Effect of Atorvastatin Monotherapy and Low-Dose Atorvastatin/Ezetimibe Combination on Fasting and Postprandial Triglycerides in Combined Hyperlipedemia

Abstract

Postprandial triglyceride (TG) levels are easy to measure and are associated with future cardiovascular risk. The aim of this study was to compare the effects of statin monotherapy and low-dose statin/ezetimibe on lipid parameters including fasting and postprandial TG. After a 4-week dietary run-in period, 78 patients with combined hyperlipidemia were randomized into 1 of 2 treatment groups for 8 weeks: atorvastatin 20 mg or atorvastatin/ezetimibe 5 mg/5 mg. An oral fat load test was performed before and after the drug-treatment period. The low-dose combination had a tendency to decrease fasting TG more than atorvastatin monotherapy. The combination regimen showed a greater reduction in postprandial TG (−13% ± 42% and −34% ± 30%, in the atorvastatin and combination groups, respectively, P = .03) and total cholesterol (TC; P = .03). The changes in low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) were not different between the 2 groups. The reduction in apo B/A1 was greater in the combination group (−32% ± 19% and −42% ± 13%, in the atorvastatin and combination groups, respectively, P = .02). In conclusion, these results demonstrated a potential beneficial effect of low-dose atorvastatin/ezetimibe combination treatment on postprandial TG control after comparable LDL-C lowering in patients with combined hyperlipidemia.

Keywords

atorvastatin ezetimibe postprandial period hypertriglyceridemia

Introduction

Currently, lipid-lowering is the mainstay of medical therapy for cardiovascular event prevention. Among pharmacologic approaches, statins have a strong lipid-lowering efficacy and have been established as a standard agent. Although the efficacies of statins are frequently evaluated by low-density lipoprotein-cholesterol (LDL-C) lowering, they also affect other lipids and lipoprotein levels.^1,2 Ezetimibe reduces LDL-C levels by inhibiting the absorption of dietary and biliary cholesterol. This agent reduces the transport of cholesterol from the intestine to the liver and enhances clearance of apolipoprotein (apo) B-containing lipoproteins.³ Ezetimibe is commonly combined with ongoing statin therapy and has been reported to have an additive lipid-modifying effect.⁴ The beneficial effect of ezetimibe on surrogate markers or clinical outcomes has not been clearly shown in studies conducted in populations with several specific diseases, such as familial hypercholesterolemia,⁵ aortic stenosis,⁶ or coronary artery disease.⁷ However, data on its effect has been limited in other various populations with elevated cardiovascular risk.

Triglyceride (TG) levels, especially obtained during a postprandial state, reflect the presence of remnant lipoproteins that may promote atherosclerosis. In a general population cohort, elevated postprandial TG levels were shown to be associated with the risk of coronary artery disease.⁸ The predictive value of postprandial TG levels for cardiovascular risk was not smaller than that of fasting TG levels.⁹ In addition, daytime triglyceridemia was revealed to be linked to premature coronary artery disease in fasting normotriglyceridemic participants.¹⁰ Easier measurement of postprandial TG may place itself as a useful indicator of cardiovascular risk. Several studies have been performed to evaluate the effect of lipid-lowering drugs on postprandial lipemia.¹¹ However, reports on postprandial lipid-lowering in patients with combined hyperlipidemia are very limited.¹² Increased risk of coronary artery disease has been well established in patients with combined hyperlipidemia. Therefore, postprandial elevation of TG in these patients may be worth controlling as an important therapeutic target. Although a few investigators compared statin monotherapy and low-dose statin/ezetimibe combination on postprandial lipemia, the participants were not combined hyperlipidemia patients, and their numbers were not sufficient to provide reliable results.^13,14

In the present study, the effects of 2 statin regimens, atorvastatin 20 mg and atorvastatin/ezetimibe 5 mg/5 mg, on fasting and postprandial TG were compared in patients with combined hyperlipidemia. A potential differential effect between the 2 regimens on postprandial lipid parameters after comparable reduction in LDL-C was observed.

Methods

Study Population

Men and women aged 20 to 79 years with LDL-C levels >130 mg/dL and TG levels between 150 and 499 mg/dL were initially screened. Participants who met the same lipid criteria after a 4-week dietary run-in period were included in the study. Criteria for exclusion included familial hypercholesterolemia, pregnancy or breastfeeding, a history of acute cerebrovascular accident, myocardial infarction within 3 months of trial entry, serum creatinine >2.0 mg/dL, transaminase level >2 × upper limit of normal (ULN), thyroid dysfunction, serum creatine kinase >2.5 × ULN, infection, inflammatory diseases, cancer, or a history of adverse reaction to test drugs.

Study Design

The present study was a 12-week (4-week dietary run-in period followed by 8 weeks of drug treatment), randomized, open-label, single-center study. The study protocol was approved by the local institutional review board, and all patients provided written informed consent. At the initial screening visit, patients were interviewed to record their medical histories. Patients underwent a complete physical examination and laboratory assessment. After discontinuation of any lipid-lowering agent, patients entered the 4-week dietary run-in period. Thereafter, patients who met the lipid criteria were randomized in a 1:1 ratio into 2 treatment groups for 8 weeks: atorvastatin 20 mg (Lipitor, Pfizer, New York, New York) or atorvastatin/ezetimbe 5/5mg (Lipitor, Pfizer and Ezetrol, Merck & Co, Whitehouse Station, New Jersey). We decided upon these 2 regimens by considering prior literature in which higher dose statins and lower dose statin/ezetimibe combinations had been compared and yielded similar LDL-C reducing effects.^15,16 A total of 100 patients were initially screened and 78 were randomized into 1 of the 2 treatment groups. In all, 22 patients did not meet the lipid criteria after the dietary run-in period.

Oral Fat Load

An oral fat load test was performed before and after the 8-week drug treatment. After an overnight fast, a mixed meal type of oral fat (Meiji Dairies Corporation, Tokyo, Japan) was administered to each patient. The total energy content of the meal was 750 kcal with 31% energy from fat, 14% energy from protein, and 55% energy from carbohydrates. The fat load was approximately 26 g. Blood samples were drawn before and 2 hours after the fat load. Prior studies reported that postprandial TG reached its peak at 3 to 4 hours after the meal. However, because its elevation was obvioius by the 2 hour mark in those studies,^12,17 we sampled postprandial blood at 2 hours.

Laboratory Examination

Blood samples were collected upon randomization and after 8 weeks of drug treatment. Patients were instructed to fast and avoid alcohol consumption and cigarette smoking for at least 12 hours prior to sampling. Samples were analyzed within 4 hours of collection. All analyses were performed by a local laboratory, certified by the Korean Society of Laboratory Medicine. Lipid levels were measured in fasting plasma using an auto-analyzer. Biochemical tests for the evaluation of alanine aminotransferase (ALT) and creatine kinase (CK) levels were conducted using standard laboratory techniques. Tolerability assessments were based on reported adverse reactions, physical examinations, and clinical laboratory evaluations such as liver enzyme elevation >3 × ULN or CK elevation >10 × ULN. The causal relationship of adverse reactions to test drugs was assessed by the investigators.

Statistical Analysis

The primary endpoints were the percentage changes in levels of fasting and postprandial TG from baseline to week 8 of drug treatment. Secondary end points included the percentage changes in other lipid and apoprotein parameters (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], LDL-C, and apo B/A1) during the same period. Changes in parameters within the same group from baseline to week 8 of drug treatment were also included in the secondary endpoints. A minimum of 27 patients per treatment group was planned, assuming a power of 0.80 to demonstrate inequality between the groups. A 20% ± 25% difference in postprandial TG between the 2 groups was predefined as significant. To compensate for 20% dropout, at least 34 participants were to be recruited for each group. Efficacy analyses were conducted on the population that completed the study. Group differences in categorical variables were assessed using the chi-square test, and continuous variables were evaluated using Student’s t test. The paired t test was used to assess the differences in parameters before and after treatment within each group. Differences in percentage changes of parameters between the 2 groups were considered significant if the P value was <.05 (2-sided). All data were analyzed using SPSS 17.0 version (SPSS Inc, Chicago, Illinois).

Results

Baseline Characteristics

Sixty of the randomized patients completed the study, while 18 dropped out; 11 because of withdrawal of consent and 7 because of protocol violation. The clinical characteristics of the participants who completed the study are listed in Table 1. The mean age was 62 years and 57% were females. History of coronary artery disease was marginally more frequent in the atorvastatin group (P = .06). Otherwise, each group had similar clinical characteristics (Table 1). The baseline levels for the lipid profile were well-matched in the 2 groups (Table 2).

Table 1.

Baseline Characteristics of the Patients Who Completed the Study (n = 60)^a

	Total (n = 60)	Atorvastatin (n = 28)	Atorvastatin/Ezetimibe (n = 32)	P
Age, years	62 ± 11	63 ± 8	62 ± 12	.82
Female gender, no (%)	34 (57)	18 (64)	16 (50)	.27
Body mass index, kg/m²	25.8 ± 2.4	25.9 ± 2.2	25.7 ± 2.6	.77
Medical history, no (%)
Diabetes mellitus	5 (8)	2 (7)	3 (9)	.76
Hypertension	27 (45)	14 (50)	13 (41)	.47
Current smoker	4 (7)	2 (8)	2 (6)	.89
Coronary artery disease	6 (10)	5 (18)	1 (3)	.06

^aData are mean ± SD.

Table 2.

Lipid Parameters Before and After Drug Treatment (n = 60)^a

		Atorvastatin (n = 28)	Atorvastatin/Ezetimibe (n = 32)	P ^b
TC, mg/dL	Before	249 ± 17	241 ± 16	.08
	After	187 ± 47	161 ± 30	.01
	Absolute change	−62 ± 39	−81 ± 32	.04
	P ^c	<.001	<.001
Fasting TG, mg/dL	Before	199 ± 43	192 ± 25	.44
	After	162 ± 58	132 ± 40	.02
	Absolute change	−37 ± 51	−60 ± 49	.08
	P ^c	0.001	<0.001
Postprandial TG, mg/dL	Before	220 ± 88	222 ± 49	.91
	After	177 ± 79	139 ± 48	.02
	Absolute change	−43 ± 106	−83 ± 69	.08
	P ^c	0.04	<0.001
HDL-C, mg/dL	Before	47.6 ± 7.7	45.7 ± 8.4	.35
	After	49.0 ± 7.5	49.3 ± 9.5	.91
	Absolute change	1.4 ± 4.9	3.6 ± 6.7	.15
	P ^c	0.15	0.01
LDL-C, mg/dL	Before	161 ± 16	159 ± 12	.60
	After	105 ± 38	90 ± 26	.08
	Absolute change	−56 ± 32	−69 ± 28	.10
	P ^c	<0.001	<0.001
Apo B, mg/dL	Before	121 ± 17	116 ±12	.18
	After	88 ± 30	72 ± 16	.01
	Absolute change	−33 ± 22	−44 ± 20	.047
	P ^c	<0.001	<0.001
Apo A1, mg/dL	Before	145 ± 19	139 ± 25	.28
	After	153 ± 14	150 ± 26	.58
	Absolute change	8 ± 21	11 ± 21	.55
	P ^c	0.046	0.004
Apo B/A1	Before	0.85 ± 0.18	0.86 ± 0.20	.80
	After	0.59 ± 0.23	0.48 ± 0.10	.03
	Absolute change	−0.26 ± 0.18	−0.38 ± 0.18	.02
	P ^c	<.001	<.001

Abbreviations: Apo: apolipoprotein; TG, triglyceride; corrected postprandial TG, postprandial TG-fasting TG; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol.

^aData are mean ± SD.

^b P values refer to comparisons between groups.

^c P values refer to comparison in a group before and after treatment.

Changes in Lipid Parameters

Fasting and postprandial TG levels were significantly lowered in both groups. TC and LDL-C levels were significantly reduced by both treatment regimens. High-density lipoprotein-cholesterol did not change significantly in the atorvastatin group but was elevated in the combination group (Table 2). The percentage reduction of fasting TG was greater in the combination group, although not significantly (−18% ± 25% and −30% ± 25% in the atorvastatin and combination groups, respectively, P = .07), whereas the percentage reduction of postprandial TG was significantly greater in the combination group (−13% ± 42% and −34% ± 30%, respectively, P = .03). To calculate net postprandial TG elevation, we subtracted baseline TG from postprandial TG. It was reduced significantly only within the combination group during the period (30 ± 43 mg/dL and 6 ± 25 mg/dL before and after drug treatment, respectively, P = .01), while the atorvastatin group did not show change in net postprandial TG elevation (21 ± 69 mg/dL and 15 ± 43 mg/dL, respectively, P = NS). However, this value was not different between the groups before and after drug treatment.

The percentage reduction in TC was higher in the combination group than in the atorvastatin group (P = .03), but the percentage changes in LDL-C and HDL-C were not significantly different between the 2 groups (Figure 1). Apo B was significantly reduced in both groups, and both groups experienced significant increases in apo A1. Apo B/A1 was reduced in both groups (Table 2). The percentage reduction in apo B was higher in the combination group than in the atorvastatin group (P = .04), but there was no difference in the increase in apo A1 between the 2 groups. The percentage reduction in apo B/A1 was significantly larger in the combination group (−32% ± 19% in the atorvastatin group and −42% ± 13% in the combination group, P = .02; Figure 1).

Figure 1.

Bar graphs showing the effects of atorvastatin versus atorvastatin/ezetimibe on plasma levels of total cholesterol (TC), fasting triglyceride (TG), postprandial TG, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) (A), apolipoprotein (apo) B, apo A1, and apo B/A1 (B).

Changes in ALT and CK

Both regimens were well tolerated, and there were no instances of elevation of liver enzymes >3 × ULN or CK >10 × ULN. The mean levels of ALT and CK did not change significantly in either group throughout the drug treatment. The percentage changes in ALT and CK were not different between the 2 groups (Table 3).

Table 3.

Alanine Aminotransferase (ALT) and Creatine Kinase (CK) Before and After Drug Treatment (n = 60)^a

		Atorvastatin (n = 28)	Atorvastatin/Ezetimibe (n = 32)	P ^b
ALT, IU/mL	Before	28 ± 14	32 ± 16	.26
	After	33 ± 31	34 ± 15	.95
	P ^c	0.29	0.53
CK, IU/mL	Before	84 ± 54	89 ± 38	.68
	After	80 ± 29	93 ± 45	.21
	P ^c	0.65	0.59

Abbreviations: ALT, alanine transaminase; CK, creatine kinase.

^aData are mean ± SD.

^b P values refer to comparisons between groups.

^c P values refer to comparison in a group before and after treatment.

Discussion

In this study, an 8-week treatment with atorvastatin/ezetimibe 5 mg/5 mg combination reduced postprandial TG levels more than atorvastatin 20 mg after comparable LDL-C lowering. The combination regimen had a tendency to decrease fasting TG levels more than atorvastatin monotherapy, and the percentage reduction in apoB/A1 was greater in patients receiving the combination treatment. The present study demonstrated a beneficial effect of a low-dose statin/ezetimibe combination on postprandial TG control.

To date, studies that have evaluated the effects of statin monotherapy and statin/ezetimibe combination have been limited. Furthermore, evidence for their differential effects on TG levels is not sufficient. Olijhoek et al compared the effects of simvastatin 80 mg and those of simvastatin/ezetimibe 10 mg/10 mg on fasting and post fat load TG levels. After a 6-week treatment, post fat load TG levels were higher after combination therapy.¹³ In another study by the same group, the 2 regimens did not show statistically different effects on fasting or postprandial TG levels.¹⁴ In the present study, a greater reduction in postprandial TG was observed using a low-dose atorvastatin/ezetimibe combination.

Although the discordance between the present results and those of prior studies is not completely understood, it can be partly explained by the number and characteristics of study participants. The present study used a larger number of participants, and this might have caused more of a difference between the 2 regimens. The baseline fasting TG levels were less than 150 mg/dL in prior reports, and greater than 190 mg/dL in the present study. This discrepancy in baseline TG levels may have caused the different effects on TG to be more obvious in the current study’s population. However, we cannot rule out that atorvastatin 20 mg was a dose lower than an equivalent LDL-C-lowering dose of atorvastatin/ezetimibe 5 mg/5 mg, and so this could have lessened the TG-lowering effect of atorvastatin as a single agent. The differing extent of reduction in postprandial TG (−13% and −34%, in the atorvastatin and combination groups, respectively) between the 2 regimens may be partly due to their distinct mechanisms of action. Statins lower plasma TG levels via inhibition of very low density lipoprotein (VLDL) synthesis. Very low density lipoprotein and LDL compete for the same removal mechanism, and reduction of LDL may, therefore, increase VLDL removal.¹⁸ Postprandial lipoprotein accumulation may be reduced due to competition for lipolysis between exogenous and endogenous TG-rich lipoproteins. However, it has been reported that atorvastatin does not affect the initial rise in chylomicron levels after a meal.¹⁹ Additionally, statins are not known to directly regulate chylomicron remnant receptors.¹¹ In contrast, ezetimibe decreases postprandial elevations in cholesterol and TG levels and is related to the suppression of postprandial chylomicron particle production. This was recently illustrated by Masuda et al, who investigated the effects of ezetimibe in patients with type IIb hyperlipidemia.¹² Sandoval et al, using a mouse model, demonstrated that ezetimibe reduces postprandial TG by blocking both cholesterol absorption and intracellular fatty acid metabolism in enterocytes.²⁰

In the present study, the HDL-C changes did not differ significantly between the 2 groups. However, after drug treatment, HDL-C was elevated only in the combination group (P = .01, comparison between baseline and follow-up values). Ezetimibe, when combined with a statin, has been demonstrated to produce an additive effect in increasing HDL-C level.²¹ In addition, atorvastatin is reported to have a smaller HDL-C increasing effect at higher doses.¹ The results of these 2 previous studies may help to explain the significant increase in HDL-C only by low-dose atorvastatin/ezetimibe in the current study data.

The apo B/A1 ratio reduction was greater in the combination group in the present study. When combined with ongoing statin therapy, ezetimibe was shown to decrease the apo B/A1 ratio by 17% to 18%.²² Comparison data of statin monotherapy and low-dose statin/ezetimibe for apo B/A1 change has been extremely limited. Recently, we reported that combination therapy was more effective at lowering apo B/A1 in hypercholesterolemic patients.²³ Notably, the current study demonstrated a similar difference in a population with combined hyperlipidemia. In our results, because apo B decreased more in the combination group and the apo A1 change was similar between the 2 groups, the difference in apo B/A1 change may be mainly associated with that of apo B reduction. Ezetimibe may decrease apo B levels via negative hepatic cholesterol balance by blocking cholesterol reabsorption.²⁴ In addition, the combination of statin and ezetimibe is shown to decrease VLDL and LDL apo B levels through reduced VLDL production and enhanced LDL clearance.²⁵ Although the mechanism of the combination therapy’s stronger effect on apo B levels is not certain, the distinct action mechanisms mentioned above may partly explain our results.

Several strengths are evident in the present study. Our study is one of the most systematic comparisons of the effects of the 2 regimens, statin and low-dose statin/ezetimibe, on postprandial TG. Particularly, the participants in the present study consisted of patients with combined hyperlipidemia in whom control of postprandial lipemia may be important. The results in this specific population may have a greater clinical implication than in those for patients without this condition. The current study has a few limitations. First, although a possible explanation for the results has been suggested, the underlying mechanism of the findings cannot be completely clarified by the present data. However, the elucidation of the exact mechanism of the difference is beyond the purpose of this study and will hopefully be evaluated by a further investigation. Second, the postprandial laboratory values were assessed at a single time point. Analysis of values serially obtained after a meal could have added more information with regard to the drug effects. However, measurement of postprandial or nonfasting values at a specific postprandial time is reported to be a more convenient indicator of cardiovascular risk.²⁶ The clinical relevance of single or multiple time values needs to be further clarified. Third, although LDL-C lowering was not significantly different between the 2 groups, the small number of study participants may have influenced the data. It it is also worth noting that differences in the data could also be due to different doses and statins used.

In conclusion, the atorvastatin/ezetimibe 5 mg/5 mg combination was more effective at reducing postprandial TG levels and apo B/A1 than was atorvastatin 20 mg after comparable LDL-C lowering. The combination regimen had a tendency to decrease fasting TG levels more than atorvastatin monotherapy. The present study demonstrated the potential beneficial effects of low-dose statin/ezetimibe combination on postprandial TG control. However, because the total clinical impact of statin regimens can be influenced by multiple biological effects other than lipid-modification, interpretation and clinical application of the current study results should be done with caution.

Footnotes

The author(s) declared no conflicts of interest with respect to the authorship and/or publication of this article.

The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: A grant from the Ministry of Health and Welfare, Republic of Korea (A000385), a grant of the Seoul R&BD Program, Republic of Korea (10526), a grant of the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A085136) and a grant from Cardiovascular Research Center, Seoul, Republic of Korea.

References

Jones

Davidson

Stein

. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol. 2003;92(2):152–160.

Deedwania

Hunninghake

Bays

Jones

Cain

Blasetto

JW.

STELLAR Study Group. Effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on atherogenic dyslipidemia in patients with characteristics of the metabolic syndrome. Am J Cardiol. 2005;95(3):360–366.

Tremblay

Lamarche

Cohn

Hogue

Couture

Effect of ezetimibe on the in vivo kinetics of apob-48 and apob-100 in men with primary hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2006;26(5):1101–1106.

Gagne

Gaudet

Bruckert

Efficacy and safety of ezetimibe coadministratered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105(21):2469–2475.

Kastelein

Akdim

Stroes

. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358(14):1431–1443.

Rossebo

Pedersen

Boman

. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343–1356.

Taylor

Villines

Stanek

. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361(22):2113–2122.

Nordestgaard

Benn

Schnohr

Tybjarg-Hansen

Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298(3):299–308.

Eberly

Stamler

Neaton

JD.

Relation of triglyceride levels, fasting and nonfasting, to fatal and nonfatal coronary heart disease. Arch Intern Med. 2003;163(9):1077–1083.

10.

van Wijk

Halkes

de Jaegere

Plokker

Erkelens

Cabezas

MC.

Normalization of daytime triglyceridemia by simvastatin in fasting normotriglyceridemic patients with premature coronary sclerosis. Atherosclerosis. 2003;171(1):109–116.

11.

Karpe

Postprandial lipemia-effect of lipid-lowering drugs. Atherosclerosis Suppl. 2002;3(1):41–46.

12.

Masuda

Nakagawa-Toyama

Nakatani

. Ezetimibe improves postprandial hyperlipidemia in patients with type IIb hyperlipidemia. Eur J Clin Invest. 2009;39(8):689–698.

13.

Olijhoek

Hajer

van der Graaf

Dallinga-Thie

Visseren

FL.

The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial. J Cardiovasc Pharmacol. 2008;52(2):145–150.

14.

Hajer

Dallinga-Thie

van Vark-van der Zee

Visseren

FL.

The effect of statin alone or in combination with ezetimibe on postprandial lipoprotein composition in obese metabolic syndrome patients. Atherosclerosis. 2009;202(1):216–224.

15.

Piorkowski

Fischer

Stellbaum

. Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets?. J Am Coll Cardiol. 2007;49(10):1035–1042.

16.

Liu

Lin

Chen

Liao

JK.

Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on Rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation. 2009;119(1):131–138.

17.

Cabezas

Verseyden

Meijssen

Jansen

Erkelens

DW.

Effects of atorvastatin on the clearance of triglyceride-rich lipoproteins in familial combined hyperlipidemia. J Clin Endocrinol Metab. 2004;89(12):5972–5980.

18.

Parhofer

Laubach

Barrett

PH.

Effect of atorvastatin on postpranial lipoprotein metabolism in hypertriglyceridemic patients. J Lipid Res. 2003;44(6):1192–1198.

19.

Guerin

Egger

le Goff

Soudant

Dupuis

Chapman

MJ.

Atorvastatin reduces postprandial accumulation and cholesteryl ester transfer protein-mediated remodeling of triglyceride-rich lipoprotein subspecies in type IIb hyperlipidemia. J Clin Endocrinol. Metab. 2002;87(11):4991–5000.

20.

Sandoval

Nakagawa-Toyama

Masuda

. Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia. J Atheroscler Thromb. 2010;17(9):914–924.

21.

Feldman

Koren

Insull

Jr . Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. Am J Cardiol. 2004;93(12):1481–1486.

22.

Denke

Pearson

McBride

Gazzara

Brady

Tershakovec

AM.

Ezetimibe added to ongoing statin therapy improves LDL-C goal attainment and lipid profile in patients with diabetes or metabolic syndrome. Diab Vasc Dis Res. 2006;3(2):93–102.

23.

Her

Kim

Kang

. Effects of atorvastatin 20 mg, rosuvastatin 10 mg, and atorvastatin/ezetimibe 5 mg/5 mg on lipoproteins and glucose metabolism. J Cardiovasc Pharm Ther. 2010;15(2):167–174.

24.

Basso

Freeman

. Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited. J Lipid Res. 2007;48(1):114–126.

25.

Telford

Sutherland

Edwards

Andrews

Barrett

Huff

MW.

The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin. J Lipid Res. 2007;48(3):699–708.

26.

Warnick

Nakajima

Fasting versus nonfasting triglycerides: implications for laboratory measurements. Clin Chem. 2008;54(1):14–16.

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