Endocrine Journal 2010, 57 (4), ***-***

Note Advance Publication

doi: 10.1507/endocrj. K10E-165

Efficacy and safety of ezetimibe in patients undergoing

hemodialysis
Sachiko Hattori 1) and Yoshiyuki Hattori 2)
1)
Endocrinology and Metabolism, Tsunemicho Hospital, Ashikaga 326-0022, Japan
2)
Endocrinology and Metabolism, Dokkyo University School of Medicine, Tochigi 321-0293, Japan

Abstract. Patients with dyslipidemia and advanced renal failure are at markedly increased risk of cardiovascular morbidity
and mortality. We evaluated the efficacy and safety of ezetimibe administration to patients with endstage renal failure
(ESRF) who are undergoing hemodialysis. Ezetimibe at 10 mg/day was given to 20 patients for 12 weeks. Efficacy was
determined by monitoring lipids, and safety was determined by monitoring clinical and laboratory parameters. We also
evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis. Compared to baseline
values, LDL-cholesterol (LDL-C) was reduced by 24.9% (p<0.005) after 12 weeks of ezetimibe administration. Treatment
with ezetimibe did not change HDL-cholesterol, triglyceride and HbA1c values but caused a significant reduction in
remnant like particles-cholesterol (RLP-C, p<0.05) and high-sensitive C-reactive protein (hsCRP, p<0.05). Ezetimibe
therapy decreased cholesterol absorption markers (campesterol and sitosterol) and increased a marker of cholesterol
synthesis (lathosterol). A highly significant correlation was observed between alterations in LDL-C and campesterol levels
in response to ezetimibe therapy. No patients reported musculoskeletal symptoms. None of the patients experienced
elevations in their creatine kinase or liver transaminase levels. Ezetimibe not only reduced serum LDL-C, but also RLP-C
and hsCRP, in ESRF patients. Inhibition of cholesterol absorption by ezetimibe is an important therapeutic option in these
patients due to its efficacy and safety.

Key words: Ezetimibe, Hemodialysis, Remnant, CRP

Advanced and endstage renal failure (ESRF) are
associated with a markedly increased risk of prema-
ture atherosclerosis and cardiovascular sequelae [1].
Several risk factors, including lipoprotein abnormali-
ties, have been implicated in the high cardiovascular
mortality observed in this group [2, 3].
Statins reduce the incidence of cardiovascular
events in patients with elevated cardiovascular risk.
However, the benefit of statin administration in pa-
tients undergoing hemodialysis has not been proven.
Recently, the AURORA trial was conducted in patients
undergoing hemodialysis to determine if rosuvastatin
might reduce death from cardiovascular causes, nonfa-
tal myocardial infarction, or nonfatal stroke [4]. This
study showed that rosuvastatin significantly lowered
Received Jun. 2, 2010; Accepted Aug. 23, 2010 as K10E-165
Released online in J-STAGE as advance publication Sep. 25, 2010
Correspondence to: Sachiko Hattori, Endocrinology and
Metabolism, Tsunemicho Hospital, Ashikaga, Tochigi 326-0022,
Japan. E-mail: sachikohat@hb.tp1.jp
©The Japan Endocrine Society
low density lipoprotein cholesterol (LDL-C) but did
not reduce cardiovascular events or total mortality. In
contrast, the JUPITER trial in healthy men and wom-
en (with an LDL-C less than 103 mg/dL and a hs-CRP
greater than 2.0 mg/dL) was stopped after a median
follow-up of 1.9 years because of a reduction in car-
diovascular and overall mortality in the rosuvastatin
group compared to the placebo group [5].
Statins have been associated with two important
side effects; namely, liver dysfunction (transaminitis)
[6] and myopathy/myositis [7], both of which are un-
commonly seen, except with high doses [8] or in the
setting of drug interactions, particularly with impaired
hepatic or renal function at baseline [9]. Of note, the
risk of developing a myopathy with statin therapy ap-
pears to be increased in patients with ESRF.
Ezetimibe is a selective intestinal cholesterol trans-
porter inhibitor which selectively inhibits cholesterol
absorption by inhibiting NPC1L1 protein [10, 11]. A
growing body of evidence linking cholesterol absorp-
2 Hattori et al.
tion with risk of cardiovascular events has made in-
vestigators aware of the potential role of inhibition of
cholesterol absorption in the prevention of cardiovas-
cular events [12]. The metabolism of ezetimibe is not
associated with kidney.
Based on these considerations, we examined the
clinical benefit and side effects of ezetimibe, as well as
its effect on surrogate markers of cholesterol synthesis
and absorption in patients undergoing hemodialysis.
Materials and Methods
Study protocols and laboratory examinations
We treated 20 hypercholesterolemic ESRF patients
undergoing hemodialysis with 10 mg ezetimibe for 12
weeks to determine the effects on LDL-C, high densi-
ty lipoprotein cholesterol (HDL-C), triglyceride (TG),
high-sensitive (hs) C-reactive protein (CRP), and rem-
nant like particles-cholesterol (RLP-C) levels. Two
plant sterols, campesterol and sitosterol, were also
measured as markers of cholesterol absorption, and a
cholesterol synthesis intermediate called lathosterol
was measured as a marker of cholesterol synthesis [13].
Although rare, severe rhabdomyolysis has been re-
ported in patients given lipid-lowering agents. Given
that particular attention to this possibility is required
for ESRF patients, we checked blood creatinine phos-
phokinase (CPK) levels at baseline and at 4, 8, and 12
weeks after commencement of treatment. ALT and
AST were also measured to monitor for the develop-
ment of a transaminitis. Data are presented as mean
values ± SD. Comparisons of data were performed
using the paired or unpaired Student’s t test, and corre-
lation coefficients were determined using standard lin-
ear regression methods. A value of p<0.05 was con-
sidered statistically significant. The study was carried
out in accordance with the Declaration of Helsinki
(2000) of the World Medical Association, and was
approved by the Ethics Committees of the hospital.
Written informed consent was obtained from each pa-
tient after full explanation of the purpose, nature and
risk of the procedure.
Results
Twenty patients in this study are aged 66.2 ± 8.9,
which gender is female 8/ male 12. Thirteen patients
are with endstage diabetic nephropathy and 7 pa-
tients are with renal failure due to other renal diseases.
Endocrine Journal Advance Publication
Among the 20 patients who received ezetimibe for 12
weeks, serum LDL-C levels fell from 111 ± 36 to 85 ±
27 (p<0.005). Total cholesterol levels decreased from
172 ± 45 to 145 ± 34 (p<0.005). On the other hand,
HbA1c, HDL-C, and TG levels were not significant-
ly altered by ezetimibe therapy compared with base-
line values. Ezetimibe also improved serum levels of
hsCRP from 5142 ± 4771 to 2739 ± 2234 (p<0.05) and
RLP-C from 6.2 ± 3.3 to 4.7 ± 1.6 (p<0.05) (Table 1).
Ezetimibe significantly reduced levels of the cho-
lesterol absorption markers by 60 % for campesterol
(p<0.005) and 45 % for sitosterol (p<0.005). On the
other hand, serum levels of lathosterol (a marker of
cholesterol synthesis) increased by 29% (p<0.005) af-
ter ezetimibe treatment (Fig. 1).
As shown in Fig. 2, changes in campesterol levels
correlated with changes in LDL-C (r=0.764, p<0.0001).
However, a significant correlation was not observed be-
tween changes in RLP-C and campesterol, or between
changes in hsCRP and campesterol (Table 2).
No clinical adverse events potentially related to
ezetimibe therapy occurred during the study period.
CPK levels remained within normal limits in all pa-
tients throughout the study period. No abnormality in
ALT and AST levels were observed.
Discussion
This study demonstrates a significant reduction
in LDL-C with ezetimibe without adverse effects in
ESRF patients undergoing hemodialysis. Ezetimibe
not only reduced serum LDL-C, but also RLP-C and
hsCRP, in ESRF patients. No patients reported mus-
culoskeletal symptoms. None of the patients expe-
rienced elevations in their creatine kinase or liver
transaminase levels. Thus, ezetimibe could be an im-
portant therapeutic option in these patients due to its
efficacy and safety.
Although a tendency toward increased HDL-C and
reduced TG levels were observed, these changes were
not statistically significant, probably due to the lim-
ited number of patients examined. However, signifi-
cant reductions in hsCRP and RLP-C were observed
in ESRF patients treated with ezetimibe in the present
study. As expected, ezetimibe caused a marked reduc-
tion in the cholesterol absorption markers campesterol
and sitosterol, a finding which correlated with altera-
tions in LDL-C. This suggests that ezetimibe may re-
duce LDL-C mainly by blocking the NPC1L1 chan-
 Efficacy and safety of ezetimibe 3

Table 1 Effects of ezetimibe on lipid parameters, HbA1c, and hs-CRP

Baseline Week12 p value
Total cholesterol (mg/dL) 172 ± 45 145 ± 34 p<0.005 (p=0.00195)
LDL cholesterol (mg/dL) 111 ± 36 85 ± 27 p<0.005 (p=0.00104)
HDL cholesterol (mg/dL) 41 ± 13 43 ± 12 NS (p=0.219)
Triglyceride (mg/dL) 109 ± 59 93 ± 26 NS (p=0.111)
HbA1c (%) 5.6 ± 1.1 5.4 ± 1.0 NS (p=0.088)
hs CRP (ng/mL) 5142 ± 4771 2739 ± 2234 p<0.05 (p=0.045)
RLP choesterol (mg/dL) 6.2 ± 3.3 4.7 ± 1.6 p<0.05 (p=0.011)
NS: not significant.

Fig. 1 Sterol levels at base and after treatment with ezetimibe Fig. 2 Changes in campesterol levels (dCampst) correlated with
for 12 weeks. **P<0.005 compared with basal levels. changes in LDL-C (dLDL-C).

Table 2 Linear regression analyses of the relation between changes of

campesterol and various parameters.
Variables r p values
LDL-C 0.653 0.0013
RLP-C 0.142 0.5565
hsCRP -0.253 0.2864

nel of intestinal cholesterol absorption. On the other
hand, the observed reductions in RLP-C and hsCRP
did not correlate with changes in campesterol, sug-
gesting that improvement of RLP-C and hsCRP lev-
els by ezetimibe may be independent of its inhibition
of cholesterol absorption. The mechanism by which
ezetimibe exerts pleiotropic effects, including im-
provements in RLP-C and hsCRP, remains to be elu-
cidated. It has been reported that ezetimibe is more
effective in diabetic populations. Thus, we com-
pared the reduction of LDL-C and campesterol after
ezetimebe between diabetic (n=13) and non-diabetic
(n=7) patients with ESRD undergoing hemodialysis.
Efficacy of ezetimibe was not statistically different be-
tween these two groups (data not shown).
Statins have been associated with two important
side effects; namely, transaminitis [6] and myopathy/
myositis [7], both of which are uncommonly seen, ex-
cept with high doses [8] or in the setting of drug inter-
actions, particularly in setting of pre-existing hepatic or
renal impairment [9]. No clinically significant adverse
effects were observed with ezetimibe in the present

Endocrine Journal Advance Publication

4 Hattori et al.
study, and elevations in CPK, ALT and AST were not
observed. Levels of lathosterol, a marker of choles-
terol synthesis, appear to be reduced in ESRF patients.
Indeed, the lathosterol levels observed in the ESRF pa-
tients of the present study were significantly lower than
those observed in healthy volunteers (1.5 ± 0.97 vs. 3.7
± 1.8, p<0.0005). Thus, ezetimebe may be a more suit-
able drug for reducing LDL-C than statin therapy, par-
ticularly in patients with renal dysfunction.
In the AURORA trial, despite a 43% reduction in
LDL-C in patients undergoing hemodialysis, rosu-
vastatin did not reduce cardiovascular events or to-
tal mortality [4]. The patients receiving rosuvastatin
in this study showed a modest but significant in-
crease in HDL-C and a significant reduction in hsCRP.
Nevertheless, the observed benefits were very small
at best. Thus, studies regarding statin monotherapy
and cardiovascular risk appear to be coming to a con-
clusion. The next phase of clinical trials will likely
evaluate the benefits of other classes of drug or statin
therapy combined with another agent in patients who
experience less gain or greater risk with statin thera-
py including ESRF patients. Reduced cholesterol ab-
sorption has been associated with fewer recurrent car-
References
1. Brown JH, Hunt LP, Vites NP, Short CD, Gokal R,
Mallick NP (1994) Comparative mortality from car-
diovascular disease in patients with chronic renal fail-
ure. Nephrol Dial Transplant 9: 1136-1142.
2. Cheung AK (2009) Is lipid control necessary in hemo-
dialysis patients? Clin J Am Soc Nephrol 4 Suppl 1:
S95-101.
3. Shoji T, Nishizawa Y (2006) Plasma lipoprotein ab-
normalities in hemodialysis patients--clinical implica-
tions and therapeutic guidelines. Ther Apher Dial 10:
305-315.
4. Fellström BC, Jardine AG, Schmieder RE, Holdaas H,
Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe
SM, Grönhagen-Riska C, De Lima JJ, Lins R, Mayer G,
McMahon AW, Parving HH, Remuzzi G, Samuelsson
O, Sonkodi S, Sci D, Süleymanlar G, Tsakiris D, Tesar
V, Todorov V, Wiecek A, Wüthrich RP, Gottlow M,
Johnsson E, Zannad F; AURORA Study Group (2009)
Rosuvastatin and cardiovascular events in patients un-
dergoing hemodialysis. N Engl J Med 360: 1395-407.
5. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto
AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti
AJ, Macfadyen JG, Nordestgaard BG, Shepherd J,
Endocrine Journal Advance Publication
diovascular events and with better survival in elderly
patients [12]. This might be related to ingestion of ox-
idized cholesterol, which is found in fast food and mi-
crowaved meals. Ezetimebe limits oxidized cholester-
ol absorption in addition to lowering LDL-C, RLP-C,
and hsCRP, as observed in the present study [14].
Therefore, ezetimebe might have different benefits
than statin therapy. In this regard, the Study of Heart
and Renal Protection (SHARP) study is expected to
report in 2010 on the clinical benefits of combination
treatment with simvastatin/ezetimibe versus placebo
in a large population of patients with advanced kidney
disease [15].
Limitations
This was a clinical study in a small number of pa-
tients undergoing hemodialysis. Because this was not
a comparative study with other group, it may be uncer-
tain that observed effects are really due to ezetimibe.
To evaluate the side effects of ezetimibe in renal fail-
ure patients, more number of patients and longer peri-
od of observation would be necessary.
Willerson JT, Glynn RJ; JUPITER Trial Study Group
(2009) Reduction in C-reactive protein and LDL cho-
lesterol and cardiovascular event rates after initiation of
rosuvastatin: a prospective study of the JUPITER trial.
Lancet 373: 1175-1182.
6. Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER
(2010) Statins in the treatment of dyslipidemia in the
presence of elevated liver aminotransferase levels: a
therapeutic dilemma. Mayo Clin Proc 85: 349-356.
7. Cham S, Evans MA, Denenberg JO, Golomb BA (2010)
Statin-associated muscle-related adverse effects: a case
series of 354 patients. Pharmacother 30: 541-553.
8. Grundy SM (2005) The issue of statin safety: where
do we stand? Circulation 111: 3016-3019.
9. Bakker-Arkema RG, Davidson MH, Goldstein RJ,
Davignon J, Isaacsohn JL, Weiss SR, Keilson LM,
Brown WV, Miller VT, Shurzinske LJ, Black DM
(1996) Efficacy and safety of a new HMG-CoA re-
ductase inhibitor, atorvastatin, in patients with hyper-
triglyceridemia. JAMA 275: 128-133.
10. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM,
Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M,
Wang L, Murgolo N, Graziano MP (2004) Niemann-
 Efficacy and safety of ezetimibe 5

Pick C1 Like 1 protein is critical for intestinal choles-
terol absorption. Science 303: 1201-1204.
11. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE,
Burnett DA, Braun MP, Crona JH, Davis HR Jr, Dean
DC, Detmers PA, Graziano MP, Hughes M, Macintyre
DE, Ogawa A, O’neill KA, Iyer SP, Shevell DE,
Smith MM, Tang YS, Makarewicz AM, Ujjainwalla
F, Altmann SW, Chapman KT, Thornberry NA (2005)
The target of ezetimibe is Niemann-Pick C1-Like 1
(NPC1L1). Proc Natl Acad Sci U S A 102: 8132-8137.
12. Strandberg TE, Tilvis RS, Pitkala KH, Miettinen TA
(2006) Cholesterol and glucose metabolism and recur-
rent cardiovascular events among the elderly: a pro-
spective study. J Am Coll Cardiol 48: 708-714.
13. Miettinen TA, Ahrens EH Jr, Grundy SM (1965)
Quantitative isolation and gas-liquid chromatograph-
ic analysisof total dietary and fecal neutral steriods. J
Lipid Res 6: 411-424.
14. Staprans I, Pan XM, Rapp JH, Moser AH, Feingold KR
(2006) Ezetimibe inhibits the incorporation of dietary
oxidized cholesterol into lipoproteins. J Lipid Res 47:
2575-2580.
15. Montecucco F, Quercioli A, Mach F (2009) Ezetimibe/
simvastatin. Expert Opin Drug Saf 8: 715-725.

Endocrine Journal Advance Publication