Comparison of different statin therapy to change low-density lipoprotein cholesterol and high-density lipoprotein cholesterol level in Korean patients with and without diabetes

Accepted Manuscript Comparison of different statin therapy to change LDL cholesterol and HDL cholesterol level in Korean patients with and without diabetes Ah Reum Khang, Young Shin Song, Kyoung Min Kim, Jae Hoon Moon, Soo Lim, Kyong Soo Park, Hak Chul Jang, Sung Hee Choi PII:

S1933-2874(15)00474-2

DOI:

10.1016/j.jacl.2015.12.013

Reference:

JACL 862

To appear in:

Journal of Clinical Lipidology

Received Date: 28 February 2015 Revised Date:

15 December 2015

Accepted Date: 16 December 2015

Please cite this article as: Khang AR, Song YS, Kim KM, Moon JH, Lim S, Park KS, Jang HC, Choi SH, Comparison of different statin therapy to change LDL cholesterol and HDL cholesterol level in Korean patients with and without diabetes, Journal of Clinical Lipidology (2016), doi: 10.1016/j.jacl.2015.12.013. 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.

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Comparison of different statin therapy to change LDL cholesterol and HDL cholesterol level in Korean patients with and without diabetes Running title: The efficacy of different statins in Asians

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Ah Reum Khang1, Young Shin Song2, Kyoung Min Kim3, Jae Hoon Moon3, Soo Lim2,3, Kyong Soo Park2, Hak Chul Jang2,3, Sung Hee Choi2,3

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Department of Internal Medicine, Kyungpook National University college of Medicine, Daegu, Korea

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Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

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Ah Reum Khang ([email protected])

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Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

Young Shin Song ([email protected])

Kyoung Min Kim ([email protected])

Soo Lim ([email protected])

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Jae Hoon Moon ([email protected])

Kyong Soo Park ([email protected])

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Hak Chul Jang ([email protected])

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Sung Hee Choi ([email protected])

Contribution

(1) the conception and design of the study or acquisition of data, or analysis and interpretation of data, : Ah Reum Khang, Kyoung Min Kim, Jae Hoon Moon, Soo Lim, Kyung Soo Park, Sung Hee Choi (2) drafting the article or revising it critically for important intellectual content, : Ah Reum Khang, Sung Hee Choi, Hak Chul Jang (3) final approval of the version to be submitted. : Sung Hee Choi, Hak Chul Jang, Kyong Soo Park, Soo Lim 1

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Correspondence : Sung Hee Choi, MD., PhD. Department of Internal Medicine, Seoul National University College of Medicine & Seoul National

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University Bundang Hospital, 300, Gumi-dong Bundang-gu, Seongnam city, Gyeonggi-do, 463-707, South Korea Tel: +82-31-787-7033

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Fax:+82-31-787-4052

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[email protected]

Total number: Table 4, Figure 2, supplement table 3, Word count: 3566 Financial disclosures: All authors have no financial disclosures

Abbreviations:

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ACC/AHA , American College of Cardiology/American Heart Association; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; CHD, Coronary heart disease; HbA1c, Glycated hemoglobin; OR, Odds ratio; CI, Confidence interval; MPR, Medication possession ratio; CETP,

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Cholesterol ester transfer protein

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Abstract Background: It is difficult to apply the proper intensity of statin for new treatment guidelines in clinical settings, because of few data about the statin efficacy in Asians. We conducted a retrospective,

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observational study to estimate the percentage changes in lipid parameters and glucose induced by different statins.

Methods: We analyzed 3,854 patients including those with non-diabetes and diabetes treated at the

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outpatient clinic between 2003 and 2013 who were statin-naïve and maintained fixed-dose of statin for at least 18 months.

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Results: Moderate- and low-intensity statin therapy was effective in reducing low-density lipoprotein cholesterol (LDL-C) to < 100 mg/dl (70.3%, 83.0%, and 87.2% of diabetic patients in the low-, moderate-, and high-intensity therapy groups, respectively). The rapid decrease of LDL-C was observed in the first 8 months and LDL-C lowering effect was maintained throughout the observation period in even the lowintensity statin group. The effects of statins in elevating high-density lipoprotein cholesterol (HDL-C)

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were similar in each statin groups, except the ezetimibe–simvastatin group (4.5±2.1%) and high-dose atorvastatin groups (9.7±3.3% and 8.7±2.4% for 40 mg and 80 mg of atorvastatin/day, respectively). HDL-C increased less and LDL-C decreased more in diabetes than in non-diabetes. There were no

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significant changes of fasting glucose after statin use in non-diabetic patients. Conclusions: Moderate- or low-intensity statin was effective enough in reaching NCEP ATP III LDL-C

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target goals in Koreans. Low-intensity statin showed around 30% LDL-C reduction from the baseline level in Koreans, which is comparable to moderate-intensity statin in new guideline. Key words dyslipidemias ⋅ diabetes⋅ statin efficacy ⋅ hydroxy methylglutaryl-CoA reductase inhibitors ⋅ lipoproteins ⋅ HDL ⋅ LDL ⋅ Triglycerides

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The use of statins has revolutionized the management of the risk of developing cardiovascular disease (CVD), and currently more than 25 million individuals use statins worldwide. Statins have a great potential to lower the risk of developing CVD by decreasing serum levels of low-density lipoprotein

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cholesterol (LDL-C) [1, 2]. That is, the incidence of CVD decreases by 20% for each 1 mmol/L reduction in LDL-C concentration[1]. Moderate- (10–20 mg atorvastatin or 20–40 mg simvastatin daily) and highintensity statin therapy (40–80 mg atorvastatin or 20 mg rosuvastatin daily) lower LDL-C by about 30%

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and 50%, respectively [3, 4]. The importance of statins to reducing LDL-C in patients at high cardiovascular risk was also highlighted in the 2013 American College of Cardiology/American Heart

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Association (ACC/AHA) guideline [5], despite no recommendation for LDL-C goal to achieve. Data about the efficacy of various statins given at different intensities are lacking in Asian countries. Thus, the application of new guidelines to Asian patients is difficult, in particular when determining the appropriate statin intensity. It would be valuable to estimate the efficacy of statins in lowering LDL-C and other lipid profiles in the clinical setting in Asian populations with and without diabetes, which may differ from

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Western populations in lifestyle, food consumption, exercise, and past or current medications. The effects of statins in elevating high-density lipoprotein cholesterol (HDL-C) may contribute to lowering the residual risk of developing CVD [6, 7]. To date, large-scale studies have shown that HDL-C

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or apolipoprotein A-I (apo A-I) are independent risk factors for developing CVD [8-10]. HDL-C is thought to delay the progression of atherosclerosis by stimulating cholesterol efflux from foam cell

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macrophages in atherosclerotic lesions [11, 12] and by triggering antioxidant and anti-inflammatory reactions [13, 14]. There is great variability between studies on the effects of statins on HDL-C. Numerous studies have shown that statins are effective in lowering LDL-C, and thereby lowering the risk of developing CVD, and that they are both safe and well tolerated. However, it remains unclear whether statins are associated with an increased risk of developing type 2 diabetes (T2D). In the Justification for the Use of Statins in Primary Prevention (JUPITER) trial, there was a small but significant increase in incident T2D and glycated hemoglobin (HbA1c) [15]. Moreover, a meta-analysis of 13 statin trials (n = 91,140) found a 9% increase in the risk of developing T2D across a 4-year period 4

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after treatment with statins (atorvastatin 10 mg, pravastatin 40 mg, simvastatin 40 mg, or rosuvastatin 20 mg daily) (odds ratio (OR) = 1.09, 95% confidence interval (CI) = 1.02–1.17)[16]. This also suggests that statin therapy might be related to incident T2D. Given the above background, we conducted this

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retrospective, observational study to estimate the percentage changes in LDL-C and HDL-C, and glucose alteration after the use of various statins. We also attempted to identify whether there are differences in

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statin efficacy between diabetic and non-diabetic patients.

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MATERIALS AND METHODS Study population We conducted the current study using a retrospective, observational design. Patients who visited the

March 2013 were included. The inclusion criteria for the current study were:

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1. statin-naïve patients; i.e., this was their first treatment with statins;

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outpatient clinic of the Seoul National University Bundang Hospital (SNUBH) between May 2003 and

2. maintenance of a fixed dose of statins for a certain period of time (at least 18 months);

4. 20 years or older; 5. 100% medication possession ratio (MPR).

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3. data for lipid levels at both the baseline and endpoint within 19–36 months of the start of statin therapy;

The exclusion criteria for the current study were:

1. a very high TG (> 500 mg/dl) or very low LDL-C (≤ 70 mg/dl) at the baseline;

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2. abnormal liver or renal function and/or uncontrolled hypothyroidism or hyperthyroidism; 3. use of other antihyperlipidemic drugs (e.g. omega3, fibrates, niacin). Patients were excluded with only ezetimibe or ezetimibe plus other statin except simvastatin The

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current study was approved by the Institutional Review Board of our medical institution (B-1410/272-

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112). Informed consent was waived due to the retrospective nature of the current study.

Outcome measures and medication compliance We evaluated the lipid profile, including the levels of total cholesterol, HDL-C, LDL-C, and TG, at various intervals after the use of statins. We evaluated the early and final responses within the first 8 months and after at least 18 months, up to 36 months after the first use of statins. The response to statins was estimated by calculating the percentage change of each lipid variable. The primary outcome measures were the percentage changes in serum levels of LDL-C and HDL-C from the baseline. The secondary 6

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outcome measures were the correlations between the percentage changes in LDL-C and HDL-C and other predictive values (baseline HDL-C, LDL-C, TG, and glucose levels), and the changes in fasting glucose and HbA1c after the start of statins in the non-diabetic patients.

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Adherence to statin therapy was assessed by patient-reported adherence and by the MPR, which is calculated as the number of days of medication supplied within the refill interval divided by the number of days in the refill interval. In the current study, we enrolled only patients with 100% MPR who were

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prescribed continued statin medication for follow-up duration.

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Serum biochemical parameters

To quantify lipid parameters, we collected blood samples from the patients in a fasting state and then transferred the blood samples to the Medical Laboratories of SNUBH for laboratory measurement. The fasting serum levels of total cholesterol, TG, HDL-C, LDL-C, apoA-I, apoB, and glucose were measured using the Toshiba TBA 200FR chemistry analyzer (Toshiba, Tokyo, Japan). HbA1c was quantified using

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high-performance liquid chromatography on the Bio-Rad Variant II analyzer at SNUBH. For the clinical assessment, we defined the diabetic status as two fasting glucose measurements of > 126 mg/dl (> 7.0 mmol/l); HbA1c of ≥ 6.5%; current treatment with an antidiabetic drug; or diabetic retinopathy,

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nephropathy, or neuropathy. We defined hypertensive status as current treatment with an antihypertensive drug. Cerebrovascular events or CVD were defined as a history of stroke, heart failure, fatal or nonfatal

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myocardial infarction, angina pectoris, or coronary revascularization.

Statistical analysis

Statistical analysis was performed using the SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL). All data are expressed as mean ± standard deviations for continuous variables, such as demographic and biochemical data, and the frequency (percentage) for categorical variables. We compared the change from the baseline to the endpoint between groups for continuous and categorical variables using one-way 7

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analysis of variance (ANOVA) and the χ2 test, respectively. We also used paired t tests to compare lipid parameters between the baseline and endpoint in each group. Repeated-measure ANOVA and Bonferroni analysis were used to test the significance of the repeated-measured outcomes. Pearson’s correlation

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coefficient was used to identify significant correlations between the changes in lipid parameters. Finally, linear regression analysis was used to identify factors related to the percentage changes in LDL-C and

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HDL-C in the statin groups. A P-value of < 0.05 was considered significant.

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RESULTS Baseline and clinical characteristics The baseline and clinical characteristics of the patients are shown in Table 1. We enrolled 3,854

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patients who had been treated with a fixed dose of statins for at least 18 months. In our series, the most commonly used statins were atorvastatin (n = 2,044) and rosuvastatin (n = 742). Supplementary table 1 lists the frequency of different doses of various statin. At the time of the start of treatment, the ezetimibe–

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simvastatin group was the youngest (60.7 ± 10.3 years) and the simvastatin-only group was the oldest (64.8 ± 9.7 years). The mean treatment period was slightly shorter in the ezetimibe–simvastatin group (107 ± 15 weeks) than in the pravastatin (115 ± 17 weeks) or simvastatin (112 ± 17 weeks) groups.

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Among all patients, 74% were overweight or obese according to BMI (≥ 23 kg/m2), but the number of patients who were overweight or obese did not differ significantly between the statin groups. The percentage of diabetic patients was higher in the simvastatin group (57.9%) and the ezetimibe–simvastatin group (62.6%) compared with the other groups. The percentage of patients with hypertension was higher

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in the simvastatin (73.3%) and pitavastatin groups (63.9%) compared with the other groups. Patients with diabetes (n=1923) were older than them without diabetes (Table 2). The initial TG was higher and the initial HDL-C was lower in patients with diabetes than in their non-diabetic counterparts.

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There were 2,062 patients (53.5%) with a history of cerebrovascular events or CVD. Total cholesterol and LDL-C were initially the highest in the rosuvastatin group. The TG and HDL-C were initially the

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highest and the lowest, respectively, in the ezetimibe–simvastatin group. 340 patients were treated with low-intensity statin therapy, comprising atorvastatin 5 mg, pravastatin 10 mg, or simvastatin 10 mg, and 226 patients were treated with high-intensity statin therapy comprising atorvastatin 40 mg, 80 mg, or rosuvastatin 20 mg. The initial total cholesterol, TG, and LDL-C did not differ between the moderate- and high-intensity statin groups (118.2 ± 31.5 mg/dl and 121.2 ± 34.4 mg/dl, respectively; Supplementary table 2).

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Effects of statins on LDL-C and HDL-C There was a rapid decrease in LDL-C during the first 8 months from 118.0 ± 31.6 to 80.5 ± 21.4 mg/dl (Table 3). In all statin groups, the percentage changes in LDL-C were largest (–28.6 ± 25.5%) within the

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first 8 months, and these levels remained constant throughout the rest of the observation period (–24.4 ± 26.3% at the endpoint). Within the first 8 months, the mean LDL-C decreased to < 100 mg/dl in all statin groups, and these levels remained constant throughout the observation period. Low-intensity statin

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therapy was also effective in reducing LDL-C within the first 8 months, and these levels were maintained during a mean period of 110 weeks (Fig. 1A). There was a dose-dependent decrease in LDL-C in all statin

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groups. At the endpoint, the mean LDL-C was significantly lower in the ezetimibe–simvastatin group than in the simvastatin group (77.9 ± 20.5 mg/dl versus 85.3 ± 20.6 mg/dl, P < 0.001). In all patients, 27.6% and 75.7% had LDL-C < 70 mg/dL and < 100 mg/dL, respectively, thus achieving the National Cholesterol Education Program Adult Treatment Panel III LDL-C goals [17, 18]. The percentages of diabetic patients with LDL-C < 70 mg/dL and < 100 mg/dL were 53.5% and 87.2% in the high-intensity

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therapy group and 16.0% and 70.3% in the low-intensity therapy group, respectively (Fig. 2A). Almost all patients without diabetes were reached LDL-C < 160 mg/dL (Fig. 2B) There were no significant differences in the mean percentage change in HDL-C from the baseline to the

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endpoint (> 18 months) between the statin groups (Table 3). HDL-C was significantly higher at the endpoint (at 110 ± 17 weeks on average after the start of statin therapy) compared with baseline by 4.2%

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± 1.3% only in the ezetimibe–simvastatin group (51.8 ± 12.5 mg/dl versus 50.4 ± 12.3 mg/dl, P = 0.037, paired t test). In the atorvastatin and pitavastatin groups, HDL-C remained constant throughout the observation period. By contrast, HDL-C were significantly lower at the endpoint than at the baseline in the rosuvastatin group (55.2 ± 13.6 mg/dl versus 56.2 ± 14.2 mg/dl, P = 0.007, paired t test). The percentage changes in HDL-C according to dosage were the highest in the ezetimibe–simvastatin 10 mg/day group (4.5 ± 2.1%) and in the high-dose atorvastatin groups (9.7 ± 3.3% for 40 mg atorvastatin/day and 8.7 ± 2.4% for 80 mg atorvastatin/day). There was a dose-dependent change in HDLC over the dose range in the atorvastatin group. As shown in Fig. 1B, the effect of statins in elevating 10

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HDL-C was significantly higher in the high-intensity statin group than in the moderate- or low-intensity

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statin groups.

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Predictors of changes in serum LDL-C and HDL-C The baseline LDL-C and HDL-C were the strongest predictors of the percentage changes in the LDL-C and HDL-C in the multivariate linear regression analysis (Table 3). There was a weak correlation

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between increased HDL-C and decreased LDL-C only in the atorvastatin group (r = 0.075, P = 0.001). HDL-C was more increased and LDL-C was more decreased in the patients whose baseline TG were higher, based on comparison between the lowest (Q1) and highest quintile (Q5) of baseline TG (–2.0 ±

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0.6% and 5.1 ± 0.7% increases in HDL-C in Q1 and Q5, respectively, and 21.3 ± 0.9% and 27.8 ± 0.9% decreases in LDL-C in Q1 and Q5, respectively, P < 0.001 for both comparisons). However, the baseline

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TG was not a significant predictor of the percentage change in HDL-C and LDL-C after adjusting for age, sex, and baseline HDL-C and LDL-C in diabetic patients (Supplementary table 3). The percentage change in LDL-C was smaller in the non-diabetic patients than in their diabetic counterparts (–22.6% ± 0.6% versus –26.2% ± 0.6%, P < 0.001). The percentage change in LDL-C was smaller in hypertensive patients than in non-hypertensive patients (–23.7% ± 0.5% versus –25.5% ± 0.7%,

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P = 0.046). As shown in Table 3, the statin-induced decrease in LDL-C was greater in patients with diabetes mellitus (B = –3.232, P < 0.01) and was smaller in hypertensive patients than in nonhypertensive patients (B = 1.776, P < 0.01) after adjusting for the baseline LDL-C. The smaller lowering

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effect of statin in hypertensive patients is constant only in multivariate analysis for diabetic patients (Supplementary table 3). The percentage change in LDL-C was smaller in the non-diabetic patients than

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in their diabetic counterparts (–22.6% ± 0.6% versus –26.2% ± 0.6%, P < 0.001). The percentage change in LDL-C was smaller in hypertensive patients than in non-hypertensive patients (–23.7% ± 0.5% versus –25.5% ± 0.7%, P = 0.046). As shown in Table 3, the statin-induced decrease in LDL-C was greater in patients with diabetes mellitus (B = –3.232, P < 0.01) and was smaller in hypertensive patients than in non-hypertensive patients (B = 1.776, P < 0.01) after adjusting for the baseline LDL-C. The smaller lowering effect of statin in hypertensive patients is constant only in multivariate analysis for diabetic patients (Supplementary table 3).

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Changes in HDL-C were significantly less in the patients with diabetes mellitus or hypertension compared with those without diabetes mellitus or hypertension. HDL-C increased by 0.5% ± 0.4% in diabetic patients and by 2.3% ± 0.4% in non-diabetic patients from the baseline to the endpoint (P =

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0.002). In the multivariate analysis (Table 3), the statin-induced increase in HDL-C was smaller in patients with diabetes mellitus after adjusting for baseline HDL-C (B = –3.205, P < 0.01). By contrast, the percentage change in LDL-C was smaller in the non-diabetic patients than in their diabetic counterparts (–

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22.6% ± 0.6% versus –26.2% ± 0.6%, P < 0.001).

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Changes in serum glucose and HbA1c in non-diabetic patients

Of the 3,854 patients treated with statins, 1,931 did not have diabetes. Their mean age was 66.4 ± 10.5 years. Their baseline serum glucose and HbA1c were 97.5 ± 13.0 mg/dl and 5.7% ± 0.4%, respectively. Of the patients treated with statins, 48.5% (n = 936) were men. Of the 1,931 non-diabetic patients, 994 (51.5%) had hypertension and 1,086 (56.2%) had a history of CVD or cerebrovascular events. There were

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no significant differences in baseline glucose or HbA1c between the statin groups. Serum of fasting glucose (n = 565) and HbA1c (n = 122) levels did not change significantly during a mean follow-up of

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110 weeks in the non-diabetic patients with dyslipidemia (Fig. 3).

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DISCUSSION In Asians, moderate- and low-intensity statin treatment showed enough LDL-C lowering to < 100 mg/dl in statin-naïve patients of dyslipidemia within the first 8 months (83.0% and 70.3% of diabetic

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patients in the moderate- and low-intensity statin groups, respectively) and these levels remained constant during the observation period in all different statin groups. When we applied new statin guideline, we could consider the use of lower intensity statin in Asians compared to Caucasian. The effects of statins in

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elevating HDL-C were similar in all statin groups, except for the ezetimibe–simvastatin and high-dose atorvastatin groups, which showed significant increase of HDL-C. The HDL-C increased less in patients

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with diabetes mellitus. Serum glucose and HbA1c levels did not change significantly in the non-diabetic patients according to different statin treatment during a mean follow-up of 110 weeks. Jones et al. [19], who enrolled mainly white and African American ethnicity, reported that atorvastatin reduced the LDL-C dose dependently across the dose range of 10–40 mg (38%–51%). The LDL-C was decreased by 19%–34% by pravastatin 10–40 mg and by 28%–41% by simvastatin 10–40 mg in the

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corresponding order. The incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) study for comparing lipid lowering effect on the risk of cardiovascular disease of a high dose of atorvastatin (80mg/d), or usual-dose simvastatin (20mg/d) showed a reduction of LDL-C of 49% and 33%,

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respectively, which included 99.2% Caucasian patients [20]. We found smaller decreases in LDL-C in all statin groups compared with previously published randomized controlled studies. This difference might

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reflect the long-term retrospective nature of the current study in a heterogeneous population of patients in a real clinical setting. However, we could see the enough LDL-C reduction (< 100 mg/dl or near 20% reduction) in even the low-intensity statin group. The goal of an LDL-C level < 100 mg/dl was achieved in > 80 % of patients in both the moderate- and high-intensity statin groups. The current guideline is based on previous statin trials in Caucasian populations, whose average body surface area and body weight differ from those of Asian populations. We could assume that the optimal doses of statins for Asians are significantly lower than those for Caucasians. Our study results support the notion that highintensity statin can be replaced with moderate-intensity statin in Asian people, which is recommended for 14

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high-risk groups in the ACC/AHA guidelines. In a double-blind study that compared atorvastatin 80 mg and pravastatin 40 mg [21], HDL-C increased by 2.9% and 5.6%, respectively, from the baseline to 18 months. HDL-C were significantly higher, by 1.2

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to 1.9 mg/dl, in the simvastatin 20 mg group compared with the atorvastatin 80 mg group during a median follow-up of 4.8 years, although the difference diminished in the fifth year of observation [20]. We found that the HDL-C was higher than the baseline level at the endpoint only in the ezetimibe–simvastatin or

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high-dose atorvastatin groups (40 mg and 80 mg). The percentages of patients who achieved an HDL-C level > 40 mg/dl in men and > 50 mg/dl in women were very low and did not differ significantly between

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the high- and low-intensity statin groups. These data suggest that pharmacological therapy in addition to statin should be considered in patients with dyslipidemia, particularly in those with a low HDL-C level. There are conflicting data about the effects of statins on the risk of incident type 2 diabetes mellitus, although statins are generally safe and well tolerated. Healthy adults treated with rosuvastatin for 1.9 years had newly diagnosed diabetes more frequently than those treated with placebo (3.0% versus 2.4%,

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P = 0.01) [15]. By contrast, in the West of Scotland Coronary Prevention Study, pravastatin was associated with a 30% reduction compared with placebo in the risk of developing T2D after 5 years [22]. A meta-analysis of 13 statin trials showed that statin therapy was associated with a 9% increased risk for

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incident T2D over 4 years [16]. Another meta-analysis reported that the potential diabetogenic effects of statins may be dose related [23]. Statins are also known to improve insulin resistance in animal models

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and thus the mechanism of diabetogenic effect is difficult to identify. In the current study, diabetic patients were excluded for assessing the changes in glucose retrospectively because the exact information of oral agent or insulin usage, the dose titration, and the concomitant drug information was not available in our subjects. Non-diabetic patients showed no significant changes in fasting plasma glucose and HbA1c with mean follow-up period 110 weeks though subjects with data of HbA1c and fasting glucose both at baseline and at endpoint were relatively small in number. The previously reported increased risk cannot be ignored, but the diabetogenic effect of statins seems to be low in actual clinical settings in Koreans. 15

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The strength of the current study is that we collected data about patients who had been started with statin treatment at the fixed doses and who had shown good compliance for at least 18 months during a mean period of 110 weeks in an actual clinical setting. However, there are some limitations of the current

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study. First, there was no attempt to standardize dietary intake or exercise during the observation period, although these might have affected the effects of statins on serum cholesterol levels. Second, we did not consider that a smoking history might affect the effects of statins on lipid levels.

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Clinicians are still facing to make a choice between intensive (usually high-intensity) and standard (moderate-intensity) statin therapy. Although patients with intensive statin treatment have fewer major

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CVDs, standard statin therapy at a less intensive dose could be recommended for Asian people with dyslipidemia, considering the efficacy of statin-induced LDL-C reduction in our study, which performed in homogenous Asian ethnic background, and unknown diabetogenic effects of statins. We could consider ezetimibe–simvastatin therapy or high-dose atorvastatin therapy over other statins for patients with low

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HDL-C.

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Gordon DJ, Factors affecting high-density lipoproteins. Endocrinol Metab Clin North Am, 1998;27: p. 699709, xi. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, and Steiner E, High apolipoprotein B, low

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apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet, 2001;358: p. 2026-33. 11.

Von Eckardstein A, Langer C, Engel T, Schaukal I, Cignarella A, Reinhardt J, Lorkowski S, Li Z, Zhou X,

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Cullen P, and Assmann G, ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocyte-derived macrophages. FASEB J, 2001;15: p. 1555-61. Brewer HB, Jr., Remaley AT, Neufeld EB, Basso F, and Joyce C, Regulation of plasma high-density

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lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease. Arterioscler Thromb Vasc Biol, 2004;24: p. 1755-60. 13.

Nofer JR, Kehrel B, Fobker M, Levkau B, Assmann G, and von Eckardstein A, HDL and arteriosclerosis:

14.

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beyond reverse cholesterol transport. Atherosclerosis, 2002;161: p. 1-16.

Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, and Fogelman AM, Antiinflammatory properties of HDL. Circ Res, 2004;95: p. 764-72.

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, Koenig W, Libby P, Lorenzatti

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AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, and Glynn RJ, Rosuvastatin to prevent

16.

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vascular events in men and women with elevated C-reactive protein. N Engl J Med, 2008;359: p. 2195-207. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SRK, McMurray JJ, Freeman DJ, and Jukema JW, Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. The Lancet, 2010;375: p. 735-42.

17.

Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation, 2002;106: p. 3143-421.

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18.

Grundy SM, Cleeman JI, Merz CN, Brewer HB, Jr., Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Jr., and Stone NJ, Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation, 2004;110: p. 227-39. Jones P, Kafonek S, Laurora I, and Hunninghake D, Comparative dose efficacy study of atorvastatin versus

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19.

simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol, 1998;81: p. 582-7.

Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS,

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Lindahl C, Szarek M, and Tsai J, High-dose atorvastatin vs usual-dose simvastatin for secondary prevention

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after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA, 2005;294: p. 2437-45. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, and DeMaria AN, Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA, 2004;291: p. 1071-80. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW,

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22.

McKillop JH, Packard CJ, Shepherd J, and Gaw A, Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation,

Preiss D, Seshasai SRK, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, and Sabatine MS, Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a

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2001;103: p. 357-62.

meta-analysis. JAMA, 2011;305: p. 2556-64.

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ACCEPTED MANUSCRIPT Table 1. Baseline demographics and clinical characteristics in the different statin groups

Ezetimibe– Atorvastatin

Rosuvastatin

Simvastatin

Pitavastatin

Pravastatin simvastatin

(n = 2044)

(n = 742)

(n = 401)

(n = 391)

P-value* (n = 86)

(n = 190) SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

67.1

10.2

66.1

10.5

71.1

9.8

67.9

9.7

64.4

10.3

70

10.8

<0.0001

62.5

10.1

61.0

10.5

64.8

9.7

63.3

9.5

60.7

10.3

64.5

11.0

<0.0001

Age at start of statin, years 1005 (49.2%)

358 (48.2%)

228 (56.9%)

194 (49.6%)

110

18

111

17

112

17

111

Body weight, kg

64.7

10.9

65.6

10.4

62.9

10.3

64.5

Body mass index, kg/m2

24.9

3.2

25.1

3.0

24.7

Diabetes mellitus, n (%)

996 (48.7%)

368 (49.6%)

Hypertension, n (%)

1195 (58.5%)

427 (57.5%)

1133 (55.4%)

397 (53.5%)

Duration of follow-up,

Cardiovascular disease, n (%) Total

3.0

25.0

53 (61.6%)

0.024

17

107

15

115

17

0.002

11.1

65.4

10.6

65.2

10.7

0.045

3.1

24.9

3.5

0.623

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weeks

102 (53.7%)

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Male, n (%)

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Age, years

Mean

3.5

25.1

232 (57.9%)

172 (44.0%)

119 (62.6%)

36 (41.9%)

<0.0001

294 (73.3%)

250 (63.9%)

80 (42.1%)

52 (60.5%)

<0.0001

178 (44.4%)

215 (55.0%)

90 (47.4%)

49 (57.0%)

<0.0001

39.4

217.5

40.9

204.5

37.9

210.2

37.3

208.8

39.8

201.1

33.4

<0.0001

TG

144.6

68.9

154.3

74.0

146.4

69.3

147.1

69.6

170.9

84.5

141.7

63.2

<0.0001

HDL-C

53.2

13.3

56.2

14.2

54.0

12.6

53.0

12.7

50.4

12.3

51.4

12.0

<0.0001

LDL-C

117.3

31.8

122.8

32.7

114.6

31.8

118.4

28.2

116.7

31.0

111.9

26.9

<0.0001

Lipid,

111.6

PP2, mg/dL

195.3

HbA1c, %

29.7

112.5

32.0

118.9

31.5

108.9

25.5

120.9

40.4

110.4

28.7

<0.0001

78.0

210.5

76.5

215.6

77.2

195.4

69.3

216.9

93.8

199.4

85.5

0.066

1.1

6.8

1.2

6.4

1.0

7.1

1.3

6.6

1.0

<0.0001

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Glucose, fasting, mg/dl

EP

mg/dL

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206.1 cholesterol

6.6

1.3

6.5

* P-value represents the significant differences between six statins groups. PP2, postprandial glucose concentration 2 h after a meal.

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ACCEPTED MANUSCRIPT Table 2. Baseline demographics and clinical characteristics in patients with or without diabetes Diabetes

Non-diabetes

(n = 1923)

(n = 1931)

P-value SD

Mean

SD

Age, years

68.3

10.0

66.4

10.5

<0.0001

Age at start of statin, years

63.2

9.9

61.7

10.4

<0.0001

Male, n (%)

949 (49.3%)

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Mean

936 (48.5%)

0.61

Duration of follow-up, weeks

110

18

111

18

0.021

Body weight, kg

64.6

10.6

64.7

10.8

0.829

Body mass index, kg/m2

25.0

3.2

24.8

3.1

0.198

1304 (67.8%)

994 (51.5%)

Cardiovascular disease, n (%)

976 (50.8%)

1086 (56.2%) 40.3

Triglyceride

156.6

73.3

HDL-C

52

12.6

LDL-C

118.3

32

Glucose, fasting, mg/dl

125.6

35.1

PP2, mg/dl

213.4

77.3

HbA1c, %

7.1

1.3

Lipid, mg/dl

38.7

0.001 0.684

140

67.7

<0.0001

54.4

13.7

<0.0001

117.8

31.1

0.645

97.5

13

<0.0001

126.1

33.7

<0.0001

5.7

0.4

<0.0001

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PP2, postprandial glucose concentration 2 h after a meal.

208.8

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208.3

0.054

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Total cholesterol

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Hypertension, n (%)

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ACCEPTED MANUSCRIPT Table 3. Mean LDL-C and HDL-C and mean percent changes in LDL-C and HDL-C from baseline in each statin group at each time point during a mean period of 110 weeks.

Mean% change of LDL-C from baseline

≤8mo

9-18mo

>18mo

115.9±31.2

89.2±22.4

89.1±21.0

91.6±21.8

-24.3

-28.5

-29.0

53.5±12.0

53.1±12.2

53.7±12.0

53.1±12.3

-0.4

-0.4

-1.0

Atorvastatin 10mg

117.4±32.0

81.5±20.7

82.8±19.9

84.6±20.6

-32.7

-34.3

-38.1

52.7±13.2

52.2±12.8

52.4±12.6

52.3±12.7

-0.4

-0.5

-0.6

Atorvastatin 20mg

116.5±29.9

77.1±21.2

77.3±21.3

79.3±20.2

-37.2

-39.5

-42.2

52.2±12.6

51.3±11.7

52.2±12.6

52.3±12.6

0.0

0.0

-0.7

Atorvastatin 40mg

121.1±39.0

70.1±24.8

70.4±24.2

76.9±28.1

-44.1

-52.5

-53.7

48.6±12.6

50.5±11.0

51.5±11.6

51.4±11.3

2.8

1.8

2.7

Atorvastatin 80mg

118.7±31.8

59.7±20.4

67.7±18.7

71.3±18.2

-47.4

-50.0

-58.8

45.2±10.9

45.8±12.1

47.2±11.6

48.7±13.7

3.5

1.7

0.5

Rosuvastatin 5mg

118.9±33.1

69.5±21.8

79.5±24.1

79.6±17.9

-39.2

-38.3

-51.4

55.5±14.3

55.1±12.3

54.3±11.7

56.1±13.5

0.6

-0.8

-0.2

Rosuvastatin 10mg

123.1±32.6

77.7±22.9

79.2±23.3

81.0±23.2

-42.1

-43.9

-47.7

57.0±14.4

56.3±13.9

56.0±14.9

55.6±13.7

-1.3

-1.1

-0.5

Rosuvastatin 20mg

123.5±33.4

75.7±21.5

79.0±26.1

81.8±24.4

-41.7

-45.7

-47.0

51.6±12.4

52.6±12.6

51.9±11.1

51.9±12.3

0.4

0.7

0.3

Simvastatin 10mg

113.9±30.8

86.8±21.1

87.6±17.8

89.0±22.3

-24.9

-26.3

-29.0

54.0±11.7

55.0±10.5

55.4±10.8

54.0±12.2

0.0

1.2

0.1

Simvastatin 20mg

114.8±32.1

82.7±18.1

82.7±17.7

84.2±20.0

-30.7

-33.3

-32.3

54.0±12.9

54.2±13.5

54.3±12.9

53.4±13.4

-0.6

0.4

0.0

Pitavastatin 2mg

118.4±28.2

84.3±18.3

85.7±18.6

88.8±19.8

-29.6

-32.7

-35.6

52.9±12.7

52.5±12.2

52.5±12.1

52.9±12.3

-0.1

-0.2

-0.1

Ezetimibe-simvastatin 10mg Ezetimibe-simvastatin 20mg Pravastatin 10mg

113.2±28.4

74.3±22.0

74.3±23.5

76.3±18.0

-36.9

-40.2

-40.4

49.7±11.8

50.7±12.6

51.1±13.6

51.2±12.2

1.5

1.6

0.8

119.7±32.9

76.2±18.8

77.8±18.6

79.3±22.4

-40.4

-43.1

-47.3

51.0±12.7

51.9±11.6

52.1±13.9

52.2±12.9

1.2

0.9

0.2

111.9±26.9

92.7±20.7

90.7±21.3

95.7±20.9

-24.0

51.4±12.0

53.0±11.5

51.1±1.9

50.9±12.5

-0.5

0.0

1.5

≤8mo

9-18mo

-16.2

>18mo

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>18mo

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9-18mo

-21.6

≤8mo

9-18mo

>18mo

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* mo: months

≤8mo*

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Base

Atorvastatin 5mg

AC C

Base

Mean% change of HDL-C from baseline

Level of HDL-C (mg/dl)

SC

Level of LDL-C (mg/dl)

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ACCEPTED MANUSCRIPT Table 4. Hierarchical regression analysis to identify the variables predicting percentage changes in HDL-C and LDL-C

Model 1a

Variables

B

SE

Model 2b Adjusted

β

B

SE

R2 (%)

β

Adjusted R2 (%)

0.005

0.028

0.003

0.024

0.029

0.013

Sex

1.99

0.601

0.052**

2.021

0.598

0.053**

Baseline HDL-C

–0.581

0.024

–0.403**

–0.588

0.023

–0.408**

Baseline TG

–0.001

0.004

–0.004

0.002

0.004

0.007

Baseline LDL-C

–0.011

0.009

–0.018

–0.011

0.009

–0.018

Diabetes mellitus

–3.205

0.576

–0.084**

Hypertension

–0.859

0.586

–0.022

–0.151

0.032

–0.059**

M AN U

SC

Age at start of statin

Percent change in LDL-C decrease

15.3

RI PT

Percent change in HDL-C increase

–0.155

0.032

–0.060**

Sex

5.156

0.678

0.980**

5.091

0.676

0.097**

Baseline HDL-C

0.018

0.027

0.009

0.009

0.026

0.004

Baseline TG

–0.005

0.005

–0.013

–0.004

0.005

–0.009

Baseline LDL-C

–0.554

0.01

–0.665**

–0.554

0.01

–0.664**

–3.232

0.65

–0.061**

1.776

0.662

0.033**

Diabetes mellitus Hypertension

43.8

TE D

Age at start of statin

16.0

44.1

a Model 1 coefficients were adjusted for age, sex, and baseline serum levels of HDL-C, LDL-C, and TG.

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b Model 2 coefficients were adjusted also for age, sex, baseline serum HDL-C level, and the presence of hypertension and diabetes mellitus.

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B,Unstandardized regression coefficient ;SE, Standard Error; β, standardized regression coefficient. ** P < 0.01.

1

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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Figure 2. Percentages of participants who reached the LDL-C target goal. (A) Percentages of patients with diabetes who reached the LDL-C goal (< 100 mg/dl or < 70 mg/dl). (B) Percentages of patients * P-value < 0.05.

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SC

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without diabetes who reached the LDL-C goal (< 160 mg/dl).

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ACCEPTED MANUSCRIPT

Figure 3. Statin medication was associated with no significant change in fasting glucose and hemoglobin A1c levels in non-diabetic patients. These values remained constant over time. Values are mean ±

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standard deviation.

ACCEPTED MANUSCRIPT Highlights Statin efficacy in Asians with and without diabetes.




Low-intensity statin was effective in reducing serum LDL-C to <100 mg/dl.




Ezetimibe-simvastatin and high dose atorvastatin significantly elevated HDL-C.




HDL-C increased less and LDL-C decreased more in diabetes compared to non-diabetes.




There was no significant statin-induced glucose elevation in non-diabetes.

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ACCEPTED MANUSCRIPT Supplementary table1. The frequency of different doses of various statins used Percent (%)

Atorvastatin 5mg

162

4.2

Atorvastatin 10mg

1375

35.7

Atorvastatin 20mg

375

9.7

Atorvastatin 40mg

61

1.6

Atorvastatin 80mg

72

1.9

Rosuvastatin 5mg

54

1.4

Rosuvastatin 10mg

595

15.4

Rosuvastatin 20mg

92

2.4

Simvastatin 10mg

92

2.4

Simvastatin 20mg

309

8.0

Pitavastatin 2mg

391

10.1

Ezetimibe-simvastatin 10mg

88

2.3

Ezetimibe-simvastatin 20mg

102

Pravastatin 10mg

86

SC

M AN U

3854

2.6 2.2

100.0

AC C

EP

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Total

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Frequency

1

ACCEPTED MANUSCRIPT Supplementary table 2. Baseline demographics and clinical characteristics in the statin groups according to statin intensity Moderate-intensity Low-intensity statins

High-intensity statins

P-

P-

P-

(n = 226)

value*

value**

value§

statins (n = 340) (n = 3288) SD

Mean

SD

Mean

SD

Age, years

69.5

10.1

67.3

10.1

64.3

11.9

0.001

<0.0001

<0.0001

Age at start of statin, years

64.0

10.1

62.4

10.0

60.6

12.1

0.027

0.030

<0.0001

0.690

<0.0001

<0.0001

17

0.036

0.955

0.147

10.6

0.002

0.581

0.005

0.034

0.424

0.695

86 (38.1%)

0.776

<0.0001

0.002

95 (42.0%)

0.054

<0.0001

<0.0001

178 (78.8%)

<0.0001

<0.0001

<0.0001

Male, n (%)

160 (47.1%)

1585 (48.2%)

140 (61.9%)

113

17

110

17

110

Body weight, kg

62.2

10.0

64.9

10.8

65.7

Body mass index, kg/m2

24.4

3.1

25.0

3.2

1662 (50.5%)

Hypertension, n (%)

223 (65.6%)

1980 (60.2%)

Cardiovascular disease, n (%)

137 (40.3%)

24.7

M AN U

175 (51.5%)

SC

Duration of follow-up, weeks

Diabetes mellitus, n (%)

RI PT

Mean

1747 (53.1%)

2.9

203.2

35.4

209.2

39.6

207.4

43.4

0.028

0.794

0.475

Lipid,

Triglyceride

140.7

66.0

148.9

71.4

147.5

71.9

0.125

0.956

0.537

mg/dl

HDL-C

53.1

11.9

53.5

13.3

48.8

12.2

0.874

<0.0001

0.001

LDL-C

114.4

30.0

118.2

31.5

121.2

34.4

0.106

0.371

0.040

Glucose, fasting, mg/dl

113.8

PP2, mg/dl

195.6

HbA1c, %

6.6

PP2, postprandial glucose concentration 2 h after a meal.

TE D

Total cholesterol

29.9

113.2

31.0

104.8

27.0

0.949

0.001

0.007

78.5

205.8

77.8

166.9

81.9

0.511

0.001

0.082

1.2

6.7

1.2

6.3

1.2

0.982

0.001

0.025

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* Low-intensity statins versus moderate-intensity statins.

** Moderate-intensity statins versus high-intensity statins.

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§ Low-intensity statins versus high-intensity statins.

1

ACCEPTED MANUSCRIPT Supplementary table 3. Hierarchical regression analysis to identify the variables predicting percentage changes in HDL-C and LDL-C in patients with or without diabetes (A) In diabetic patients Model 1a Variables

B

SE

Model 2b

β

Adjusted (%)

14.1

R2

B

SE

0.037

0.041

β

Adjusted R2 (%)

Age at start of statin Sex

0.041

0.019

2.29

0.836

0.061**

2.301

0.837

Baseline HDL-C

-0.591

0.034

–0.397**

-0.590

0.034

Baseline TG

-0.008

0.006

-0.030

-0.007

0.006

Baseline LDL-C

0.005

0.013

0.008

0.005

0.013

Hypertension

-0.485

Percent change in LDL-C decrease -0.154

0.046

–0.058**

4.575

0.931

0.087**

Baseline HDL-C

0.054

0.038

0.026

Baseline TG

–0.005

0.006

–0.014

Baseline LDL-C

–0.555

0.014

–0.678**

Hypertension

(B) In non-diabetic patients

Variables

B

SE

Percent change in HDL-C increase

TE D

Model 1a

45.1

-0.165

β

Adjusted (%)

0.002

17.7

–0.396** -0.029

0.008

-0.012

0.046

–0.063**

4.508

0.929

0.086**

0.048

0.038

0.023

–0.006

0.006

-0.017

–0.554

0.014

–0.677**

3.000

0.953

0.053**

R2

B

SE

β

Adjusted R2 (%)

0.012

0.04

0.006

17.8

1.744

0.856

0.045*

0.004

0.039

1.684

0.855

Baseline HDL-C

-0.582

0.032

–0.414**

-0.582

0.032

–0.414**

Baseline TG

0.013

0.006

0.046*

0.014

0.006

0.048*

Baseline LDL-C

-0.028

0.013

–0.045*

EP

AC C

Hypertension

45.4

Model 2b

Age at start of statin Sex

0.044*

14

0.061**

0.858

M AN U

Age at start of statin Sex

0.020

SC

0.036

RI PT

Percent change in HDL-C increase

-0.028

0.013

–0.046*

-1.210

0.804

-0.032

-0.138

0.046

–0.054*

Percent change in LDL-C decrease Age at start of statin Sex Baseline HDL-C

-0.134

0.045

–0.053**

42.5

5.774

0.982

0.110**

5.744

0.983

0.109*

-0.027

0.037

-0.014

-0.027

0.037

-0.014

Baseline TG

–0.001

0.015

-0.656

-0.001

0.007

-0.001

Baseline LDL-C

-0.555

0.015

–0.656**

-0.555

0.015

–0.656*

0.623

0.923

0.012

Hypertension

42.5

a Model 1 coefficients were adjusted for age, sex, and baseline serum levels of HDL-C, LDL-C, and TG. b Model 2 coefficients were adjusted also for age, sex, baseline serum HDL-C level, and the presence of hypertension. B,Unstandardized regression coefficient ;SE, Standard Error; β, standardized regression coefficient

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* P < 0.05, ** P < 0.01.

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