Effect of Pitavastatin Treatment on ApoB-48 and Lp-PLA2 in Patients with Metabolic Syndrome: Substudy of PROspective Comparative Clinical Study Evaluating the Efficacy and Safety of PITavastatin in Patients with Metabolic Syndrome

Hyo-Sun Lee; Chang Hee Jung; Sung Rae Kim; Hak Chul Jang; Cheol-Young Park

doi:10.3803/EnM.2016.31.1.120

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Lee, Jung, Kim, Jang, Park, and PROPIT Study Team: Effect of Pitavastatin Treatment on ApoB-48 and Lp-PLA2 in Patients with Metabolic Syndrome: Substudy of PROspective Comparative Clinical Study Evaluating the Efficacy and Safety of PITavastatin in Patients with Metabolic Syndrome

Original Article

Clinical Study

Endocrinology and Metabolism 2016; 31(1): 120-126.

Published online: 16 March 2016

DOI: https://doi.org/10.3803/EnM.2016.31.1.120

Effect of Pitavastatin Treatment on ApoB-48 and Lp-PLA₂ in Patients with Metabolic Syndrome: Substudy of PROspective Comparative Clinical Study Evaluating the Efficacy and Safety of PITavastatin in Patients with Metabolic Syndrome

Hyo-Sun Lee¹, Chang Hee Jung², Sung Rae Kim³, Hak Chul Jang⁴, Cheol-Young Park¹

; PROPIT Study Team

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

²Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

³Department of Endocrinology, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁴Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Corresponding author: Cheol-Young Park. Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea. Tel: +82-2-2001-1869, Fax: +82-2-2001-1588, cydoctor@chol.com

Received 25 July 2015 Revised 3 August 2015 Accepted 4 August 2015

(open-access, http://creativecommons.org/licenses/by-nc/4.0/):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Apolipoprotein (Apo) B-48 is an intestinally derived lipoprotein that is expected to be a marker for cardiovascular disease (CVD). Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a vascular-specific inflammatory marker and important risk predictor of CVD. The aim of this study was to explore the effect of pitavastatin treatment and life style modification (LSM) on ApoB-48 and Lp-PLA₂ levels in metabolic syndrome (MS) patients at relatively low risk for CVD, as a sub-analysis of a previous multi-center prospective study.

Methods

We enrolled 75 patients with MS from the PROPIT study and randomized them into two treatment groups: 2 mg pitavastatin daily+intensive LSM or intensive LSM only. We measured the change of lipid profiles, ApoB-48 and Lp-PLA₂ for 48 weeks.

Results

Total cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and ApoB-100/A1 ratio were significantly improved in the pitavastatin+LSM group compared to the LSM only group (P≤0.001). Pitavastatin+LSM did not change the level of ApoB-48 in subjects overall, but the level of ApoB-48 was significantly lower in the higher mean baseline value group of ApoB-48. The change in Lp-PLA₂ was not significant after intervention in either group after treatment with pitavastatin for 1 year.

Conclusion

Pitavastatin treatment and LSM significantly improved lipid profiles, ApoB-100/A1 ratio, and reduced ApoB-48 levels in the higher mean baseline value group of ApoB-48, but did not significantly alter the Lp-PLA₂ levels.

Keywords: Apolipoprotein B-48, Lp-PLA₂, Metabolic syndrome, Pitavastatin

INTRODUCTION

With an increasing prevalence worldwide, metabolic syndrome (MS) has become a leading health concern [1]. MS is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality [2]. Dyslipidemia is one diagnostic criteria for the MS and these lipid abnormalities are recognized risk factors for cardiovascular disease (CVD) [3]. Statins decrease significant CVD risk in patients with MS by reducing low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and possibly by decreasing inflammation [4].

Apolipoprotein B (ApoB) is the main structural surface protein found on all β lipoproteins and is known to cause atherosclerosis [5]. Of two type of ApoB, ApoB-48 is an intestinally derived lipid with a chylomicron remnant that increases in postprandial hyperlipidemia, a known risk factor of coronary artery disease (CAD) [6]. The effect of statins on hepatic ApoB-100 is well known [7], but the direct effect of statins on intestinal ApoB-48 is less well understood.

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂), an emerging biomarker of cardiovascular risk, is an inflammatory enzyme expressed in macrophages of atherosclerotic plaques and carried in the circulation predominantly bound to LDL-C [8 9]. Recently, analysis of data from 32 prospective studies linked LP-PLA₂ activity directly with the risk of CVD [10]. Previous studies report that increased Lp-PLA₂ activity is associated with MS and incident fatal and non-fatal CVD [11]. High Lp-PLA₂ activity is observed in subjects with the MS and associated with several lipid-related risk factors such as ApoB [12].

Therefore, the purpose of the present study was to evaluate the effect of pitavastatin and life style modification (LSM) treatment on ApoB-48 and Lp-PLA₂ levels in subjects with MS, using serum samples from the PROPIT (PROspective comparative clinical study evaluating the efficacy and safety of PITavastatin in patients with metabolic syndrome) trial.

METHODS

Trial design

The PROPIT trial was a 12-month, multicenter, prospective, randomized open label study at 10 clinical centers in Korea. The detailed protocol for PROPIT has been previously described [13]. Briefly, after screening, selected subjects with MS were randomized into two groups: the pitavastatin (2 mg daily)+intensive LSM group or the intensive LSM only group. Subjects with LDL ≥190 mg/dL or glycated hemoglobin (HbA1c) ≥8% at the 24-week (6-month) follow-up visit were withdrawn from the study because there was a drug-naïve arm in our study design. All subjects were trained for LSM with the same protocol at the time of enrollment by health professionals.

Study subjects

Between February 2008 and December 2010, 164 MS patients were enrolled in the PROPIT study. Among them, we randomly selected 37 and 38 subjects for the pitavastatin and LSM groups, respectively, after matching for age, sex, and body mass index.

Eligible patients were men and women aged 18 to 75 years with central obesity (waist circumference: men ≥90 cm, women ≥85 cm, according to guideline of the Korean Society for the Study of Obesity) [14] and impaired fasting glucose (fasting glucose ≥100 mg/dL), which are essential components of MS, and one or more of the followings components: (1) TG ≥150 mg/dL; (2) high density lipoprotein (HDL) for men ≤40 mg/dL, and for women ≤50 mg/dL; and (3) systolic blood pressure ≥130 mm Hg or diastolic blood pressure (DBP) ≥85 mm Hg. Selected subjects had no prior history of atherosclerosis or CVD. They were statin naïve, with no prior use of oral hypoglycemic agents.

The exclusion criteria were the use of statins within the preceding 3 months; uncontrolled hypertension (DBP ≥95 mm Hg); poorly controlled diabetes (HbA1c ≥8.0%); high cholesterolaemia (LDL ≥190 mg/dL or TG ≥400 mg/dL); a past medical history of coronary disease, atherosclerosis, malignancy or severe infective disease; renal dysfunction (creatinine ≥2.0 mg/dL) or hepatic dysfunction (aspartate aminotransferase or alanine aminotransferase ≥upper normal limit [UNL] ×2.5); uncontrolled hypothyroidism (thyroid-stimulating hormone ≥UNL ×1.5); creatine phosphokinase ≥UNL ×2; pregnancy or possible pregnancy; and lactation.

Measurement of plasma levels of ApoB-48 and Lp-PLA2

Plasma concentration of ApoB-48 was measured by enzyme-linked immunosorbent assay (ELISA) kit (product code: SEB883Hu) which is a sandwich enzyme immunoassay for in vitro quantitative measurement of ApoB-48 in human serum, plasma, and other biological fluids. The plasma concentration of Lp-PLA₂ was determined by a commercially available Lp-PLA₂ ELISA kit (Uscn Life Science Inc., Houston, TX, USA).

Endpoint assessment

The primary end-point was the change from baseline in plasma level of ApoB-48 and Lp-PLA₂ after the 12-month intervention. Secondary end-points included changes from baseline in lipid profiles (TG, HDL, non-HDL, and LDL), ApoB-100/A1 ratio and high molecular weight (HMW) adiponectin.

Statistical analysis

The data are presented as mean±standard deviation for continuous variables and as proportions (%) for categorical variables. Baseline clinical and biochemical characteristics between the two treatment groups were compared using two-sample t test for continuous variables and chi-square test for categorical variables. The changes of the primary end-point and other parameters from baseline within groups were analyzed using a paired t test, and the significance of the changes between the treatment groups were analyzed using a two-sample t test. In a separate analysis, changes from baseline in the levels of ApoB-48 and LpPLA₂ according to their baseline values (i.e., below and above median values) were compared using a Wilcoxon signed rank test, and differences in changes between the treatment groups was analyzed using a Mann Whitney U test. All statistical analyses were carried out with SPSS version 21.0 (IBM Co., Armonk, NY, USA). A two-tailed P<0.05 was regarded as statistically significant.

RESULTS

Baseline patient characteristics

All subjects were patients with MS, obesity and prediabetes, and all were statin naïve, with no prior use of oral hypoglycemic agents. The two groups of patients were well-matched according to lipid profile, blood glucose level and the pattern of life style including the frequency of exercise, alcohol consumption and smoking. The mean body mass index and fasting plasma glucose level were around 27 kg/m² and 115 mg/dL, respectively. The number of subjects with coronary heart disease family history, insulin resistance (homeostasis model assessment of insulin resistance), and inflammation state (high-sensitivity C-reactive protein) did not differ between groups. Baseline characteristics of the study subjects are summarized in Table 1.

Changes in metabolic parameters, apolipoprotein, and Lp-PLA₂ in both groups after 12 months of treatment

After the 12 months of treatment, LDL-C and non-HDL cholesterol (HDL-C) were significantly reduced in the pitavastatin +LSM group compared with those in the LSM only group (Table 2). TG level was significantly lower in the pitavastatin +LSM group but slightly higher in LSM only group, but the differences were not significant (TG change: -24.7±54.1 mg/dL vs. 2.7±98.1 mg/dL, P=0.143).

The ApoB-100/A1 ratio was also significantly lower in both groups, but was much greater in the pitavastatin+LSM group (ApoB-100/A1 ratio change: -0.21±0.16 vs. -0.05±0.12, P<0.001).

HMW adiponectin increased in both groups, but there was no significant difference between the two groups. We evaluated the change of Lp-PLA₂ and ApoB-48 levels before and after intervention. Pitavastatin+LSM did not significantly affect ApoB-48 levels in subjects overall, but when we evaluated changes from baseline in ApoB-48 level according to baseline values (i.e., below and above median values), pitavastatin+LSM significantly reduced ApoB-48 levels in the group with above median baseline value of ApoB-48. There was no effect of pitavastatin+LSM on Lp-PLA₂ in either group (Table 3).

DISCUSSION

We conducted a sub-analysis of the PROPIT study to evaluate the effect of combined therapy with a statin and LSM on lipid profiles, ApoB-48 and Lp-PLA₂ in MS patients. In our study, pitavastatin treatment significantly improved lipid profiles and reduced ApoB-48 levels in the higher mean baseline value group of ApoB-48, but did not significantly alter the Lp-PLA₂ levels.

Insulin resistance is a major component of MS and represents major complications associated with atherogenic dyslipidemia [15]. Atherogenic dyslipidemia in MS patients is characterized by low HDL-C and high TG levels. TGs are associated with TG-rich lipoproteins (TRLs), and chylomicron remnants have been implicated as significant risk factors for atherosclerosis [6 16]. The small intestine regulates lipid metabolism in fed and fasting states and plays a central role in lipid homeostasis [17 18]. Since the small intestine consists of insulin sensitive tissue, lipid synthesis pathways in the small intestine are also influenced by insulin resistance. ApoB-48 is present only in intestinally derived lipoproteins such as chylomicron and chylomicron remnants. High ApoB-48 levels suggest delayed metabolism of TRLs, which are commonly associated with insulin resistance and abdominal obesity [19]. In our study showed that pitavastatin+LSM did not change the level of ApoB-48 in subjects overall, but the level of ApoB-48 was significantly lower in the higher mean baseline value group of ApoB-48.

Some previous studies report that plasma level of ApoB-48 could be a marker of new onset as well as chronic CAD [20 21]. Therapeutically, statins are most commonly used to reduce dyslipidemia via inhibition of endogenous hepatic cholesterol synthesis (inhibition of 3-hydroxy-3-methylglutaryl CoA reductase). Because the effect of statins on the intestine is relatively unknown, some other investigators have examined the effect of statins on levels of ApoB-48. Dane-Stewart et al. [22] reported that 80 mg/day of atorvastatin significantly lowered ApoB-48 levels in 10 normolipidemic patients with CAD. Lamon-Fava et al. [23] also documented that atorvastatin at both 20 and 80 mg/day significantly lowered ApoB-48 in the fed state in nine patients with combined hyperlipidemia.

There were some differences between our study and prior studies. Previously, the effect of statins on ApoB-48 was measured in the post-prandial setting by meal challenge test, because ApoB-48 reflects TG-rich remnant lipoproteins which are risk factors for CVD and increase in postprandial hyperlipidemia. In our study, we measured ApoB-48 in the fasting condition, and so the change of ApoB-48 level after intervention was lower than in prior studies. However, some studies report that a high fasting serum concentration of ApoB-48 also may be a risk factor for CAD [20 24]. Although the change of ApoB-48 in the fasting state was smaller than in the fed state, we thought that it was important to measure ApoB-48 in the fasting state.

Lp-PLA₂, also known as low density associated platelet-activating factor acetylhydrolase, is released from the macrophages of atherosclerotic plaques into circulation [25]. Lp-PLA₂ hydrolyzes oxidized phospholipids on LDL to lysophosphatidylcholine and oxidizes fatty acids, and lysophosphatidylcholine activates several second messengers with potentially atherogenic effects [26]. Several investigations report that Lp-PLA₂ is a cardiovascular risk marker independent of, and in addition to, traditional risk factors [27 28]. As an important predictor of CVD, Lp-PLA₂ has received attention as a potential new therapeutic target. The advent of some novel pharmacological inhibitors of this enzyme such as darapladib and varespladib may help to reduce the risk of CAD [29]. A previous study revealed that darapladib, when added to statins, prevents necrotic core expansion and offers great benefit in the reduction of plaque formation [30]. Some researchers have investigated the effect of statins on Lp-PLA₂ activity. Winkler et al. [31] reported that 80 mg/day of fluvastatin for 8 weeks decreased the activity of Lp-PLA₂ by 22.8% in subjects with type 2 diabetes. Schaefer et al. [32] also reported that 40 mg/day of atorvastatin reduced mean Lp-PLA₂ values by 26% over 36 weeks in 84 patients who had coronary heart disease and LDL-C levels >130 mg/dL. In contrast to previous studies, pitavastatin (2 mg/day) treatment did not reduce Lp-PLA₂ levels in our study.

There were several differences between our study and previous studies in Lp-PLA₂ as well. Previous studies evaluated the effect of statins on Lp-PLA₂ activity in subjects at high risk for CVD due to previous coronary disease or diabetes mellitus. However, this study excluded subjects at high risk for CVD (uncontrolled hypertension [DBP ≥95], poorly controlled diabetes [HbA1c ≥8.0%], or high cholesterolemia [LDL ≥190 mg/dL or TG ≥400 mg/dL]). Possibly because we focused on patients at relatively low risk for CVD, the effect of pitavastatin on the change of Lp-PLA₂ was lower than in previous studies. Another difference compared to other studies was the dosage of statin. Pitavastatin 2 mg shows similar effects to atorvastatin 10 mg in improving lipid profiles [33]. Prior studies investigating the effect of statins on the level of Lp-PLA₂ used a higher dosage of statin sufficient to reduce the level of Lp-PLA₂. We thought that the dosage of pitavastatin in present study was not enough to change the levels of Lp-PLA₂. In addition, we measured the mass concentration of Lp-PLA₂ by commercial assay. The median value of Lp-PLA₂ has varied widely in prior epidemiologic studies, making it difficult to use this assay for clinical purposes. It has been suggested that a measure of Lp-PLA₂ activity might serve as a more reproducible and representative biomarker of enzyme functions [34]. If we measured Lp-PLA₂ activity with Lp-PLA₂ mass concentration, we would have more accurate results for the effect of pitavastatin on Lp-PLA₂.

Some important limitations of this study deserve mention. First, it was a sub-study with a relatively small number of subjects. Accordingly, the plasma levels of ApoB-48 and Lp-PLA₂ had wide standard deviations and statistical power was reduced. The strength of this study was that it is the first interventional study that investigated the effect of pitavastatin on the level of ApoB-48 and Lp-PLA₂.

In conclusion, pitavastatin+LSM in MS patients at relatively low risk for CVD significantly reduced ApoB-48 levels in the higher baseline mean value group of ApoB-48, but did not significantly alter Lp-PLA₂ levels. Further studies with modified dosage and larger populations are needed to evaluate the effects of pitavastatin treatment on Lp-PLA₂ and ApoB-48.

ACKNOWLEDGMENTS

We thank other investigators for their cooperation in this study. The full list of other investigators for this study is as follows: PROPIT Study Team Sung Hee Choi (Seoul National University Bundang Hospital, Seongnam, Korea), Soo Lim (Seoul National University Bundang Hospital, Seongnam, Korea), Ji A Seo (Korea University Ansan Hospital, Ansan, Korea), Jung Hyun Noh (Inje University Ilsan Paik Hospital, Goyang, Korea), Ji Oh Mok (Soonchunhyang University Bucheon Hospital, Bucheon, Korea), Ki Young Lee (Gachon University Gil Medical Center, Incheon, Korea), Jong Sook Park (Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea), Dae Jung Kim (Ajou University Hospital, Suwon, Korea), and Chang Beom Lee (Hanyang University Guri Hospital, Guri, Korea).

Notes

CONFLICTS OF INTEREST: This study was supported by JW Pharmaceutical, Seoul, Republic of Korea. The sponsor participated in the study design, data collection and analysis of the data, but not in writing the manuscript and the decision to submit the manuscript for publication.

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Table 1

Baseline Characteristics of Subjects in the Sub-Analysis

Variable	Pitavastatin+LSM (n=37)	Only LSM (n=38)	P value
Age, yr	52.9±8.5	52.0±9.1	NS^a
Male sex	22 (59.5)	25 (65.8)	NS^b
BMI, kg/m²	26.8±2.2	27.1±3.6	NS^a
WC, cm	91.8±4.4	94.3±6.5	NS^a
SBP, mm Hg	129.6±10.1	126.3±11.1	NS^a
DBP, mm Hg	80.7±6.6	80.8±7.3	NS^a
Exercise, time/wk			NS^b
>3	15 (40.5)	18 (47.4)
1–3	10 (27.0)	6 (15.8)
Never	12 (32.4)	14 (36.8)
Current smoker	10 (27.0)	12 (31.6)	NS^b
Alcohol habits, time/wk			NS^b
≥3	14 (37.8)	17 (44.7)
<3	14 (37.8)	11 (28.9)
Never	9 (24.3)	10 (26.3)
CHD family history	9 (24.3)	9 (23.7)	NS^b
FPG, mg/dL	114.1±11.1	116.5±14.9	NS^a
Total cholesterol, mg/dL	223.6±28.7	215.5±26.5	NS^a
HDL-C, mg/dL	49.2±9.6	46.9±10.0	NS^a
LDL-C, mg/dL	144.7±19.8	136.1±24.0	NS^a
Non-HDL-C, mg/dL	174.4±28.8	168.6±24.4	NS^a
TG, mg/dL	162.4±50.6	175.8±72.9	NS^a
hs-CRP, mg/dL	0.15±0.16	0.19±0.32	NS^a
HOMA-IR	2.9±1.2	3.5±1.7	NS^a

Values are expressed as mean±SD or number (%).

LSM, life style modification; NS, not significant; BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; CHD, coronary heart disease; FPG, fasting plasma glucose; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TG, triglyceride; hs-CRP, high sensitivity C-reactive protein; HOMA-IR, homeostasis model assessment of insulin resistance.

^aThe P values are computed from two-sample t test; ^bThe P values are computed from v2-test.

Table 2

Changes of Metabolic Parameters after 12 Months Intervention in Both Groups

Variable	Pitavastatin+LSM (n=37)			LSM only (n=38)			P value^a
Variable	Baseline	12 months	Change	Baseline	12 months	Change	P value^a
TC, mg/dL	223.6±28.7	178.2±25.9	–45.4±34.7^b	215.7±26.8	215.7±22.7	0±22.5	<0.001
TG, mg/dL	162.4±50.6	137.7±54.2	–24.7±54.1^b	175.8±72.9	179.6±106.6	2.7±98.1	NS
HDL-C, mg/dL	49.2±9.6	49.9±9.0	0.7±6.2	47.2±10.0	49.2±8.5	2.0±7.3	NS
LDL-C, mg/dL	144.7±19.8	103.0±24.5	–41.7±29.6^b	135.8±24.3	134.1±22.3	–1.7±23.2	<0.001
Non-HDL-C, mg/dL	174.4±28.8	138.4±28.7	–46.0±34.4^b	168.6±24.4	166.5±22.8	–2.0±21.2	<0.001
ApoB-100/A1 ratio	0.75±0.17	0.55±0.18	–0.21±0.16^b	0.71±0.18	0.66±0.13	–0.05±0.12^b	<0.001
Adiponectin, µg/mL	2.40±0.997	3.37±1.47	0.965±1.38^b	3.15±1.87	3.67±1.76	0.519±1.14^b	NS
HMW-adiponectin, µg/mL	2.20±1.30	2.61±1.70	0.404±1.01^b	2.20±1.30	3.06±2.77	0.775±1.07^b	NS
ApoB-48, µg/mL	5.64±1.55	5.36±1.75	–0.272±2.17	5.98±3.20	6.36±2.62	0.382±4.05	NS
Lp-PLA₂, µg/mL	1.20±0.262	1.25±0.251	0.048±0.225	1.21±0.241	1.33±0.316	0.116±0.288^b	NS

Values are expressed as mean±SD.

LSM, life style modification; TC, total cholesterol; TG, triglyceride; NS, not significant; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; ApoB-100, apolipoprotein B100; ApoA1, apolipoprotein A1; HMW, high molecular weight; Lp-PLA₂, lipoprotein-associated phospholipase A₂.

^aComparison of the changes between the groups by two-sample t test; ^bP<0.05 by paired t test.

Table 3

Changes from Baseline in the Levels of ApoB-48 and Lp-PLA₂ according to Their Baseline Values (i.e., Below and Above Median Values)

Variable	Pitavastatin+LSM (n=37)			LSM only (n=38)			P value^a
Variable	Baseline	12 months	Change	Baseline	12 months	Change	P value^a
Below median, µg/mL
ApoB-48	4.54 (4.02–4.89)	4.64 (3.83–6.35)	0.15 (–0.65 to 2.09)	4.57 (4.11–4.94)	5.46 (4.70–6.11)	0.68 (0.21–1.70)	0.234
Lp-PLA₂	1.02 (0.86–1.17)	1.12 (0.94–1.38)	0.16 (0.00–0.30)	1.02 (0.91–1.11)	1.22 (1.14–1.30)	0.19 (0.10–0.33)	0.331
Above median, µg/mL
ApoB-48	6.09 (5.62–7.30)	5.07 (4.67–5.75)	–0.88 (–2.51 to –0.65)^b	6.41 (5.64–7.70)	5.99 (5.11–6.63)	0.14 (–1.69 to 0.67)	0.045^b
Lp-PLA₂	1.44 (1.27–1.48)	1.40 (1.27–1.56)	–0.03 (–0.15 to 0.11)	1.34 (1.29–1.44)	1.44 (1.15–1.54)	0.06 (–0.18 to 0.15)	0.598

Values are expressed as median (interquartile range). The values corresonding to the median of baseline apoB-48 and Lp-PLA₂ are 5.42 and 1.23 µg/mL, respectively.

ApoB-48, apolipoprotein B48; Lp-PLA₂, lipoprotein-associated phospholipase A₂; LSM, life style modification.

^aComparison of the changes between the groups by Mann-Whitney U test; ^bP<0.05 by Wilcoxon signed rank test.

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