Metabolic Syndrome Causes Cardiovascular Disease under Stable Statin Medication (original) (raw)

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  4. 10.12997/jla.2017.6.2.75

Copyright © 2017 The Korean Society of Lipidology and Atherosclerosis.

Original Article

Sang-Cheol Cho, Hoonhee Lee, Hyo-Jung Nam and Ki Hoon Han

Received May 04, 2017; Revised July 06, 2017; Accepted July 21, 2017.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Statins are known to prevent only 30–50% of cardiovascular disease(CVD) by reducing low-density lipoprotein cholesterol (LDL-C). There is a controversy about whether metabolic syndrome(MS) can increase the risk of CVD. The aim of this study is to investigate whether MS can increase the risk of CVD, even after LDL-C is ideally controlled by taking statins.

Methods

As a retrospective observational study, we investigated CVD events of 909 patients (61.3±10.2 years old) by reviewing medical records for at least 1 year before and after taking statins respectively, from June 2005 to February 2008, and analyzed the risk factors of CVD.

Results

During the study period (881.4±232.8 days), 46 cases of CVD events occurred in patients with a very high risk of CVD and in patients with a high risk of CVD. In patients with a very high risk of CVD, 56.8% (21 cases over 37) of CVD events occurred in patients who achieved LDL-C goal (<70 mg/dL). A total of 9 events developed among high risk patients who reached LDL-C goal (<100 mg/dL). The patients with MS revealed significantly higher rates of CVD events [_p_=0.015; hazard ratio (HR) 3.033; 95% confidence interval (CI) 1.184–7.768]. Significantly higher rates of CVD events were also found in subgroup analysis of the patient with a past history of CVD events [_p_=0.017; HR 3.431; 95% CI 1.183–9.956]. Similar pattern was demonstrated in patients with diabetes [_p_=0.049; HR 2.738; 95% CI 0.963–7.782]. Cox regression analysis identified metabolic syndrome [_p_=0.025; HR 5.237; 95% CI 1.235–22.204], a past history of CVD events [_p_=0.000; HR 5.349; 95% CI 2.321–12.327], basal LDL-C level [_p_=0.024; HR 1.013; 95% CI 1.002–1.025] and total cholesterol level after statin therapy [_p_=0.024; HR 0.978; 95% CI 0.959–0.997] as independent predictors of CVD among LDL-C goal achieved patients.

Conclusion

Metabolic syndrome is the independent risk factor of CVD events in high risk patients with or without a past history of CVD events or diabetes. In these patients, statins could not prevent CVD events effectively.

Keywords

Statin; Cardiovascular disease; Metabolic syndrome

INTRODUCTION

Cardiovascular disease (CVD) is the second most common cause of death among Korean population.1 Lowering low density lipoprotein cholesterol (LDL-C) through statin medication reduces the number of future CVD events as much as by 20% per 1 mmol/L LDL-C reduction.2, 3 In Korea, a previous report described that more than a million adult population is currently assumed to be under statin medication and 62.6% of high-risk patients including those with diabetes achieve the LDL-C target goal recommended by National Cholesterol Education Program-Adult Treatment Panel III (NCEP-III), i.e. <100 mg/dL.1 Recently updated lipid management guidelines recommend more aggressive statin treatment, in which LDL-C levels should be maintained even <55 mg/dL in high risk group with history of acute coronary syndrome (ACS).4, 5

In Korea, the other phenotype of dyslipidemia showing high triglyceride or/and low high density lipoprotein cholesterol (HDL-C) levels is commonly found and is usually combined with abdominal obesity and elevated blood pressure and fasting glucose levels as co-morbidities for metabolic syndrome (MS). The prevalence of MS among Korean adult population is reported as high as 23.7% (male: 24.0%, female 23.4%) when NCEP-III diagnostic criteria is applied6, 7 and keep increasing. Therefore, it is highly plausible that substantial number of Koreans with high risk for CVD is under MS condition and most of them have statin medication on a daily basis.

Although it was not independently proved whether statin prevents CVD in subjects with MS in a single trial, several reports described that MS increases the risk of future CVD8, 9 and recent trials such as the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin The JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial)10 and the Heart Outcomes Prevention Evaluation HOPE-3 (Heart Outcomes Prevention Evaluation–3) trial11 included substantial number of MS subjects and showed the reduction of CVD events through statin medication. However, it is still unclear whether the risk of CVD elicited by complex dyslipidemic conditions in MS can be reduced by statin medication itself.

In this study, we tried to figure out whether the conventional statin treatment to Korean patients who were referred to tertiary hospital may achieve LDL-C target goals suggested by NCEP-III guideline. Additionally, the present study analyzed if MS may contribute to CVD events under well-maintained LDL-C condition with statin treatment.

MATERIALS AND METHODS

1. Study Subjects

This study is retrospectively designed study that included 909 subjects who visited outpatient clinic of cardiology department of Asan Medical Center, Seoul, Korea, between June, 2005 and February, 2009. All subjects had clear medical records for at least a year before the initiation of statin therapy, confirming that they did not have any serious co-morbidities other than CVD events to affect the clinical course during study period. And all subjects should have maintained fixed dose of specific statin for at least a year. The date of initiation of the statin was defined as ‘baseline’. All study subjects were followed up until the development of first CVD episode or the change of statin regimen. The last follow-up date was defined as ‘follow-up’.

CVD events in the present study were defined as follows; coronary angioplasty or stent insertion, development of ischemic stroke, admission due to coronary artery diseases (stable angina, ACS including myocardial infarction) or congestive heart failure due to ischemic heart disease. Ten-year risk for the development of CVD was calculated following NCEP-III guideline.12 High risk for CVD is defined when the 10-year-risk exceeds 20 % and very-high risk is defined when the history of CVD is combined with any of risk factors such as smoking, diabetes, hypertension and/or MS. We also used NCEP-III diagnostic criteria for MS with slight modification as follows; abdominal obesity (body mass index (BMI) ≥25 kg/m2), blood pressure ≥ 130/85 mmHg or anti-hypertensive medication, fasting blood glucose ≥100 mg/dL or hypoglycemic agents, triglyceride ≥150 mg/dL or lipid-lowering medication, HDL-C (<40 and <50 mg/dL in men and women, respectively). MS was diagnosed when any subjects had three or more of those criteria.12, 13

The collection of data was completed in February, 2009 and obtaining consent from subjects was not required by Institutional Review Board for the retrospective study at that time. Otherwise, we strictly followed the World Medical Association Declaration of Helsinki revised at 59th General Assembly, Seoul, October 2008.

2. Statistics

All data were expressed as mean±standard deviation and the change of parameters at ‘baseline’ and ‘follow-up’ was analyzed by paired _t_-test. The multiple comparison was analyzed by ANOVA and the impact of MS on the development of CVD was analyzed by Chi-square test. Cox regression analysis was used to identify factors associated with the development of CVD. The development of CVD during study period was expressed by Kaplan-Meyer survival analysis. IBM SPSS Statistics 23 version was used and we considered as statistically significant if p<0.05.

RESULTS

1. Demographic profiles

Of all subjects (n=909 ; mean 61.3±10.2 years old), 86.2% had diabetes, 37.4% had a history of CVD and 76.9% had 3 or more major CVD risk factors defined by NCEP-III guideline. Compare to women, more men were smokers, were older, had a history of CVD or ≥3 major risk factors, and showed low HDL-C levels (<40 mg/dL) while more women had diabetes than men (Table 1).

At “baseline”, either atorvastatin (10–40 mg), rosuvastatin (5–20 mg), simvastatin (10–40 mg), pravastatin (20–40 mg), fluvastatin (40–80 mg), or simvastatin/ezetimibe (10/10 or 10/20 mg) was initiated and maintained for 881.4±232.8 days. In all subjects, blood pressure levels (_p_=0.000 for both systolic blood pressure (SBP) and diastolic blood pressure (DBP)) showed significant reductions after initiation of statin medication. The reduction of fasting glucose (127.4±48.4 vs. 123.2±43.4 mg/dL; _p_=0.029) and HbA1c (7.3±1.8 vs. 7.2±1.4%; _p_=0.016) was also significant but modest. Unfortunately, BMI levels showed little changes during follow-up. Lipid parameters such as LDL-C (137.4±38.0 vs. 81.2±30.0 mg/dL; _p_=0.000), non HDL-C (174.0±37.1 vs. 109.8±33.5 mg/dL; _p_=0.000), triglyceride (192.2±125.0 vs. 147.4±89.3 mg/dL; _p_=0.000) showed significant reductions while HDL-C level showed little changes (49.4±15.01 vs. 49.7±13.36 mg/dL; _p_=0.527) (Table 2).

2. Development of CVD according to LDL-C goal achievement

Most subjects were turned out to be under high-(508/909; 55.9%) or very high risk (340/909; 37.4%) defined by status of 10-year CVD risk. The proportion who reached below target goal of LDL-C levels (less than 70, 100, 130 and 160 mg/dL for very high, high, moderate and low risk, respectively) was 45.5, 76.0, 92.0, and 97.2 % for very high (n=340), high (n=508), and moderate (n=25) or low risk (n=36) groups, respectively (Table 3), during statin medication. During study period, total of 46 major CVD events were reported in very high risk (37/340) or high risk (9/508) group. The achievement of LDL-C goal did not significantly reduce the development of CVD (_p_=0.088 ; Chi-square test) (Table 3).

3. Clinical characteristics of MS

MS defined by NCEP-III with modification was diagnosed in 73.8% (671/909), more frequently in women (_p_=0.002 ; _t_-test). Among five diagnostic criteria for MS, more women showed low HDL-C and higher fasting glucose levels compared to men (Table 4).

When the subjects were divided by the number of diagnostic criteria for MS at baseline, as the number is increasing, the prevalence of smoking, hypertension and diabetes was increasing (all _p_=0.000), and BMI (_p_=0.000), fasting blood glucose (_p_=0.003) and triglyceride (_p_=0.000) levels became higher as expected (ANOVA) while total cholesterol (TC) (_p_=0.038) and LDL-C levels (_p_=0.000) were getting lower. Statin medication significantly lowered TC, LDL-C and non-HDL-C levels in all subgroup (Table 5). On the other hand, ANOVA showed that all five components of diagnostic criteria for MS such as BMI (_p_=0.000), fasting blood glucose (_p_=0.000), SBP (_p_=0.000) and DBP (_p_=0.020), triglyceride levels (_p_=0.000) and HDL-C level (_p_=0.000) still showed significant differences between subgroups at follow-up, suggesting the management of MS is not as efficient as LDL-C-related parameters (Table 4).

4. MS and CVD events

At “baseline”, the prevalence of CVD history was not associated with the presence and the severity of MS (Table 5). During study period, the developed major CVD events were more frequently reported in MS group (41/671 ; 6.1% vs. 5/238 ; 2.1%, _p_=0.015) The relationship between MS and CVD events was consistently observed in subgroups with diabetes (_p_=0.049) and previous CVD history (_p_=0.017) (Table 6).

Cox regression analysis showed that the history of CVD (HR:5.349, 95% CI 2.321–12.327, _p_=0.000) and the initial diagnosis of MS (HR:5.237, 95% CI 1.235–22.204, _p_=0.025) were found to be related to the development of CVD among LDL-C goal achieved patients. Both LDL-C level (HR: 1.013, 95% CI 1.002–1.025, _p_=0.024) before statin treatment and total cholesterol level (HR: 0.978, 95% CI 0.959–0.997, _p_=0.024) at follow-up were also related to the development of CVD with lesser degree (Table 7). Kaplan-Meyer survival analysis showed that the occurrence of CVD events during follow-up was observed more frequently in subjects with MS or previous history of CVD (Fig. 1).

DISCUSSION

The majority of our study subjects not only had diabetes (86.2%) but also had 3 or more CVD risk factors (76.9%) and previous CVD history (37.4%). Recent studies suggest that CVD-related morbidity and mortality of Asian and Korean population are not lower than other Caucasian ethnic groups at least for high- and very high CVD risk groups as recruited in our study.14, 15 Recently, Jung et. al.16 analyzed over 2 million Korean patients with diabetes with and without history of previous coronary heart disease and showed that the annual incidence of coronary revascularization was 597.9 (without CHD history) and 4109.9 (with CHD history), respectively (per 100,000 person-years). A previous population-based study17 with Da Qing province in China described that the annual cardio-cerebrovascular death in newly-diagnosed diabetes group was 17.5 and 15.5/1000 person-years in men and women, respectively, during 23 years of follow-up.

The efficacy of statin management to patients with diabetes has been proved by Collaborative Atorvastatin Diabetes Study (CARDS),18 which proved the preventive effect of statin (atorvastatin 10 mg/day) on population with diabetes without CVD history. In this study, one-third of the subjects had history of CVD and basal LDL-C level was higher than CARDS trial, suggesting the absolute CVD risk in our subjects is presumed to be higher than subjects in CARDS trial. The statin medication in this study significantly reduced LDL-C levels by 40.9 % to 81.2±30.0 mg/dL, which is equal to or lower than CARDS trial and meets the minimal LDL-C target goal suggested by NCEP-III guideline,19 i.e. <100 mg/dL. Under these circumstances, the estimated annual incidence of CVD event during statin medication in this study was as low as 2.1%, which was comparable to the result of CARDS trial. Therefore, such results of this study highly suggest that the control of LDL-C through statin medication may have reduced CVD events in high-risk Korean subjects.

The strategy of statin use in the present study is less aggressive when compared to the updated 2013 ACC (American College of Cardiology) / AHA (American Heart Association) guideline recommending maximal-tolerable dose of statins (40 to 80 mg atorvastatin equivalent) especially to high- and very-high CVD risk groups. However, 75% of our subjects had reached <100 mg/dL LDL-C levels after statin medication, suggesting that Korean population may respond to statins more efficiently than Caucasian population1, 3 in aspects of not only LDL-C reduction but also the prevention of CVD events. But it has to be noted that ACS patients were not included in this study and all subjects were clinically stable at the “baseline”. Considering the fact that more aggressive statin management showed better CVD prevention within first year of medication,4 in ACS patients, such earlier benefit of statins maybe inadvertently excluded in this study. Therefore, our study results are not applicable to patients under more severe forms of cardio- and cerebrovascular disease and are not contradictory to the most updated guidelines to use maximal tolerable doses of potent statins. It remains to be proved whether maximal tolerable dose of potent statins may improve the early outcome in Korean population with high- and very-high CVD risks.

Considering the fact that 73.6% of our study subjects were diagnosed as MS at baseline, optimal control of the components for MS as well as the reduction of LDL-C may be necessary for the prevention of CVD events. Unfortunately, our study results show that MS is under-recognized and poorly controlled when compared to LDL-C-related parameters. Most notably, HDL-C levels and obesity were not appropriately controlled and fasting glucose and HbA1c levels showed only mild reductions throughout the study period. Moreover, subjects diagnosed as MS at baseline persistently showed higher BMI, blood pressure, glucose profile, and triglyceride levels with lower HDL-C levels during follow up. Such poor control of MS may explain the results of multivariate analysis, in which the presence of MS had shown to affect the outcome of CVD events more heavily than the achievement of LDL-C goal. Kim et. al.20 reported that active and persistent lifestyle intervention to Korean subjects with MS could lower the annual incidence of myocardial infarction by 50.5%. Therefore, if non-pharmacological as well as pharmacological intervention is actively applied to individuals with MS especially having CVD history, future development of CVD events could be further minimized in Korean population with high- and very-high CVD risks.

ACKNOWLEDGEMENT

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP : Ministry of Science, ICT & Future Planning) (No.KNRF-2016944409).

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