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: yokochan-tky@umin.ac.jp
Received 7 November 2012; revised 8 December 2012; accepted 15 December 2012
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
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
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-
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.
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I. Yokoyama / J. Biomedical Science and Engineering 6 (2013) 232-235
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.
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-
[1] De Lorgeril, M., Renaud, S., Mamelle, N., et al. (1994)
Mediterranean alpha-linolenic acid-rich diet in secondary
prevention of coronary heart disease. Lancet, 343, 1454-
1459. doi:10.1016/S0140-6736(94)92580-1
[2] Scandinavian Survival Study Group (1994) Randomised
trial of cholesterol lowering in 4444 patients with coro-
nary heart disease. Lancet, 344, 1383-1389.
[3] Shepherd, J., Cobbe, S.M., Ford, I., et al. (1995) Preven-
tion of coronary heart disease with pravastatin in men
with hypercholesterolemia. West of Scotland Coronary
Prevention Study Group. New England Journal of Medi-
cine, 333, 1301-1307.
[4] The Long-Term Intervention with Pravastatin in Ischae-
mic Disease (LIPID) Study Group (1998) Prevention of
cardiovascular events and death with pravastatin in pa-
tients with coronary heart disease and a broad range of
initial cholesterol levels. New England Journal of Medi-
cine, 339, 1349-1357.
[5] Lewis, S.J., Sacks, F.M., Mitchell, J.S., et al. (1998) Ef-
fect of pravastatin on cardiovascular events in women af-
ter myocardial infarction: The cholesterol and recurrent
events (CARE) trial. Journal of the American College of
Cardiology, 32, 140-146.
[6] Gould, K.L., Ornish, D., Kirkeeide, R., et al. (1992) Im-
proved stenosis geometry by quantitative coronary arte-
riography after vigorous risk factor modification. Ameri-
can Journal of Cardiology, 69, 845-853.
[7] Pitt, B., Waters, D., Brown, W.V., et al. (1999) Aggres-
Copyright © 2013 SciRes. OPEN ACCESS
I. Yokoyama / J. Biomedical Science and Engineering 6 (2013) 232-235 235
sive lipid-lowering therapy compared with angioplasty in
stable coronary artery disease. Atorvastatin versus revas-
cularization treatment investigators. New England Jour-
nal of Medicine, 341, 70-76.
[8] Ge, L., Wang, J., Qi, W., et al. (2008) The cholesterol
absorption inhibitor ezetimibe acts by blocking the sterol-
induced internalization of NPC1L1. Cell Metabolism, 7,
508-519. doi:10.1016/j.cmet.2008.04.001
[9] Stein, E., Stender, S., Mata, P., et al. (2004) Achieving
lipoprotein goals in patients at high risk with severe hy-
percholesterolemia: Efficacy and safety of ezetimibe co-
administered with atorvastatin. American Heart Journal,
148, 447-455. doi:10.1016/j.ahj.2004.03.052
[10] Gordon, B.R., Kelsey, S.F., Dau, P.C., et al. (1998)
Long-term effects of low-density lipoprotein apheresis
using an automated dextran sulfate cellulose adsorption
system. Liposorber Study Group. American Journal of
Cardiology, 81, 407-411.
[11] Thompson, G.R., Barbir, M., Davies, D., et al. (2010)
Efficacy criteria and cholesterol targets for LDL aphere-
sis. Atherosclerosis, 208, 317-321.
[12] Lally, S., Tan, C.Y., Owens, D. and Tomkin, G.H. (2006)
Messenger RNA levels of genes involved in dysregula-
tion of postprandial lipoproteins in type 2 diabetes: The
role of Niemann-Pick C1-like 1, ATP-binding cassette,
transporters G5 and G8, and of microsomal triglyceride
transfer protein. Diabetologia, 49, 1008-1016.
Copyright © 2013 SciRes. OPEN ACCESS