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Current Pharmaceutical Design, 2013, 19, 000-000 1
1381-6128/13 $58.00+.00 © 2013 Bentham Science Publishers
Ezetimibe Therapy for Dyslipidemia: An Update
Niki Katsiki1, Eleni Theocharidou1, Asterios Karagiannis1, Vasilios G. Athyros1 and Dimitri P. Mikhailidis2*
1Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital,
Thessaloniki, Greece; 2Department of Clinical Biochemistry (Vascular Disease Prevention Clinic) and Department of Surgery, Royal
Free Campus, University College London Medical School, University College London (UCL), London, UK
Abstract: Ezetimibe, an inhibitor of intestinal cholesterol absorption, can decrease total cholesterol (TC), low density lipoprotein choles-
terol (LDL-C), triglycerides (TGs) and apolipoprotein (apo) B levels and increase high-density lipoprotein cholesterol (HDL-C) levels.
Apart from lipid-lowering, ezetimibe may exert certain off-target actions (e.g. anti-inflammatory, anti-atherogenic and antioxidant) thus
contributing to a further decrease of cardiovascular disease (CVD) risk.
Ezetimibe trials resulted in controversial outcomes with some studies reporting atherosclerosis regression and reductions in CVD events
following ezetimibe therapy in combination with a statin while others reported negative results. The results of the ongoing IMProved Re-
duction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) which compares ezetimibe plus simvastatin with simvastatin
monotherapy with regard to CVD outcomes after acute coronary syndromes should further elucidate the effect of ezetimibe on CVD
events.
This review presents the results of up-to-date clinical trials with ezetimibe and summarizes its potential pleiotropic effects. Furthermore,
we comment on the administration of ezetimibe in treating high-risk patients [i.e. with diabetes mellitus (DM), metabolic syndrome
(MetS), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), peripheral artery disease (PAD) or carotid disease].
The use of ezetimibe either as monotherapy or as add-on therapy in daily clinical practice is also discussed.
Keywords: Ezetimibe, clinical trials, dyslipidemia, pleiotropic actions, drug combinations, cholesterol.
INTRODUCTION
Ezetimibe is a lipid-lowering drug that selectively blocks the
absorption of biliary and dietary cholesterol in the small intestine
by inhibiting the Niemann Pick C1-like1 transporter (NPC1L1), a
critical protein in cholesterol transmembrane transport in entero-
cytes [1]. Ezetimibe is minimally absorbed in the systemic circula-
tion, whereas it is involved in an enterohepatic cycle thus allowing
once daily administration [2]. The mechanisms of action of
ezetimibe are described in detail in a recent review [3].
Ezetimibe was previously shown to beneficially affect lipids by
decreasing total cholesterol (TC), low density lipoprotein choles-
terol (LDL-C), triglycerides (TGs) and apolipoprotein (apo) B lev-
els and increasing high-density lipoprotein cholesterol (HDL-C)
levels [4, 5]. It is generally regarded as a safe and well tolerated
drug since cases of myopathy and mild increases in liver tests have
been rarely reported and mainly when ezetimibe was co-
administered with a statin [6]. Although an increased risk of cancer
was observed in patients with mild-to-moderate asymptomatic aor-
tic stenosis on simvastatin plus ezetimibe compared with placebo in
the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study [7],
this was not seen in other studies [8, 9].
Ezetimibe was approved (in 2002) by the United States Food
and Drug Administration (FDA) for the treatment of both primary
(heterozygous familial and non-familial) and homozygous familial
hypercholesterolemia (FH) either as monotherapy or combined with
a statin, in conjunction with other lipid-reducing interventions such
as diet or LDL apheresis [10].
This review presents the results of up-to-date clinical trials with
ezetimibe and summarizes its potential pleiotropic effects. Further-
more, we comment on the administration of ezetimibe in treating
*Address correspondence to this author at the Department of Clinical Bio-
chemistry (Vascular Disease Prevention Clinic), Royal Free Hospital Cam-
pus, University College, London Medical School, University College, Lon-
don (UCL), Pond Street, London NW3, 2QG, United Kingdom; Tel: +44 20
7830 2258; Fax: +44 20 7830 2235; E-mail: mikhailidis@aol.com
high-risk patients such as those with diabetes mellitus (DM), meta-
bolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD),
chronic kidney disease (CKD), peripheral artery disease (PAD) or
carotid disease. The use of ezetimibe either as monotherapy or as
add-on therapy in daily clinical practice is also discussed.
RANDOMIZED CLINICAL TRIALS THAT ASSESSED THE
EFFECT OF EZETIMIBE ON CAROTID INTIMA-MEDIA
THICKNESS OR VASCULAR EVENTS
The results of randomized clinical trials with ezetimibe were
published during the last decade; however, these studies have been
the subject of substantial criticism regarding their design and inter-
pretation [3, 11-16].
In a double-blind, randomized trial, the Ezetimibe and Simvas-
tatin in Hypercholesterolemia Enhances Atherosclerosis Regression
(ENHANCE) trial [17], ezetimibe plus simvastatin (10 + 80
mg/day) did not change carotid intima-media thickness (cIMT)
compared with simvastatin monotherapy (80 mg/day) in patients
with FH (n = 720; duration = 24 months); in contrast, LDL-C, TGs
and CRP were significantly reduced in both groups with signifi-
cantly greater changes in the combination group [17].
It is important to mention that the findings of the ENHANCE
trial have been criticized as baseline cIMT measurements were low
(i.e. 0.70 mm), thus limiting any measurable decrease [3, 12, 15].
This was also the case for atorvastatin net effect in cIMT in the
Carotid Atorvastatin Study in Hyperlipidemic post-Menopausal
Women: A Randomized Evaluation (CASHMERE) trial (baseline
cIMT = 0.69 mm) that compared atorvastatin 80 mg/day vs placebo
[18]. In contrast, in the Atorvastatin versus Simvastatin on Athero-
sclerosis Progression (ASAP) trial [19], where a significant reduc-
tion in cIMT was reported following intensive treatment with
atorvastatin compared with simvastatin, baseline cIMT value was
higher, i.e. 0.925 mm. Furthermore, the vast majority of patients in
the ENHANCE study had been on statin therapy [12].
Interestingly, a beneficial effect of ezetimibe plus statin treat-
ment on cIMT has been documented in other studies mainly attrib-
2 Current Pharmaceutical Design, 2013, Vol. 19, No. 00 Katsiki et al.
uted to greater improvements in lipids compared with statin mono-
therapy [15, 20-24]. In this context, 2 meta-analyses found that the
addition of ezetimibe to a statin resulted in significantly greater
reductions in LDL-C levels, thus more patients achieved their LDL-
C targets [25, 26].
The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial
[7] was a randomized, double-blind trial comparing ezetimibe plus
simvastatin (10 + 40 mg/day) vs placebo in patients with aortic
stenosis (n = 1,873; median follow-up = 52.2 months). A significant
reduction in ischemic CVD events was observed in the ezetimibe
plus simvastatin group compared with placebo [hazard ratio (HR):
0.78; 95% confidence intervals (CI): 0.63 to 0.97; p = 0.02],
whereas no effect was found in terms of aortic valve events [7]. A
subanalysis of SEAS showed that the degree of lipid lowering by
ezetimibe plus simvastatin may predict the decrease in ischemic
cardiovascular events (ICE)in patients with mild Aortic Stenosis
but it does not affect valve-related events [27].
The Arterial Biology for the Investigation of the Treatment
Effects of Reducing Cholesterol 6-HDL and LDL Treatment
Strategies in Atherosclerosis (ARBITER 6-HALTS) trial [28], an
open-label, randomized study, compared statin (mainly atorvastatin
or simvastatin at a mean dose of 42 mg/day) combination with
ezetimibe (10 mg/day) or extended-release niacin (2,000 mg/day) in
patients with coronary heart disease (CHD) or CHD equivalent (n =
315 patients; follow-up = 14 months for 208 patients and 7 ± 3
months for another 107 after treatment). Patients were already on
statin therapy with baseline LDL-C and HDL-C levels <100 mg/dl
and <50 mg/dl (for men) or 55 mg/dl (for women), respectively.
Although niacin significantly decreased mean and maximal cIMT (-
0.0102 ± 0.0026 mm; p < 0.001 and -0.0124 ± 0.0036 mm; p =
0.001, respectively), ezetimibe did not affect cIMT. Furthermore,
cumulative exposure to ezetimibe was associated with cIMT pro-
gression, whereas increased exposure to niacin was related with
cIMT regression [28].
Interestingly, ezetimibe, in combination with a statin, reduced
the cIMT in the Vytorin on Carotid Intima-Media Thickness and
Overall Arterial Rigidity (VYCTOR) Study [23] and the Stop Athe-
rosclerosis in Native Diabetics Study (SANDS) [20]. In the ran-
domized, open-label VYCTOR study, patients with CHD (n = 90)
were initially assigned to pravastatin (40 mg/day), simvastatin (40
mg/day) or ezetimibe plus simvastatin (10 + 20 mg/day) therapy
[23]. Baseline cIMTs (combining measurements in the internal
carotid artery) were 1.33 ± 0.32, 1.30 ± 0.11 and 1.23 ± 0.28 mm,
respectively, whereas after 1 year, cIMT values were 0.93 ± 0.13,
0.90 ± 0.11 and 0.92 ± 0.01 mm [23]. Similarly, in the SANDS
study [20], aggressive LDL-C lowering by either statin monother-
apy or ezetimibe plus statins resulted in similar cIMT regressions [-
0.012 (-0.03 to 0.008) mm and -0.025 (-0.05 to 0.003) mm, respec-
tively] after 36 months of treatment in a total of 427 diabetic pa-
tients [20]; mean baseline cIMT was 0.81 mm. In contrast, cIMT
increased in the standard therapy group [0.039 (0.02 to 0.06) mm]
[20].
In the randomized, double-blind, Study of Heart and Renal
Protection (SHARP) trial [29], 9,270 patients with impaired renal
function (6,247 pre-dialysis and 3,023 on dialysis) were assigned to
ezetimibe plus simvastatin (10 + 20 mg/day) or placebo and were
followed-up for 4.9 years. Combination therapy resulted in a sig-
nificant reduction by 17% in major cardiovascular events compared
with placebo [11.3 vs 13.4%, respectively; rate ratio (RR): 0.83,
95% CI = 0.74-0.94; log-rank p = 0.0021]; significant differences
were observed in non-hemorrhagic stroke and arterial revasculariza-
tion procedures (RR: 0.75, 95% CI: 0.60-0.94; p = 0.01 and 0.79,
95% CI: 0.68-0.93; p = 0.0036, respectively) [29]. In contrast, non-
fatal myocardial infarction and CHD death did not differ between
groups.
To our knowledge, no trial has assessed the effects of ezetimibe
monotherapy on vascular events.
EZETIMIBE IN HIGH-RISK POPULATIONS
Ezetimibe and DM
Ezetimibe, combined with a statin, is both effective and safe for
treating the atherogenic dyslipidemia that characterizes DM [30-
33]; some studies even reported greater benefits in diabetics vs non-
diabetics [31]. Interestingly, male gender and elevated baseline
LDL-C levels (i.e. 140 mg/dL) were recently reported to inde-
pendently predict ezetimibe add-on therapy efficacy (with regard to
TC reduction) in type 2 DM patients [34]; a baseline TG 150
mg/dL (1.7 mmo/l) was also independently associated with TG
decreases. Others have also reported that the fall in TG levels after
adding ezetimibe is dependent on the baseline TG value [34-36].
Ezetimibe, either alone or combined with simvastatin, was also
shown to reduce small dense (sd) LDL levels in type 2 diabetics
[37, 38]. Of note, the addition of ezetimibe to atorvastatin was more
effective in decreasing TC, LDL-C and TGs levels than atorvastatin
up titration in type 2 DM patients [39, 40].
Apart from lipid-lowering, ezetimibe may improve diabetic
nephropathy by reducing urinary albumin excretion [41] and glo-
merular hypertrophy [42]. This ezetimibe-related beneficial effect
may be, at least partly, attributed to the anti-inflammatory and anti-
thrombotic actions that ezetimibe exerts in DM patients [43]. In
such patients, ezetimibe was also shown to decrease arterial stiff-
ness [44].
Ezetimibe was found to improve insulin sensitivity and secre-
tion in diabetic mice [45]. In contrast, ezetimibe co-administration
with simvastatin increased homeostasis model assessment of insulin
resistance (HOMA-IR) and fasting insulin levels in dyslipidemic
patients [46] and did not affect insulin sensitivity in prediabetic
individuals [47]. As there is a paucity of clinical data, further pro-
spective studies are needed to elucidate the impact of ezetimibe
monotherapy or add-on therapy on glycemic control in patients with
DM. There is also evidence that statins increase the risk of new
onset DM (NOD) [48]. It will therefore be relevant to establish if
any insulin sensitizing effect of ezetimibe can counteract this ad-
verse effect of statins.
Ezetimibe and MetS
In the presence of MetS, ezetimibe plus statin combination was
reported to improve the lipid profile at a greater degree than statin
monotherapy [39, 49-51]. Co-administration of ezetimibe and fi-
brate represents another therapeutic option to target mixed dyslipi-
demia in such patients [52] with the combination treatment being
more effective than either monotherapy [53]. In contrast, both statin
monotherapy and statin plus ezetimibe co-administration equally
reduced postprandial lipemia in MetS individuals [54]. Triple hy-
polipidemic treatments i.e. combination of a statin, ezetimibe and
niacin, have been also reported with a need for close monitoring
[55].
Apart from lipid-lowering, ezetimibe reduced fasting insulin
levels, HOMA-IR and visceral fat in MetS patients [56].
Ezetimibe and NAFLD
NAFLD, the hepatic manifestation of MetS, is associated with
increased vascular risk [57]; elevated activity of liver tests (LTs),
hepatic inflammation and lipid accumulation, oxidative stress and
insulin resistance may be responsible for this relationship [58].
Statins were previously reported to beneficially affect both bio-
chemical and ultrasonographic features of NAFLD [59, 60].
Apart from the intestine, NPC1L1 is highly expressed in human
liver, thus possibly contributing to cholesterol accumulation in he-
patocytes [61]. In this context, ezetimibe was shown to improve
Ezetimibe Therapy for Dyslipidemia Current Pharmaceutical Design, 2013, Vol. 19, No. 00 3
hepatic steatosis, fibrosis, inflammation and insulin sensitivity as
well as LTs in both animal and human studies [14, 62-65]. Such
effects were observed following ezetimibe monotherapy or
ezetimibe plus statin combination treatment [66, 67]. Interestingly,
non-alcoholic steatohepatitis (NASH) was recently found to alter
localization of hepatobiliary efflux transporters, thus leading to
plasma retention of the active glucuronide metabolite of ezetimibe
and raising possible safety issues [68].
Ezetimibe and CKD
Apart from lipid-lowering, statins and/or ezetimibe have been
associated with reductions in CVD morbidity in CKD patients as
reported in a recent meta-analysis [69]. Statin-induced improve-
ments in renal function have been previously observed in patients
with CKD [70, 71] or diabetic nephropathy [72], although conflict-
ing data exists [73] especially for hemodialysis patients [74]. Over-
all, statins should be prescribed for CKD patients as early as possi-
ble [75] in order to reduce CVD risk and possibly progression of
CKD [76].
Interestingly, ezetimibe either alone or co-administered with
pitavastatin reduced proteinuria in CKD patients [77, 78]. Further-
more, in the SHARP study that enrolled both dialysis-dependent
and pre-dialysis patients, ezetimibe combined with simvastatin
significantly reduced major atherosclerotic events [29]; however,
the comparison of the 2 hypolipidemic drugs vs placebo and not
with each other represents a limitation of this trial [79].
Ezetimibe and PAD
Lipid-reduction with statins has been shown shown to decrease
CVD risk and improve symptoms in patients with PAD [80, 81].
Cilostazol, a phosphodiesterase inhibitor that beneficially influ-
ences atherogenic dyslipidemia [82], may also improve walking
performance [81, 83].
In a study by West et al [84], progression of atherosclerosis in
superficial femoral artery was reported following ezetimibe mono-
therapy; this did not occur when ezetimibe was combined with a
statin. However, these findings have several limitations [81].
As clinical data are scarce, there is an urgent need for prospec-
tive, well-designed, large trials to address the issue of ezetimibe
impact on atherosclerosis of the lower extremities.
Ezetimibe and Carotid Disease
Ezetimibe was reported to reduce cIMT when co-administered
with simvastatin in high risk (VYCTOR study) [23], type 2 diabetic
patients (SANDS study) [20] and patients with FH [24]. In contrast,
in the ENHANCE study ezetimibe plus simvastatin therapy did not
change mean cIMT in FH patients when compared with simvastatin
alone [17]. However, the trial has received considerable criticism
with regard to its design [15]. Similarly, in the ARBITER 6-
HALTS study, niacin and not ezetimibe, when added on a statin,
led to regression of cIMT in patients with CHD or CHD equivalent
[28]. Furthermore, although there was no net effect on cIMT, cumu-
lative ezetimibe exposure and greater LDL-C reduction were re-
lated to cIMT progression in statin-treated high risk patients [85].
Undoubtedly, prospective, larger, well-designed studies are ur-
gently required to elucidate ezetimibe-related effect on carotid athe-
rosclerosis and vascular events [15, 86].
OTHER ACTIONS OF EZETIMIBE
Apart from lipid-lowering, ezetimibe may exert pleiotropic
properties that may or may not be beneficial [87, 88]. In this con-
text, ezetimibe, either alone or added to a statin, was shown to ame-
liorate endothelial dysfunction [via inhibition of interleukin (IL)-6
and enhancement of endothelial nitric oxide synthase expression]
[89-91], although conflicting data exist [47, 92]. Of note, these are
small studies, thus highlighting the need for large trials to assess the
effects of ezetimibe on the vasculature. Ezetimibe may also reduce
oxidative stress [93-95] and suppress lipid accumulation in the liver
[90, 96].
Certain ezetimibe-induced anti-inflammatory effects have also
been reported including reduction of tumour necrosis factor (TNF)-
alpha, nuclear factor kappa (NFk)-, IL-2 and C-reactive protein
(CRP) levels [96-99]; however, contradictory results have also been
published [100-102]. A recent meta-analysis concluded that combi-
nation of a low-dose statin with ezetimibe improves both endothe-
lial dysfunction (assessed by flow mediated dilation) and inflamma-
tion (assessed by CRP) to a similar degree as high-dose statin
monotherapy [103]. Furthermore, ezetimibe, when co-administered
with simvastatin, decreased aortic wall matrix metalloproteinase-9
and IL-6 levels, thus possibly inhibiting abdominal aortic aneu-
rysms expansion [104]. Ezetimibe co-administration with simvas-
tatin may also exert anti-thrombotic properties such as reduction of
fibrinogen and plasminogen activator inhibitor-1 (PAI-1) [24, 102].
These beneficial vascular effects of ezetimibe may account for its
potential protective role on atherosclerotic plaque development and
stability as reported in both animal [105-107] and human studies
[24].
Ezetimibe was also shown to reduce sdLDL particles and, to a
greater extent, large and medium LDL subclasses [108, 109].
sdLDL are associated with an increased CVD risk mainly due to
their atherogenic properties [110, 111]. When added to a statin,
buoyant and intermediate LDL, but not sdLDL, particles were fur-
ther decreased [112]. In general, ezetimibe may decrease choles-
terol content within very low lipoprotein cholesterol (VLDL-C),
intermediate lipoprotein cholesterol (IDL-C) and LDL-C, although
not always affecting the LDL particle size distribution profile [113,
114]; an increase in sdLDL levels following ezetimibe treatment
have been also reported in healthy men [115]. These discrepancies
may be due to the small sample size, differences in selection criteria
and variations in the methodology used to measure sdLDL [13].
Furthermore, baseline TG and sdLDL levels may independently
affect changes in sdLDL levels following statin and/or ezetimibe
administration [116]. In this context, ezetimibe significantly re-
duced sdLDL levels in hyperlipidemic patients with elevated TGs,
i.e. >1.7 mmol/L (150 mg/dl) compared with those with normal
TGs; dense HDL subfractions were also decreased [88]. Therefore,
although quantitative LDL-C changes have been consistently asso-
ciated with ezetimibe administration, whether qualitative changes
also occur, remains to be established [13, 86, 117].
Ezetimibe, either alone or in combination with a statin, was also
reported to decrease apolipoprotein (apo) B levels [51, 118] as well
as the apo B/apo A-I ratio [40]. Elevated apo B levels are associated
with increased residual CVD risk and therefore should be taken in
consideration when treating high-risk patients [119]. Ezetimibe-
induced reduction of apo C-II has been also found, although its
clinical implications need to be addressed in future trials [120].
Apart from fasting lipids, ezetimibe was shown to beneficially
affect postprandial lipemia. In this context, postprandial TC and
TGs were significantly decreased following ezetimibe administra-
tion, either alone or in combination with simvastatin [121-123], as
were glucose levels [124]. The assessment and clinical importance
of postprandial TGs were recently reviewed by an expert panel
[125-127].
Ezetimibe have been previously reported to improve arterial
stiffness [44, 128, 129], although conflicting data exist [130]. Arte-
rial stiffness is associated with traditional CVD risk factors such as
DM, obesity and smoking [131-133], representing a potential target
of residual CVD risk [134]. Several drugs may affect vascular com-
pliance including antihypertensive and lipid-lowering agents [135,
136].
With regard to adipokines, there is a paucity of data on
ezetimibe-induced effects. The few existing studies mainly found
no changes in adiponectin, leptin, visfatin and resistin levels follow-
4 Current Pharmaceutical Design, 2013, Vol. 19, No. 00 Katsiki et al.
ing ezetimibe administration [137-140]. Further research is needed
to address these potential interactions.
Interestingly, both ezetimibe and statins induce SREBP-2
(sterol-regulatory-element-binding protein-2), leading to increased
expression of cholesterol biosynthesis genes and proprotein conver-
tase subtilisin/kexin type 9 (PCSK9) [141]. Elevated PCSK9 pro-
tein decreases LDL receptor levels on the hepatic cells [142], thus
possibly raising circulating LDL-C concentrations. Combination of
ezetimibe or statins with a PCSK9 inhibitor improved the lipid
profile to a greater extent (i.e. greater reductions in TC, LDL-C,
TGs and apo B) [141].
EZETIMIBE MONOTHERAPY AND DRUG COMBINA-
TIONS
In general, ezetimibe co-administration with a statin is more
effective in improving the lipid profile (i.e. TC, LDL-C, HDL-C,
TGs and/or apo B) compared with both placebo [143] and doubling
the statin dose [50, 118, 144, 145] as also supported by meta-
analyses [25, 26]. Therefore, in statin-treated patients that do not
achieve their LDL-C targets, adding ezetimibe is an effective lipid
lowering and safe therapeutic option [146]. The question is if event
rates are reduced. Furthermore, ezetimibe and statin co-
administration may result in greater fibrinolysis and oxidative stress
reduction than with statin alone [94]. Ezetimibe may increase cho-
lesterol synthesis, whereas statins may enhance cholesterol absorp-
tion; however, their combination was shown to decrease both proc-
esses, thus further supporting the need for their combination when
LDL-C goals are not reached by monotherapy [147]. In the same
context, patients treated with high-potency statins had greater de-
creases in cholesterol absorption markers and lower increases in
cholesterol synthesis markers following the addition of ezetimibe
compared with those on statins with low or medium potency [148].
Moreover, both ezetimibe and statins may prevent gallstones forma-
tion which may occur in dyslpidemic, diabetic and obese patients
[149]. Interestingly, gender differences in the response to ezetimibe
and statin combination therapy were reported in a recently pub-
lished pooled analysis [150].
Apart from statins [151, 152], ezetimibe may also be co-
administered with fibrates to target residual risk [49, 52]. In this
context, ezetimibe-fibrate combination may be proven useful in
mixed hyperlipidemia [153]. Similarly, triple therapy with
ezetimibe, atorvastatin/pravastatin and fenofibrate was both effec-
tive and safe in treating patients with atherogenic dyslipidemia
[154, 155].
Statins remain the cornerstone of dyslipidemia treatment with
added ezetimibe being an option in cases of inadequate lipid control
[30]. However, ezetimibe may also represent a potent therapeutic
alternative in statin intolerant patients where it can be administered
either alone or in combination with fibrates [35, 153, 156-158].
Furthermore, co-administration of ezetimibe with a statin twice a
week was both effective and well-tolerated in the presence of statin
intolerance [159, 160]. Similarly, shifting from a statin to ezetimibe
plus simvastatin therapy in patients experiencing statin-related ad-
verse events restored statin tolerance [161]. Ezetimibe, when com-
bined with orlistat or rimonabant, was also reported to beneficially
alter lipid levels without serious adverse effects in statin intolerant,
nondiabetic, overweight/obese patients [162]; body weight, waist
circumference, body mass index (BMI) and apo B were similarly
reduced in both groups, whereas a greater decrease in LDL-C levels
was observed in the orlistat group and in TGs in the rimonabant
group. HDL-C concentrations were reduced in the orlistat group,
remaining stable in the rimonabant group [162]. It should be noted
that rimonabant has been withdrawn from the market.
CONCLUSIONS
Ezetimibe, either alone or added to a statin, is effective in im-
proving atherogenic dyslipidemia and achieving lipid targets; cer-
tain off-target beneficial actions such as anti-inflammatory and
antioxidant may contribute to further decrease of CVD risk.
A significant reduction in major and ischemic atherosclerotic
events following ezetimibe plus simvastatin therapy was also re-
ported (in SHARP and SEAS trials). However, the negative out-
comes of the ENHANCE and ARBITER 6-HALTS studies led to
controversies with regard to the clinical value of ezetimibe. Until
now, ezetimibe plus statin combination therapy has not been shown
to significantly reduce CVD events compared with statin monother-
apy. As ezetimibe trials have received much criticism, the results of
the IMProved Reduction of Outcomes: Vytorin Efficacy Interna-
tional Trial (IMPROVE-IT) which will compare ezetimibe plus
simvastatin combination vs simvastatin monotherapy with regard to
CVD outcomes after acute coronary syndromes, may define the
ezetimibe effect, if any, on CVD events [163].
In the wider context, we need to consider that if LDL-C goals
are not achieved with a well-tolerated statin dose, adding ezetimibe
represents a promising treatment option. Whether the ezetimibe-
induced lipid-lowering effect in these patients will also lead to re-
duced CVD morbidity and mortality needs to be confirmed by more
trial-based evidence [164].
DECLARATION OF INTERESTS
This review was written independently; no company or institu-
tion supported it financially. Some of the authors have given talks,
attended conferences and participated in trials and advisory boards
sponsored by various pharmaceutical companies. No professional
writer was involved in the preparation of this review.
ACKNOWLEDGEMENTS
Declared none.
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Received: December 19, 2012 Accepted: January 8, 2013
