lipid therapy may be more suitable for
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Chinese patients.
15
ACCEPTED MANUSCRIPT COMPETING INTERESTS
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All authors declare that they have no competing interests.
16
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ACCEPTED MANUSCRIPT Table 1. Risk stratification and LDL-C goals according to the NCEP-ATP III Risk
Definition
LDL-C goals
History of coronary heart disease, combined with:
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Very-high risk
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stratification
(1) diabetes (2) smoking
<1.8
mmol/L
(70 mg/dL)
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(3) multiple risk factors of metabolic syndrome
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(especially when TG ≥200 mg/dL combined with non-HDL-C ≥130 mg/dL and low level of HDL-C
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[<40 mg/dL])
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(4) acute coronary artery syndrome History of coronary heart disease or coronary <2.6
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High risk
risk
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Moderate-high
Moderate risk
mmol/L
heart disease risk equivalent
(100 mg/dL)
≥2 risk factors with 10-year risk of 10-20%
<3.4
mmol/L
(130 mg/dL) ≥2 risk factors with 10-year risk <10%
<3.4
mmol/L
(130 mg/dL) Low risk
0-1 risk factor
<4.1
mmol/L
(160 mg/dL)
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ACCEPTED MANUSCRIPT Table 2. Risk stratification and LDL-C goals of the 2007 Chinese guideline Risk
Definition
LDL-C value
Acute coronary artery syndrome or ischemic <2.0
SC R
Very-high risk
IP
T
stratification
cerebrovascular disease combined with diabetes High risk
NU
5-10%
D
0-1 risk factor combined with 10-year risk <5%
mmol/L
(100 mg/dL)
≥2 risk factors combined with 10-year risk of <3.4
MA
Moderate risk
mmol/L
(80 mg/dL)
Coronary heart disease or coronary heart disease <2.6 risk equivalent, or 10-year risk of 10-15%
Low risk
target
mmol/L
(130 mg/dL) <4.1
mmol/L
AC
CE P
TE
(160 mg/dL)
25
ACCEPTED MANUSCRIPT Table 3. Characteristics of the patients who reached the LDL-C goals NCEP-ATP III criteria 2007 Chinese guidelines Variable
IP
65.4±10.6
SC R
65.6±10.6 6584 (50.3)
65-74, n (%)
3849 (29.4)
>75, n (%)
2655 (20.3)
2685 (19.8)
Male, n (%)
7134 (54.5)
7446 (54.9)
Waist circumference (cm)
86.5±11.2
86.8±11.3
BMI (kg/m2)
24.5±3.2
24.5±3.2
D
NU
45-64, n (%)
MA
Age (years), mean±SD
(n=13,551)
T
(n=13,088)
3949 (29.1)
1579 (12.1)
1636 (12.1)
1146 (8.8)
1157 (8.5)
Sedentary life style, n (%)
2514 (19.2)
2617 (19.3)
Hypertension, n (%)
8520 (65.1)
8911 (65.8)
Diabetes mellitus, n (%)
3070 (23.5)
3415 (25.2)
Coronary heart disease, n (%)
3936 (30.1)
5031 (37.1)
1980 (15.1)
2169 (16.0)
124 (0.9)
145 (1.1)
1104 (8.4)
1195 (8.8)
TE
Smoking, n (%)
6917 (51.0)
AC
CE P
Alcohol consumption, n (%)
Ischemic
cerebrovascular
disease, n (%) Peripheral arterial disease, n (%) Family history of CAD, n (%) Risk classification, n (%) 26
ACCEPTED MANUSCRIPT 1369 (10.5)
1163 (8.6)
High risk
5908 (45.1)
7423 (54.8)
Moderate-high risk
201 (1.5)
-
Moderate risk
194 (1.5)
Low risk
5416 (41.4) blood
pressure 129.6±15.0
blood
pressure
IP
329.5±98.3
331.7±98.8
D
80.2±31.3
80.4±31.8
5.9±2.0
6.0±2.0
11.7±5.5
11.9±5.5
HbA1c (%)
6.8±1.6
6.9±1.6
Total cholesterol (mmol/L)
4.11±1.05
4.03±0.99
2.15±0.73
2.09±0.65
1.28±0.37
1.26±0.37
1.35(0.97-1.95)
1.36(0.97-1.98)
plasma
(mmol/L)
postprandial
plasma
AC
2-h
glucose
CE P
Fasting
TE
Serum creatinine (mmol/L)
129.4±14.9
77.3±9.5
(mmHg) Serum uric acid (mmol/L)
3302 (24.4)
77.4±9.5
MA
Diastolic
NU
(mmHg)
1663 (12.3)
SC R
Systolic
T
Very high risk
glucose (mmol/L)
Low-density
lipoprotein
cholesterol (mmol/L) High-density
lipoprotein
cholesterol (mmol/L) Triglyceride (mmol/L)
27
ACCEPTED MANUSCRIPT Non-HDL-C (mmol/L)
2.83±0.97
2.77±0.91
High-intensity
1070 (8.3)
1140 (8.5)
Moderate-intensity
10,132 (78.3)
Low-intensity
1738 (13.4)
IP
T
Statin therapy, n (%)
AC
CE P
TE
D
MA
NU
SC R
10,561 (78.8)
28
1704 (12.7)
ACCEPTED MANUSCRIPT
IP
T
Table 4. Univariate analyses of the risk factors associated with the prevalence of AD or not,
n=7134 64.5±10.4
TE D
Age (years), mean±SD
Without AD
US
With AD
With AD
Without AD
P
n=5954
MA N
Variables
2007 Chinese guidelines
CR
NCEP-ATP III criteria
P n=7719
n=5832
67.0±10.5
<0.0001
64.4±10.4
66.8±10.6
<0.0001
<0.0001
4273 (55.4)
2644 (45.3)
< 0.0001
3939 (55.2)
2645 (44.4)
65-74, n (%)
1976 (27.7)
1873 (31.5)
2135 (27.7)
1814 (31.1)
1311 (17.0)
1374 (23.6)
CE P
45-64, n (%)
1436 (24.1)
3458 (48.5)
3676 (61.7)
<0.0001
3803 (49.3)
3643 (62.5)
<0.0001
Waist circumference, n (%)
87.1±11.3
85.9±11.0
<0.0001
87.5±11.5
86.0±11.0
<0.0001
BMI (kg/m2)
24.9±3.2
24.0±3.2
<0.0001
24.9±3.2
24.0±3.2
<0.0001
Smoking, n (%)
870 (12.2)
709 (11.9)
0.6315
945 (12.2)
691 (11.8)
0.4857
Male, n (%)
1219 (17.1)
AC
>75, n (%)
29
Sedentariness, n (%)
1418 (19.9)
1096 (18.4)
Hypertension, n (%)
4662 (65.3)
3858 (64.8)
Diabetes mellitus, n (%)
1882 (26.4)
1188 (20.0)
Coronary heart disease, n (%)
1926 (27.0)
Ischemic cerebrovascular disease, n (%)
1034 (14.5)
Peripheral arterial disease, n (%)
65 (0.9)
Family history of CAD, n (%)
646 (9.1)
532 (9.1)
0.0345
0.0355
1548 (20.1)
1069 (18.3)
0.0118
0.522
5120 (66.3)
3791 (65.0)
0.1072
<0.0001
2093 (27.1)
1322 (22.7)
<0.0001
2010 (33.8)
<0.0001
2837 (36.8)
2194 (37.6)
0.3012
946 (15.9)
0.0283
1180 (15.3)
989 (17.0)
0.0086
59 (1.0)
0.7083
84 (1.1)
61 (1.0)
0.8128
458 (7.7)
0.0057
734 (9.5)
461 (7.9)
0.0011
MA N
TE D
CE P
AC
Very high risk
625 (8.1)
T
553 (9.3)
IP
593 (8.3)
CR
Alcohol consumption, n (%)
Risk classification, n (%)
0.0531
US
ACCEPTED MANUSCRIPT
<0.0001
<0.0001
1035 (14.5)
334 (5.6)
734 (9.5)
429 (7.4)
High risk
2873 (40.3)
3035 (51.0)
4139 (53.6)
3284 (56.3)
Moderate-high risk
191 (2.7)
10 (0.2)
-
-
Moderate risk
194 (2.7)
0
933 (12.1)
730 (12.5)
30
ACCEPTED MANUSCRIPT
130.0±14.9
129.1±150
Diastolic blood pressure (mmHg)
77.9±9.5
76.9±9.4
Serum uric acid (mmol/L)
338.2±102.3
319.7±92.6
Serum creatinine (mmol/L)
79.9±31.6
Fasting plasma glucose (mmol/L)
6.1±2.1
2-h postprandial plasma glucose (mmol/L)
12.3±5.4
HbA1c (%) Total cholesterol (mmol/L)
0.0015
129.9±15.0
128.7±14.7
<0.0001
<0.0001
77.8±9.6
76.6±9.3
<0.0001
<0.0001
340.9±102.2
320.1±93.0
<0.0001
80.5±30.9
0.3596
80.3±32.6
80.6±30.9
0.6586
5.7±1.7
<0.0001
6.1±2.1
5.8±1.8
<0.0001
10.7±5.4
0.0062
12.5±5.4
10.9±5.5
0.0059
7.0±1.7
6.7±1.5
<0.0001
7.0±1.7
6.7±1.5
<0.0001
4.12±1.15
4.10±0.93
0.1748
4.04±1.07
4.01±0.87
0.1493
2.15±0.76
2.15±0.69
0.8288
2.09±0.67
2.08±0.62
0.3237
1.12±0.33
1.47±0.33
<0.0001
1.10±0.32
1.46±0.33
<0.0001
1.87(1.30,
1.04(0.81,
US
MA N
CE P
AC
High-density lipoprotein cholesterol (mmol/L)
Triglycerides (mmol/L)
1389 (23.8)
T
Systolic blood pressure (mmHg)
Low-density lipoprotein cholesterol (mmol/L)
1913 (24.8)
IP
2575 (43.2)
CR
28741 (39.8)
TE D
Low risk
1.87(1.30, 2.51)
1.05(0.81, 1.32)
<0.0001
<0.0001 2.50)
31
1.31)
ACCEPTED MANUSCRIPT
2.62±0.84
T
3.00±1.03
IP
Non-HDL-C (mmol/L)
CR
Statin therapy, n (%) 583 (8.4)
477 (8.1)
Moderate-intensity
5563 (78.6)
4569 (77.9)
Low-intensity
919 (13.0)
MA N
US
High-intensity
AC
CE P
TE D
819 (14.0)
32
<0.0001
2.93±0.97
2.55±0.78
0.2561
<0.0001 0.5323
933 (12.2)
771 (13.4)
6061 (79.1)
4500 (78.3)
665 (8.7)
475 (8.3)
ACCEPTED MANUSCRIPT
IP
T
Table 5. Multivariate analyses of the risk factors associated with the prevalence of AD or not 2007 Chinese guidelines
CR
NCEP-ATP III criteria Variables p
Age
0.979 (0.973, 0.985)
<0.0001
Male
0.473 (0.414, 0.540)
<0.0001
0.438 (0.385, 0.498)
<0.0001
Waist circumference
1.001 (0.995, 1.007)
0.7790
1.002 (0.996, 1.008)
0.5780
BMI
1.082 (1.058, 1.106)
<0.0001
1.085 (1.061, 1.109)
<0.0001
Alcohol consumption
0.822 (0.670, 1.008)
0.0590
0.844 (0.691, 1.031)
0.1450
Sedentary lifestyle
1.241 (1.073, 1.436)
0.0040
1.259 (1.092, 1.451)
0.0020
Diabetes mellitus
1.361 (1.174, 1.577)
<0.0001
1.147 (0.996, 1.321)
0.0730
Coronary heart disease
0.934 (0.822, 1.062)
0.2980
1.153 (1.023, 1.300)
0.0300
Ischemic cerebrovascular disease
1.201 (1.021, 1.413)
0.0270
1.168 (0.999, 1.365)
0.0700
Family history of CAD
0.949 (0.765, 1.176)
0.6320
0.955 (0.778, 1.173)
0.6990
MA N
0.979 (0.974, 0.985)
TE D
CE P
AC
OR (95%CI)
US
OR (95%CI)
33
p <0.0001
1.000 (0.996, 1.005)
0.9200
1.003 (0.998, 1.007)
0.4390
Diastolic blood pressure
1.005 (0.997, 1.013)
0.2120
1.005 (0.998, 1.013)
0.0720
Serum uric acid
1.003 (1.002, 1.004)
<0.0001
1.003 (1.003, 1.004)
<0.0001
Fasting plasma glucose
1.076 (1.037, 1.116)
<0.0001
US
CR
T
Systolic blood pressure
IP
ACCEPTED MANUSCRIPT
AC
CE P
TE D
MA N
1.088 (1.051, 1.127)
34
<0.0001
ACCEPTED MANUSCRIPT
CR
IP
T
Figure Legends
US
Figure 1. The rates for the patients to reach the LDL-C goals
MA N
LDL-C: low-density lipoprotein cholesterol; China (NCEP ATP-III criteria): Chinese patients according to the NCEP ATP-III criteria; China (2007 Chinese guidelines): Chinese patients according to the 2007 Chinese guidelines; Canada and 11 European countries: Canada and 11
CE P
Egyptian patients; the Baltic states: Baltic states patients.
TE D
European countries’ patients; South Africa: South African patients; Belgium: Belgian patients; the Middle East: Middle Eastern patients; Egypt:
AC
Figure 2. The prevalence of atherogenic dyslipidemia in patients who reached the LDL-C goals LDL-C: low-density lipoprotein cholesterol; China (NCEP ATP-III criteria): Chinese patients according to the NCEP ATP-III criteria; China (2007 Chinese guidelines): Chinese patients according to the 2007 Chinese guidelines; Canada and 11 European countries: Canada and 11 European countries’ patients; South Africa: South African patients; Belgium: Belgian patients; the Middle East: Middle Eastern patients; Egypt: Egyptian patients; the Baltic states: Baltic states patients.
35
AC
Figure 1
CE P
TE D
MA N
US
CR
IP
T
ACCEPTED MANUSCRIPT
36
AC
Figure 2
CE P
TE D
MA N
US
CR
IP
T
ACCEPTED MANUSCRIPT
37