Ezetimibe Completely Replaced LDL-Apheresis for the Treatment of Familial Hypercholesterolemia and Coronary Artery Disease after CABG—A Case Report

doi:10.4236/jbise.2013.62A028

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J. Biomedical Science and Engineering, 2013, 6, 232-235 JBiSE

http://dx.doi.org/10.4236/jbise.2013.62A028 Published Online February 2013 (http://www.scirp.org/journal/jbise/)

Ezetimibe completely replaced LDL-apheresis for the

treatment of familial hypercholesterolemia and coronary

artery disease after CABG—A case report

Ikuo Yokoyama1,2,3

1Department of Cardiovascular Medicine, Clinical Research Center, Sanno Medical Center Hospital, International University of

Health and Welfare, Tokyo, Japan

2Department of Cardiovascular Medicine, Clinical Research Center, Sanno Hospital, International University of Health and Welfare,

Tokyo, Japa n

3Department of Cardiovascular Medicine, Department of Metabolic Diseases, Graduate School of Medicine University of Tokyo,

Tokyo, Japa n

Email: [email protected]

Received 7 November 2012; revised 8 December 2012; accepted 15 December 2012

ABSTRACT

Intensive treatment of hyperlipidemia is an important

factor in the prevention of cardiovascular disease.

Among several therapies, statins are well recognized

as playing a central role, although low density lipopro-

tein bound cholesterol-apheresis can be used to treat

very severe cases of familial hypercholesterolemia.

However, statins are not always effective on their own

and, recently, ezetimibe has emerged as a unique anti-

hypercholesterolemic drug that acts as a cholesterol

transporter inhibitor; its role is only partially under-

stood. I experienced rare case that appeared to benefit

from ezetimibe therapy, and report them as they help

increase our knowledge of this novel drug.

Keywords: Ezetimibe; Familial Hypercholesterolemia;

Statins; LDL-Apheresis; Coronary Artery Disease

1. INTRODUCTION

The effectiveness of anti-hyperlidemia therapy for pre-

venting cardiovascular events [1-5] and inducing the

regression of coronary artery stenosis [6] has been dem-

onstrated. Multicenter trials have indicated that hy-

droxymethylglutaryl co enzyme A reductase inhibitors, or

statins, aid in preventing coronary artery disease (CAD)

[2-5]. Furthermore, statin has been reported to be more

effective for reducing the incidence of ischemic events

than percutaneous transluminal coronary revascularisa-

tion therapy [7]. However, and despite the fact that stat-

ins are currently the mainstay of dyslipidemia manage-

ment, their efficacy in preventing a cardiovascular event

has limitations. This is because statin s may exert adverse

effects by restoring cholesterol levels via an enhance-

ment of the reuptake of cholesterol and/or altered cho-

lesterol derived from small intestines. Recently, ezeti-

mibe has emerged as a new class of lipid-lowering drug,

which acts via the inhibition o f Niemann-Pick C1 Like 1

(NPC1L1), a protein that is localized in jejunal entero-

cytes [8]. Combination therapy of ezetimibe and statins

has been shown to b e highly effective in the treatment of

hypercholesterolemia [9]. However, to date it has not

been established whether ezetimibe combined with statin

therapy has a much stronger effect than that of low den-

sity lipoprotein bound cholesterol (LDL)-apheresis,

which is recognized as the most effective therapy for

hyperlipidemia [10,11]. Recently, I experienced a rare

case in which ezetimibe appeared to have an effective

role, in place of LDL-apheresis, in a patient with familial

hypercholesterolemia (FH) and CAD who had undergone

a coronary artery bypass graft (CABG). I report the case

here.

2. CASE

This case concerned a 60-year-old male patient who was

admitted to the University of Tokyo Hospital from his

local clinic to treat FH. As the patient had a family his-

tory of severe hypercholesterolemia (3 of 5 brothers had

hypercholesterolemia) and CAD (one brother had CAD),

he was tested for the existence of CAD using rest to

dipyridamole stress myocardial perfusion positron emis-

sion tomography (PET) (Headtome IV Shimadzu Corp &

Ltd., Kyoto, Japan) and 13N-ammonia. The PET study

revealed that this patient was at high risk for CAD, and

because a subsequent coronary angiography showed the

presence of 3-vessel disease, he underwent CABG. After

CABG, the patient was treated with pravastatin (20 mg)

for the secondary prevention of CAD. However, the

pravastatin failed to treat his hypercholesterolemia ap-

OPEN ACCESS

I. Yokoyama / J. Biomedical Science and Engineering 6 (2013) 232-235 233

propriately, and we therefore decided to treat it using

LDL-apheresis therapy. Before the initiation of LDL-

apheresis, total cholesterol (TC) was 351 mg/dl, high

density lipoprotein bound cholesterol (HDL) was 45

mg/dl, calculated low density lipoprotein bound choles-

terol (cLDL) was 274 mg/dl, and triglycerides (TG) were

113 mg/dl. After treatment with pravastatin (20 mg/day)

and eicosapentaenoic acid (EPA) 1800 mg/day, TC,

HDL and cLDL had decreased to 309 mg/dl, 40 mg/dl,

and 222 mg/dl, respectively, and TG had increased to

188 mg/dl. Just before the initiation of LDL-apheresis,

the corresponding values were: TC 284 mg/dl, HDL 35

mg/dl, cLDL 211 mg/dl and TG 194 mg/dl. Just af ter the

LDL-apheresis, TC had declined to 75 mg/dl, as had

cLDL (47.4 mg/dl), HDL (23 mg/dl), and TG (2 3 mg/dl).

However, one week after the LDL-apheresis, TC had

increased to 163 mg/dl, as had HDL (30 mg/dl), cLDL

(103 mg/dl), and TG (55 mg/dl). Ten days after the third

LDL-apheresis, TC had increased (250 mg/dl), HDL had

decreased (38 mg/dl), cLDL had increased (190.4 mg/dl),

and TG had increased (108 mg/dl). Therefore, it was

difficult to lower the cLDL cons istently below 100 mg/dl

in this patient, even when he was treated with both

LDL-apheresis and other statins such as furuvastatin (80

mg/day), atorvastatin (40 mg/day) and rosvastatin (7.5 -

15 mg/day) (Figure 1).

Because of these results, on 21 Jan 2008, we decided

to add ezetimibe (10 mg). After combination therapy

with ezetimibe, rosvastatin (15 mg/day), EPA (2700

mg/day) and LDL-apheresis, his cLDL was maintained

consistently below 100 mg/dl. In add ition, TC was main-

tained consistently below 160 mg/dl and TG below 75

mg/dl, even when blood sampling was undertaken 2-3

weeks after the LDL-apheresis. Because of these good

results, we decided to end the patient’s LDL-apheresis

therapy on 1 Sep. 2008 without changing medications.

Four weeks later, the lipid fraction parameters were: TC

126 mg/dl, cLDL 79 mg/dl, HDL 37.0 mg/dl, and TG 50

mg/dl. Furthermore, the cLDL was kept approximately

under 100 mg/dl and there were no CAD and/or cere-

brovascular even ts between 1 Sep. 2008 and 4 Oct. 2010

(TC 131 mg/dl, cLDL 79.3 mg/dl, HDL 32.0 mg/dl, and

TG 59 mg/dl), during which period the patient had been

maintained on rosvastatin (15 mg/day), ezetimibe (10

mg/day) and EPA (2700 mg/day; this dose was initiated

before the start of ezetimibe) (Figure 1). The average TC

after stopping of LDL-apheresis (139.3 ± 10.3 mg/dl)

was similar to that during LDL-apheresis plus ezetimibe

(137.3 ± 7.73 mg/dl), and significantly lower than that

before the initiation of ezetimibe (189.9 ± 32.4 mg/dl);

average cLDL after stopping of LDL-apheresis (91.7 ±

9.31 mg/dl) was similar to that during LDL-apheresis

plus ezetimibe (93.8 ± 7.37 mg/dl) and notably lower

than that before initiation of ezetimibe (133.2 ± 28.2

mg/dl); average HDL after stopping of LDL-apheresis

Figure 1. Clinical course of the case: the patient’s plasma lipid fractions before and after ezetimibe therapy.

I. Yokoyama / J. Biomedical Science and Engineering 6 (2013) 232-235

234

Table 1. Plasma lipids fractions in the case: during LDL-apheresis therapy with statins before and after ezetimibe, and after stopping

LDL-apheresis. TC: total cholesterol; HDL: high density lipoprotein bound cholesterol; cLDL: calculated low density lipoprotein

bound cholesterol; TG: triglycerides.

Treatment regimen TC (mg/dl) HDL (mg/dl) TG (mg/dl) cLDL (mg/dl)

During LDL-apheresis plus statins (before initiation of ezetimibe) 189.9 ± 32.4 37.9 ± 6.02 93.8 ± 30.4 133.2 ± 28.2

During LDL-apheresis plus ezetimibe and rosvastatin 137.3 ± 7.73 33.9 ± 2.84 48.6 ± 11.3 93.8 ± 7.37

After stopping LDL-apheresis. Rosvastatin and ezetimibe only 139.3 ± 10.3 34.2 ± 2.27 50.8± 8.47 91.7 ± 9.31

(34.2 ± 2.27 mg/dl) was similar to that during LDL-

apheresis plus ezetimibe (33.9 ± 2.84 mg/dl), and tended

to be lower than that before initiation of ezetimibe treat-

ment (37.9 ± 6.02 mg/dl); average TG after stopping of

LDL-apheresis (50.8 ± 8.47 mg/dl) was similar to that

during LDL-apheresis plus ezetimibe (48.6 ± 11.3 mg/dl)

and notably lower than that before initiation of ezetimibe

(93.8 ± 30.4 mg/dl) (Table 1). During all of the 13-year

follow-up period, creatine phosphokinase (CK) was con-

tinuously almost within normal limits under all types of

therapy except for one mild case (CK less than 260

mg/dl). Liver enzymes such as ALT and AST were

within normal range dur ing ezetimibe therapy and almost

within normal limits during all of the follow-up period,

except for the period during which the patient was

treated with 40 mg of atorvastatin.

3. DISCUSSION

In this case, levels of TC, cLDL, and TG returned very

quickly to those recorded at baseline one week after

LDL-apheresis. Moreover, replacing LDL-apheresis with

ezetimibe notably decreased TC and cLDL to the levels

that are required for the secondary prevention of CAD

after CABG; this was not achieved with LDL-apheresis

and statins. In addition, the level of TG was also notably

decreased by approximately 54% compared with that

seen before the initiation of ezetimibe therapy. Therefore,

it appears that, in addition to reducing the level of the

cholesterol compounds absorbed from the small intes-

tines, ezetimibe also has an effect in reducing TG via

unknown but important mechanisms in small intestines.

At this stage, we can only speculate on the mecha-

nisms involved in the outcome of this case in which

ezetimibe completely replaced LDL-apheresis. Firstly,

our results could be explained by the over expression of

NPC1L1 messenger RNA, due to the very high dose of

rosvastatin used and aggressive affect of LDL-apheresis

that decreased LDL level acutely, leading to up regula-

tion of ATP-binding cassette transporters G5 and G8

(ABCG5 and ABCG8), which would in turn increase

cholesterol extraction in response to inhibitory effect of

ezetimibe to NPC1L1; a negative correlation has been

found between NPC1L1 and ABCG5 and ABCG8 [12].

This case provides strong evidence that replacing

LDL-apheresis and statin combination therapy with eze-

timibe and statin combination therapy would achieve

better results in the treatment of hypercholesterolemia.

We would therefore like to propose that, in patients with

severe hyperlipidemia, LDL-apheresis should be re-

placed by ezetimibe.

Finally, the results obtained in this study might give

great hope and encouragement to patients with FH or

severe hypercholesterolemia or severe mixed combined

hyperlipidemia who are currently treated with LDL-

apheresis.

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