clinical Consultation  Phytosterols

c l i n i c a l   c o n s u ltat i o n

Phytosterols for dyslipidemia

Jennifer M. Malinowski and Monica M. Gehret

E
levated total cholesterol and low-
density-lipoprotein (LDL) cho-
lesterol concentrations are well-
established risk factors for coronary
heart disease (CHD). 1 Outcomes
from large clinical trials suggest that
lowering total and LDL cholesterol
levels with hydroxymethylglutaryl–
coenzyme A reductase inhibitors
(statins) reduces the morbidity and
mortality associated with heart dis-
ease. Statins are also the preferred
agents for decreasing LDL cholesterol
levels.1
Unfortunately, not all patients
attain their lipid goals with statin
therapy alone.1 The 2004 National
Cholesterol Education Program
(NCEP) Adult Treatment Panel III
(ATP III) guideline update supports
aggressive LDL cholesterol reduc-
tions to as low as 70 mg/dL for ad-
ditional benefit in certain patient
populations.2 This poses a potential
therapeutic problem if the degree of
reduction required from baseline ex-
ceeds the LDL-cholesterol-lowering
capacity of available statins.
Another example of such a prob-
lem is the patient on maximal doses
of statins who has reached his or
her treatment goal but experiences
dosage-related adverse effects, such
Purpose. The efficacy and safety of phyto-
sterols for the management of dyslipidemia
are reviewed.
Summary. Phytosterols have been evalu-
ated in over 40 clinical trials. The incor-
poration of 2 g of phytosterols daily into
margarine, mayonnaise, orange juice, olive
oil, low-fat milk, yogurt, and tablets is as-
sociated with significant reductions in low-
density-lipoprotein (LDL) cholesterol from
baseline over 1–12 months in adults with
normal or high cholesterol, in children, and
in patients with type 2 diabetes mellitus.
Phytosterol dosages of 1.6–3 g daily have
been shown to reduce LDL cholesterol by
4.1–15% versus placebo within the first
month of therapy. One meta-analysis found
mean reductions of 10–11%, but results
vary. Several placebo-controlled trials
found that the addition of phytosterols to
statin therapy was associated with reduc-
tions of 7–20% in LDL cholesterol for up to
1.5 years. Overall, phytosterols are useful
for reducing LDL cholesterol in patients
as myalgias or elevations in liver
transaminases. Although statin dis-
continuation is not always warranted
in this situation, a dosage reduction
resulting in less-effective LDL choles-
terol management may be considered
if statins are deemed the causative
agent.3 Combination therapies may
who cannot reach their treatment goal by
diet alone or who are taking maximum
tolerated doses of statins. These products
offer an alternative to statins in patients
who cannot take statins or whose statin
dosage is restricted because of potential
drug interactions or concomitant diseases.
Commonly reported adverse effects are
primarily gastrointestinal in nature.
Conclusion. Phytosterol therapy produces
an average 10–11% reduction in LDL cho-
lesterol concentration, but it is unknown
whether this effect persists beyond two
years. Phytosterol products are well toler-
ated and have few drug interactions, but
their long-term safety has not been es-
tablished. Current evidence is sufficient to
recommend phytosterols for lowering LDL
cholesterol in adults.
Index terms: Dosage; Drug interactions; Hy-
percholesterolemia; Phytosterols; Toxicity
Am J Health-Syst Pharm. 2010; 67:1165-
73
be warranted in this case to boost the
LDL-cholesterol-lowering effective-
ness of the lower-dose statin.
Further, not all patients with
hypercholesterolemia will need a
statin. For patients with no or one
risk factor for heart disease (LDL
cholesterol goal of <160 mg/dL),

Jennifer M. Malinowski, Pharm.D., is Assistant Professor, Phar-
macy Practice, Nesbitt College of Pharmacy and Nursing, Wilkes
University, Wilkes-Barre, PA, and Clinical Pharmacist, Lipid Man-
agement Clinic, Geisinger Lake Scranton, Scranton, PA. Monica M.
Gehret, Pharm.D., is Pharmacy Resident, Lebanon Veterans Affairs
Medical Center, Lebanon, PA; at the time of writing she was phar-
macy student, Wilkes University.
Address correspondence to Dr. Malinowski at Nesbitt College of
Pharmacy and Nursing, Wilkes University, 84 West South Street, SLC
336, Wilkes-Barre, PA 18766 (jennifer.malinowski@wilkes.edu).
The editorial assistance of Kimberly Metka, Pharm.D., is
acknowledged.
The authors have declared no potential conflicts of interest.
DOI 10.2146/ajhp090427

Am J Health-Syst Pharm—Vol 67 Jul 15, 2010 1165

 clinical consultation  Phytosterols
The Clinical Consultation section features
articles that provide brief advice on how to
handle specific drug therapy problems. All
articles are based on a systematic review
of the literature. The assistance of ASHP’s
Section of Clinical Specialists and Scientists
in soliciting Clinical Consultation submis-
sions is acknowledged. Unsolicited submis-
sions are also welcome.
therapeutic lifestyle changes that in-
clude a diet low in saturated fat, low
in cholesterol, and high in fiber and
daily physical activity may be enough
to satisfy lipid goals. Patients with
moderate risk (LDL cholesterol goal
of <130 mg/dL) may not necessarily
require statin therapy, depending on
the severity of risk factors.1 Patients
with active acute liver disease or
unexplained liver enzyme elevations
should not take statins.3,4
For over 50 years, plant sterols
and stanols have been known to
reduce total and LDL cholesterol.1,5
The NCEP1 and the American Heart
Association 4 recognize the ben-
efits of plant sterols and stanols—
collectively known as phytosterols—
as an adjunct to therapeutic lifestyle
changes in adults with elevated
cholesterol levels. Two grams of es-
terified phytosterols daily achieves
an approximate 9–20% reduction in
LDL cholesterol in dyslipidemic pa-
tients, including those already taking
statins.1,4
This article reviews the efficacy
and safety of phytosterols in the
management of dyslipidemia.
Chemistry
Sterols are an important part of
the physiology of cell membranes.4
Cholesterol, a sterol produced by
mammals, provides structural integ-
rity to cell membranes and affects the
fluidity of the cell. Plants produce
plant sterols. While over 40 types
of plant sterols exist, the three most
abundant varieties are sitosterol,
campesterol, and stigmasterol. Plant
sterols are present in small amounts
1166 Am J Health-Syst Pharm—Vol 67 Jul 15, 2010
in fruits, vegetables, nuts, seeds,
legumes, and edible oils; marketed
sources are primarily derived from
soybean and pine tree oil. Plant
stanols are hydrogenated or satu-
rated versions of plant sterols and are
found in similar dietary sources. It is
theorized that the chemical modifi-
cation from a sterol to a stanol im-
proves the LDL-cholesterol-lowering
capacity. In contrast to plant sterols,
plant stanols are minimally absorbed
through the gastrointestinal tract.6
The typical total plant phytosterol
dietary consumption in the Western
diet is 150–350 mg daily.7,8
Phytosterols closely resemble the
structure of cholesterol, differing
only by their side chains.8 Early stud-
ies of up to 18 g of ground crystalline
phytosterol daily produced varying
lipid-lowering effects.8,9 Unpleas-
ant taste and large bulky dosages
prompted the use of phytosterol es-
terification, a process that augments
lipid solubility in foods and increases
delivery of the product to the small
intestine. Esterification reduced the
effective dose to 1/10 of the original
total daily dose needed.10 Unesterified
versions may be combined with leci-
thin to avoid the need to disperse the
phytosterols in a fatty matrix.11
Mechanism of action
Esterified phytosterols are hydro-
lyzed by cholesterol reductase post-
prandially in the small intestine to
active forms.12 Thus, it is important
for the products to be consumed
with meals for activation to occur.
Free phytosterols are then available to
limit cholesterol absorption and dis-
place it from incorporating into mi-
celles. Plant stanols may also promote
increased movement of cholesterol
into the intestinal lumen by inducing
expression of adenosine triphosphate
binding cassette transporter 1, caus-
ing increased cholesterol elimination
in the feces.13-15 Although reductions
of up to 40% in dietary cholesterol
absorption have been observed with
plant stanol administration, a com-
pensatory increase in cholesterol
synthesis counteracts some of this
effect.16 Plant sterols produce similar
effects on cholesterol absorption.
Clinical studies
Phytosterols have been evaluated
in over 40 clinical trials. Overall, the
incorporation of 2 g of phytosterols
daily into margarine, mayonnaise,
orange juice, olive oil, low-fat milk,
yogurt, and tablets is associated
with significant reductions in LDL
cholesterol from baseline over 1–12
months in adults with normal or
high cholesterol levels, in children,
and in patients with type 2 diabetes
mellitus.3,17,18 The use of 1.6–3 g of
esterified phytosterols daily has been
shown to reduce LDL cholesterol by
4.1–15% versus placebo within the
first month of therapy.7 One meta-
analysis observed mean reductions
in LDL cholesterol of 10–11%, but
results vary.17
In a study by Miettinen et al.,19
153 hypercholesterolemic patients
replaced 24 g of their daily dietary
fat intake with margarine with or
without sitostanol ester 2.6 g for 6
months. After the 6 months, patients
taking the sitostanol ester took a
reduced daily dose of 1.8 g, while
the other group remained on the
2.6-g dose. The group taking the
higher dosage experienced addi-
tional reductions in LDL cholesterol
at 12 months, averaging 14% from
baseline. The group treated with half
the dose after 6 months maintained
serum cholesterol levels present at
6 months at the 12-month evalua-
tion but did not further reduce LDL
cholesterol.
Increasing the phytosterol daily
dose beyond 3 g does not offer addi-
tional benefit and, in some cases, has
been shown to be inferior to dosages
limited to 2 g daily.15,19,20 Dosages of
<1 g do not offer a benefit.8,16 The
full effects of therapy may take up to
eight weeks. High-density lipopro-
tein (HDL) cholesterol concentra-
tions and triglycerides are not con-

sistently affected, though a recent
nine-week trial in which patients
with metabolic syndrome received
2 g of stanol esters daily revealed
significant reductions in non-HDL
cholesterol (12.8%, p = 0.011) and
triglycerides (27.5%, p = 0.044) ver-
sus placebo.16,21 The different types
of phytosterol products, wide range
of daily doses, inclusion of studies
with small populations, and short
trial durations may have influenced
the findings of these analyses.
Direct trials comparing the effica-
cy of plant stanols to plant sterols are
limited, though both have produced
similar reductions in LDL cholesterol
in most short-term studies.6 Plasma
sterol levels increase when patients
take plant sterols but not with plant
stanols.22,23 There is also a concern
that effectiveness diminishes over
time, attributable to a theoretical
reduction in cholesterol excretion
into the bile.6 A few long-term (over
one year) trials have suggested that
there is no difference in efficacy be-
tween plant sterols and plant stanols
in patients with normal and elevated
cholesterol levels, but these results
are inconsistent.24,25 Free (unesteri-
fied) versions also have similar effects
but have been studied less than the
esterified products.17 Unfortunately,
the maximum study duration for
phytosterols in the literature is less
than two years. More comparative
trials of longer durations are needed
to evaluate the persistence of effec-
tiveness over time.
The source of phytosterols (e.g.,
soybean, pine tree oil) and the type
of food or formulation in which the
phytosterol is dispersed do not ap-
pear to have affected efficacy in most
studies.5 Food matrixes containing
phytosterols that are lower in fat
appear to produce similar results as
those that are higher in fat.26 One trial
noted improved reductions in LDL
cholesterol with the same amount
of phytosterols (1.6 g daily for three
weeks) in a low-fat milk source com-
pared with bread and cereal.27
clinical Consultation  Phytosterols
It is important to note that un-
like statins, no controlled trials to
date have investigated the effect of
phytosterols on the morbidity and
mortality associated with heart dis-
ease. Animal models suggest that
phytosterols prevent the formation
of cholesterol-induced atheromas
in a dose-dependent fashion28,29 but
do not promote regression of exist-
ing atherosclerotic plaque.30 A few
small trials observed a reduction in
C-reactive protein after the initiation
of phytosterol monotherapy and in
combination with statins, but others
did not observe this reduction.31-34
More research is warranted to de-
termine the effects of phytosterols
on C-reactive protein. Overall, epi-
demiologic projections hypothesize
that consuming phytosterols as esters
or in free form will reduce coronary
lifetime risks by 20%.17
Combination with other
lipid-lowering agents
Statins. Phytosterols are not a
substitute for statins in the secondary
prophylaxis of heart disease; statins
remain the first-line treatment in pa-
tients with a prior myocardial infarc-
tion.1 Other high-risk populations
indicated for initial treatment with a
statin include patients with diabetes,
carotid artery stenosis, stroke, tran-
sient ischemic attack, or a 10-year
Framingham cardiac risk of >20%.
Baseline LDL cholesterol concentra-
tions that exceed the therapeutic goal
by 30 mg/dL or more should also be
considered for initial treatment with
a statin.
Combination therapy with phy-
tosterols is helpful for patients who
do not reach their LDL choles-
terol goal with statins alone. Patients
treated with statins may experience a
compensatory increase in cholesterol
absorption, a pharmacologic target
of phytosterols.18 A subgroup analy-
sis showed that patients who had
markers suggestive of increased ab-
sorption and reduced production of
cholesterol responded suboptimally
Am J Health-Syst Pharm—Vol 67 Jul 15, 2010
to statin therapy in the landmark
Scandinavian Simvastatin Survival
Study.35 This patient population ap-
peared to have lower reductions in
LDL cholesterol and cardiovascular
complications compared with those
of patients without markers for in-
creased cholesterol absorption. Fur-
ther study is needed to determine the
importance of this finding. Phyto-
sterols, which decrease the absorp-
tion of cholesterol and promote in-
creased synthesis (via compensatory
mechanisms), could potentially be
the ideal treatment for this group of
poor responders.20
Several placebo-controlled trials
found that the addition of phyto-
sterols to existing statin therapy was
associated with greater reductions
in LDL cholesterol (7–20% for up to
1.5 years), though not all reductions
were consistently deemed statistically
significant.36-42 Patients with higher
baseline LDL cholesterol values
while on statins appear to have the
strongest response to the addition of
phytosterols.3 Some of these results
are detailed in Table 1. The reduction
associated with combining phyto-
sterols with statins is higher than or
comparable to the expected 5–7%
reduction in LDL cholesterol that is
seen with doubling the statin dose.43
Phytosterols can be statin dose spar-
ing, particularly in patients who are
sensitive to adverse effects at higher
statin doses or who are on restricted
statin doses because of concomitant
medications or diseases.17
Other lipid-modifying agents.
Triple therapy with statins, bile acid
sequestrant, and margarine contain-
ing esterified phytosterol resulted in
a 67% reduction in LDL cholesterol
in one trial.44 This therapy may be
helpful in patients with resistant
hyperlipidemia or who may not be
able to tolerate maximum doses of
phytosterols, statins, or both due to
adverse effects.
When added to fibrates, marga-
rine containing plant sterol is as-
sociated with an approximate 9%
1167
 clinical consultation  Phytosterols

Table 1.
Changes in Low-Density-Lipoprotein (LDL) Cholesterol Associated with the Addition of Phytosterols to
Existing Statin Therapy
Patient Statin Phytosterol % Change
Ref. n Characteristics Regimen Regimen in LDL Cholesterola p
36 148 Hypercholesterolemia, LDL Varied Stanol ester 5.1 g/day –10 <0.0001
cholesterol of ≥130 mg/dL for 8 wk
37 30 Familial hypercholesterolemia, Varied Stanol ester 2.5 g/day –11 <0.0001
triglycerides of >250 mg/dL for 8 wk
38 75 Hypercholesterolemia, mean LDL Cerivastatin Stanol ester 2 g/day –7 0.29
cholesterol = 206 mg/dL sodium 0.4 mg/ for 4 wk
day
42 54 Body mass index of <32 kg/m2, Varied Stanol ester 2.5 g/day –13.1 0.006
mean LDL cholesterol = 122 for 85 wk
mg/dL Sterol ester 2.5 g/day –8.7 NSb
for 85 wk
Statin plus phytosterol compared with statin plus placebo.
a

NS = not significant.
b

reduction in LDL cholesterol from
baseline.45 Sitostanol 3 g daily added
to bezafibrate 200 mg daily resulted
in an additional reduction in LDL
cholesterol of 5% over two years.8
Ezetimibe may inhibit absorp-
tion of plant sterols in addition to
inhibiting cholesterol absorption,
despite being classified as a selec-
tive cholesterol-absorption inhibi-
tor.46 Results from a study of 40 pa-
tients suggested that the addition of
plant sterols to ezetimibe treatment
was not statistically different from
ezetimibe treatment alone in patients
with mild hypercholesterolemia (de-
fined as a baseline LDL cholesterol
concentration of 136.5–195 mg/dL).
Until additional information is avail-
able, the combination of ezetimibe
and plant sterols should be avoided.
Phytosterols in diabetes mellitus
Several small studies found that
phytosterols used alone or in com-
bination with statins reduced LDL
cholesterol in patients with diabetes
mellitus. These reductions were
similar to those observed in patients
without diabetes mellitus (LDL
cholesterol decreased 14%). Phytos-
terols do not appear to affect glucose
control.16,47
Phytosterols in pregnancy and in
children
Total cholesterol can increase by
60% during pregnancy as a result of
hormonal changes and diet.48 Unfor-
tunately, experience with cholesterol-
lowering agents in pregnancy is
limited. Statins are in Food and Drug
Administration (FDA) pregnancy
category X and are also contrain-
dicated in breast-feeding women.48
Plant stanols may offer an alternative
for these patients in the future be-
cause they are minimally absorbed,
unlike plant sterols. One pilot study
evaluated the efficacy of at least 1 g of
plant stanol daily during pregnancy
and lactation.49 There was no change
in LDL cholesterol or any other lipid
value from baseline, but the dose
used was subtherapeutic. More stud-
ies are needed, particularly using
higher doses, to determine the role of
plant stanols in this population.
Data regarding phytosterol use in
children are limited. Plant stanols
produce similar LDL cholesterol re-
ductions in children as in adults with
high cholesterol following a low-fat,
low-cholesterol diet.50-54 One study
evaluated the use of a mean 1.5 g of
plant stanol ester in margarine daily
to 81 healthy children older than six
years. LDL cholesterol significantly
decreased by 7.5% from baseline at
three months (p = 0.0001).52
The American Heart Association
and the NCEP do not specifically
encourage the use of phytosterols in
children. Due to limited data, phy-
tosterols are not recommended in
children less than six years of age.17
Adverse effects
In general, phytosterols are well
tolerated and recognized as safe.55-59
A meta-analysis of 42 randomized,
double-blind, placebo-controlled
trials found that adverse effects are
generally mild, transient, and dose
related.16 Commonly reported ad-
verse effects are primarily gastroin-
testinal in nature (nausea, dyspepsia,
diarrhea, constipation, flatulence,
feces discoloration, gastroesophageal
reflux, appetite changes).
Phytosterols may result in re-
duced absorption and transport of
hydrocarbon carotenes, specifically
a-carotene, b-carotene, and lyco-
pene. 14 LDL cholesterol is also a
carrier for fat-soluble vitamins, so
if the levels are reduced, there is
less transport. This is also observed
with other lipid-lowering strategies
such as cholestyramine and wheat

1168 Am J Health-Syst Pharm—Vol 67 Jul 15, 2010


bran.14 Divided doses appear to result
in greater changes in antioxidants
compared with once-daily dosing,
though these changes were not sta-
tistically significant.60 Beta-carotene
appears to be the only vitamin whose
absorption is lessened to a clinically
significant extent, with levels reduced
by 6.8–17.4% but remaining within
the normal range.52 Incorporation
of phytosterols into an orange juice
matrix has not been associated with
changes in b-carotene absorption.7
The reduction of b-carotene absorp-
tion can also be ameliorated by eat-
ing sufficient amounts of fruits and
vegetables such as carrots, pumpkin,
apricots, spinach, and broccoli.61,62
Daily multivitamin supplementation
is also effective.
There is some concern that reduc-
ing b-carotene may be detrimental
from a public health standpoint,
because low amounts of b-carotene
have been associated with an in-
creased risk of chronic disease, such
as cancers and CHD.18 It is not clear if
this is entirely causal or if other con-
founding variables play a role. There
has been concern that the absorp-
tion of fat-soluble vitamins would
be reduced by phytosterols,63 though
reductions are likely to be clinically
insignificant.14,64
Although the addition of high-fat
products enriched with phytosterols
may seem counterintuitive to a low-
fat, heart-healthy diet, their con-
sumption has not been associated
with significant increases in total
body weight or body mass index.
Subsequently, a meta-analysis of 42
trials of phytosterols did not observe
significant changes in blood pres-
sure or heart rate or concentrations
of serum hepatic transaminases,
glucose, uric acid, or blood urea
nitrogen.16
Recent animal and human studies
suggest that phytosterols cross the
blood-brain barrier.65 One trial in pa-
tients with hypercholesterolemia on
statins and phytosterol supplements
did not demonstrate significant
clinical Consultation  Phytosterols
changes in neurocognitive behavior
or mood over 85 weeks.66
Phytosterols have been associ-
ated with a shortened lifespan of
red blood cells (RBCs) in rats, pos-
sibly because cholesterol is replaced
by phytosterols in the erythrocyte
membrane. It is theorized that the
RBCs would become more fragile,
resulting in anemias. RBC fragility
was unaffected in one study using
phytosterol-containing margarine in
combination with statins.67 Anemia
is not a common adverse effect of
phytosterol use.
Other less-commonly reported
adverse effects include increased
mean thyrotropin16 and fibrinogen
concentrations.68 Additional study
is warranted to elucidate the signifi-
cance of these findings.
Precautions and contraindications
There are a number of studies
that suggest a positive association
between elevated serum phytosterol
concentrations and CHD risk.14,34,69,70
Others have found that moderately
increased phytosterol levels are asso-
ciated with a reduced risk of cardio-
vascular events.71
Some investigators have expressed
concerns that supplemental phytos-
terols could lead to atherosclerosis,
based on the clinical experience with
sitosterolemia; however, this idea is
controversial.14,21,58,72 Sitosterolemia is
an extremely rare inherited disorder
associated with the accumulation of
phytosterols, normal total choles-
terol, anemia, and an elevated CHD
risk. Since plant stanols are minimal-
ly absorbed and have a significantly
shorter half-life than do plant sterols,
it is theorized that this potential
adverse effect is primarily associated
with plant sterol supplementation.73
About 5% of consumed plant sterol
supplements are absorbed.
Plant sterol oxidation also results
in oxysterols, which are atherogenic.14
Nonetheless, oxysterols are not only
seen in patients with sitosterolemia
but in healthy patients. Until addi-
Am J Health-Syst Pharm—Vol 67 Jul 15, 2010
tional data accumulate, phytosterol
supplementation should be avoided
in patients with this disorder. Also,
since it may be difficult to identify a
patient with sitosterolemia, the use
of phytosterols should be avoided in
patients without high cholesterol.7
Published data on the safety of
phytosterols in pregnancy or lacta-
tion are limited.48,49 There is no evi-
dence to suggest teratogenic effects
in humans.17 Until additional experi-
ence becomes available, phytosterols
are generally not recommended in
pregnancy. One small animal study
found that fewer pregnancies were
associated with local intravaginal and
intrauterine application of phytoster-
ols.74 The significance of this remains
to be determined, since these routes
are not used for phytosterols. Higher
oral doses in animals are associated
with reduced sperm concentration
and testicular weight.75
Drug interactions
Drug interactions with phyto-
sterols are minimal. No significant
pharmacokinetic interactions have
been noted between statins and
phytosterols to date. Cholestyramine
administration should be separated
from phytosterol use by two to four
hours to avoid binding of the latter
in the gut.
Vitamin K levels are not affected
by the consumption of phytoster-
ols.76 A small study of patients taking
4.5 g of phytostanols for eight weeks
concomitantly with warfarin did not
show a change in the International
Normalized Ratio.77 The dosage of
anticoagulants should not be affected
by concomitant administration of
phytosterols.
Dosing and administration
The safest and most effective sup-
plemental dosage of phytosterols ref-
erenced by most sources is approxi-
mately 2 g daily. The accepted dosing
range is generally 1–3 g daily.1,2,4 Daily
doses of <1 g are not effective, and
daily doses beyond 2–3 g do not show
1169
 clinical consultation  Phytosterols
Table 2.
Selected Phytosterol-Containing Productsa
Product (Manufacturer)
Spreads
Promise Active Light Spread (Unilever)
Benecol Light Spread (McNeil Nutritionals)
Smart Balance Omega Plus (Smart
Balance)
Juice
Minute Maid Heartwise orange juice
(Coca Cola Company)
Dairy products
Lifetime low-fat cheese (Lifeline)
Rice Dream Heartwise rice milk (Hain 650 mg/8 oz 16 oz daily
Celestial Group)
Supplements
Centrum Cardio (Wyeth Consumer)
One A Day Cholesterol Plus (Bayer 100 mg/tabletc
Healthcare)
Benecol Chews (McNeil Nutritionals)
Cholestoff (Nature Made)
a
Information from package labeling.
b
Stanol esters.
c
Sterols.
d
Free phytosterols.
additional reductions in cholester-
ol.17 Most studies divide the total
daily requirements into three sepa-
rate doses to be taken with each meal,
based on the theory that the product
requires food to stimulate biliary
flow for maximal incorporation into
micelles. However, one trial found
that once-daily dosing of 2.5 g plant
stanol esters at lunch or dinner was as
effective as thrice-daily dosing, which
may be helpful in less-compliant pa-
tients.60 Other trials have not found
improvements in LDL cholesterol if
products are taken three times a day
versus once daily.63 Nonetheless, the
manufacturers’ labeling still recom-
mends that products be taken with
meals to ensure that hydrolysis in
the small intestine occurs. The type
of meal (e.g., high fat versus low fat)
does not appear to influence effec-
tiveness. Table 2 summarizes some of
the available phytosterol products.
1170 Am J Health-Syst Pharm—Vol 67 Jul 15, 2010
Phytosterol Product
Content Dosage
1 tbsp twice daily
1000 mg/tbsp
850 mg/tbspb
450 mg/tbsp
1000 mg/8 oz 8 oz daily
650 mg/ozc 2 oz daily
400 mg/tabletd 1 tablet twice
daily
1 tablet daily
850 mg/chewable 1 or 2 tablets
tabletb daily
450 mg/caplet 2 caplets twice
daily
Discussion
Phytosterols are useful for re-
ducing LDL cholesterol in patients
who cannot reach their LDL choles-
terol goals by diet alone (lower-risk
groups) or who are taking maximum
tolerated doses of statins (higher-risk
groups). These products offer an
alternative to statins in patients who
cannot take statins (active liver dis-
ease) or whose statin dosage must be
restricted because of potential drug
interactions (concomitant fibrate
administration) or diseases (renal
disease). Patients with normal cho-
lesterol levels should not be encour-
aged to take these products based on
a lack of efficacy and safety data in
this population.
The NCEP ATP III does not differ-
entiate between stanol esters or sterol
esters.1 Therefore, product selection
can be based on patient preference
and cost. Of course, patients’ taste
preferences and convenience prefer-
ences should also be considered early.
Cost is another concern with some of
the products. Phytosterol-containing
foods are typically more expensive
than the same foods without phy-
tosterols. Some patients, in an effort
to save money, may ask whether
cholesterol lowering is observed with
smaller serving sizes than recom-
mended. It is not known if a ben-
efit would be observed, though some
products with higher concentrations
of phytosterols may offer a benefit at
lower doses. FDA allows products to
claim that their use reduces patients’
risk of heart disease if they contain
the following daily amounts: 1.3 g
of plant sterol esters, 3.4 g of plant
stanol esters, or 800 mg of free phy-
tosterols.78 One A Day Cholesterol
Plus (Bayer Healthcare) does not
contain this specified amount and
should not be recommended for cho-
lesterol lowering.
Patients should consider the ca-
loric and fat content of available
products to avoid excessive intake.
The fat content in some food sources
such as margarine contributes to
increased saturated fat consumption.
While the phytosterol-containing
spreads may be a good substitute
for patients desiring a replacement
for regular margarine or butter, they
may not be the best way to introduce
phytosterols into a diet that does not
already incorporate butter spreads.
Because of the sugar content and
acidity, orange juice formulations
should be used with caution in pa-
tients with diabetes mellitus and
reflux esophagitis. Dairy products
containing phytosterols may be use-
ful in patients trying to increase their
calcium intake through diet, though
these products may not be available
in all markets.
Phytosterols supplied as supple-
ments are another alternative but will
contribute to the overall “pill burden”
for the patient. It is important to
clarify to patients that vitamins con-
taining phytosterols must be taken

twice daily for the full effect, espe-
cially since most vitamins are taken
once daily. Whether one product is
superior to another is unknown.
A diet rich in fruits and vegetables,
concomitant multivitamin adminis-
tration, or both should be considered
to counteract potential reductions
in b-carotene absorption. Phytos-
terols should be avoided in children
and in women who are pregnant or
lactating until additional safety data
become available. More research
is needed to evaluate whether the
reduced absorption associated with
plant stanols versus plant sterols is
clinically relevant. Reduced systemic
absorption of plant stanols may
be a potential advantage, but their
adverse-effect profile is similar to that
of plant sterols. Most products on the
market contain sterol esters, with the
exception of Benecol (McNeil). Stud-
ies evaluating effectiveness and safety
beyond two years are needed.
Definitive studies may never be
available for phytosterols. Large tri-
als enrolling 10,000–15,000 people
would be needed to provide appro-
priate power for an anticipated CHD
reduction of 12–20%. 18 Surrogate
marker (e.g., reduction in intima me-
dia thickness) trials may be available
in the future. Although the products
are helpful in lowering LDL choles-
terol, it is unknown whether a mor-
bidity or mortality benefit exists.
Conclusion
Phytosterol therapy produces an
average 10–11% reduction in LDL
cholesterol concentration, but it is
unknown whether this effect per-
sists beyond two years. Phytosterol
products are well tolerated and have
few drug interactions, but their long-
term safety has not been established.
Current evidence is sufficient to rec-
ommend phytosterols for lowering
LDL cholesterol in adults.
References
1. National Heart, Lung, and Blood In-
stitute. Third report of the National
Cholesterol Education Program Expert
clinical Consultation  Phytosterols
Panel on detection, evaluation, and treat-
ment of high blood cholesterol in adults
(Adult Treatment Panel III): executive
summary. www.nhlbi.nih.gov/guidelines/
cholesterol/atp3xsum.pdf (accessed 2009
Jul 31).
2. Grundy SM, Cleeman JI, Bairey Merz
CN et al. Implications of recent clini-
cal trials for the National Cholesterol
Education Program Adult Treatment
Panel III guidelines. www.nhlbi.nih.gov/
guidelines/cholesterol/atp3upd04.htm
(accessed 2009 Jul 31).
3. McKenney J, Davidson M, Jacobson T et
al. Final conclusions and recommenda-
tions of the National Lipid Association
Statin Safety Assessment Task Force. Am J
Cardiol. 2006; 97(suppl):89C-94C.
4. Lichtenstein A, Deckelbaum R. Stanol/
sterol ester containing foods and blood
cholesterol levels: a statement for health-
care professionals from the Nutrition
Committee of the Council on Nutrition,
Physical Activity, and Metabolism of the
American Heart Association. Circulation.
2001; 103:1177-9.
5. Mietinnen T, Gylling H. Plant stanol and
sterol esters in prevention of cardiovascu-
lar diseases. Ann Med. 2004; 36:126-34.
6. Devaraj S, Jialal I. The role of dietary
supplementation with plant sterols and
stanols in the prevention of cardiovascu-
lar disease. Nutr Rev. 2006; 64:348-54.
7. O’Neill FH, Sanders TA, Thompson GR.
Comparison of efficacy of plant stanol
ester and sterol ester: short-term and
longer-term studies. Am J Cardiol. 2005;
96(suppl):29D-36D.
8. Thompson GR, Grundy SM. History and
development of plant sterol and stanol
esters for cholesterol-lowering purposes.
Am J Cardiol. 2005; 96(suppl):3D-9D.
9. Lees RS, Lees AM. Effects of sitosterol
therapy on plasma lipid and lipoprotein
concentrations. In: Greten H, ed. Lipo-
protein metabolism. Berlin: Springer-
Verlag; 1976:119-24.
10. Wester I. Dose responsiveness to plant
stanol esters. Eur Heart J Suppl. 1999;
1:S104-8.
11. Ostlund RE Jr, Spilburg CA, Stenson
WF. Sitostanol administered in lecithin
micelles potently reduces cholesterol
absorption in humans. Am J Clin Nutr.
1999; 70:826-31.
12. Nessinen M, Gylling H, Vuoristo M et al.
Micellar distribution of cholesterol and
phytosterols after duodenal plant stanol
ester infusion. Am J Physiol Gastrointest
Liver Physiol. 2002; 282:G1009-15.
13. Salo P, Wester I. Low-fat formulations of
plant stanols and sterols. Am J Cardiol.
2005; 96(suppl):51D-54D.
14. Plat J, Mensink RP. Increased intestinal
ABCA1 expression contributes to the
decrease in cholesterol absorption after
plant stanol consumption. FASEB J. 2002;
16:1248-53.
15. Yu L, Hawkins J, Berge KE et al. Over-
expression of ABCG5 and ABCG8 pro-
motes biliary cholesterol secretion and
reduces fractional absorption of dietary
Am J Health-Syst Pharm—Vol 67 Jul 15, 2010
cholesterol. J Clin Invest. 2002; 100:671-
80.
16. Miettinen TA. Cholesterol absorption
inhibition: a strategy for cholesterol-
lowering therapy. Int J Clin Pract. 2001;
55:710-6.
17. Chen JT, Wesley R, Shamburek RD et al.
Meta-analysis of natural therapies for
hyperlipidemia: plant sterols and stanols
versus policosanol. Pharmacotherapy.
2005; 25:171-83.
18. Katan MB, Grundy SM, Jones P et al.
Efficacy and safety of plant stanols and
sterols in the management of blood
cholesterol levels. Mayo Clin Proc. 2003;
78:965-78.
19. Miettinen TA, Puska P, Gylling H et al.
Reduction of serum cholesterol with
sitostanol-ester margarine in a mildly
hypercholesterolemic population. N Engl
J Med. 1995; 333:1308-12.
20. Thompson GR. Additive effects of plant
sterol and stanol esters to statin therapy.
Am J Cardiol. 2005; 96(suppl):37D-39D.
21. Plat J, Brufau G, Dallinga-Thie GM. A
plant stanol yogurt drink alone or com-
bined with low-dose statin lowers serum
triacylglycerol and non-HDL cholesterol
in metabolic syndrome patients. J Nutr.
2009; 139:1143-9.
22. Moghadasian MH, Frohlich JJ. Effects of
dietary phytosterols on cholesterol me-
tabolism and atherosclerosis: clinical and
experimental evidence. Am J Med. 1999;
107:588-94.
23. Ketomaki A, Gylling H, Miettinen T.
Effects of plant stanol and sterol esters
on serum phytosterols in a family with
familial hypercholesterolemia including
a homozygous subject. J Lab Clin Med.
2004; 143:255-62.
24. Hallikainen MA, Sarkkinen ES, Gylling
H et al. Comparison of the effects of
plant sterol ester and plant stanol ester-
enriched margarines in lowering serum
cholesterol concentrations in hypercho-
lesterolaemic subjects on a low-fat diet.
Eur J Clin Nutr. 2000; 54:715-25.
25. Weststrate JA, Meijer GW. Plant sterol-
enriched margarines and reduction of
plasma total- and LDL-cholesterol con-
centrations in normocholesterolaemic
and mildly hypercholesterolaemic sub-
jects. Eur J Clin Nutr. 1998; 52:334-43.
26. Jones PJ, Vanstone CA, Sarjaz MR et al.
Phytosterols in low and non-fat beverages
as part of a controlled diet fail to lower
plasma lipid levels. J Lipid Res. 2003;
44:713-9.
27. Clifton PM, Noakes M, Sullivan D et
al. Cholesterol lowering effects of plant
sterol esters differ in milk, yogurt, bread
and cereal. Eur J Clin Nutr. 2004; 58:503-9.
28. Moghadasian MH, McManus BM, Prit-
chard PH et al. “Tall oil”-derived phy-
tosterols reduce atherosclerosis in ApoE
deficient mice. Arterioscler Thromb Vasc
Biol. 1997; 17:119-26.
29. Volger OL, Mensink RP, Plat J et al.
Dietary vegetable oil and wood derived
plant stanol esters reduce atherosclerotic
lesion size and severity in apo E 3-Leiden
1171
 clinical consultation  Phytosterols
transgenic mice. Atherosclerosis. 2001;
157:375-81.
30. Moghadasian MH, Godin DV, McManus
BM et al. Lack of regression of atheroscle-
rotic lesions in phytosterol treated apo E
deficient mice. Life Sci. 1999; 64:1029-36.
31. Jenkins DJ, Kendall CC, Marchie A et al. Ef-
fects of a dietary portfolio of cholesterol-
lowering foods vs lovastatin on serum
lipids and C-reactive protein. JAMA.
2003; 290:502-10.
32. Cater NB, Garcia AB, Vega GL et al.
Responsiveness of plasma lipids and
lipoproteins to plant stanol esters. Am J
Cardiol. 2005; 96:23D-28D.
33. De Jong A, Plat J, Bast A et al. Effects of
plant sterol and stanol ester consumption
on lipid metabolism, antioxidant status
and markers of oxidative stress, endothe-
lial function and low-grade inflammation
in patients on current statin treatment.
Eur J Clin Nutr. 2008; 62:263-73.
34. Mensink R, Ebbing S, Lindhout M et al.
Effect of plant stanol esters in low fat
yoghurt on serum lipids, lipoproteins,
noncholesterol sterols and fat soluble an-
tioxidant concentrations. Atherosclerosis.
2002; 100:205-13.
35. Miettinen TA, Strandberg T, Gylling H; for
the Finnish Investigators of the Scandina-
vian Simvastatin Survival Study Group.
Noncholesterol sterols and cholesterol
lowering by long-term simvastatin treat-
ment in coronary patients. Arterioscler
Thromb Vasc Biol. 2000; 20:1340-6.
36. Blair SN, Capuzzi DM, Gottlieb SO et
al. Incremental reduction of serum total
cholesterol and LDL-C with the addition
of plant stanol-ester containing spread to
statin therapy. Am J Cardiol. 2000; 86:46-
52.
37. Neil HA, Meijer GW, Roe LS. Ran-
domised controlled trial of use by hyper-
cholesterolaemic patients of a vegetable
oil sterol-enriched fat spread. Atheroscle-
rosis. 2001; 156:327-9.
38. Simons LA. Additive effect of plant sterol
ester margarine and cerivastatin in lower-
ing LDL-C in primary hypercholester-
olemia. Am J Cardiol. 2002; 90:737-40.
39. O’Neill FH, Brynes A, Mandeno R et al.
Comparison of effects of dietary plant
sterol and stanol esters on lipid metabo-
lism. Nutr Metab Cardiovasc Dis. 2004;
14:133-42.
40. Castro Cabezas M, de Vries JH, Van
Oostrom AJ et al. Effects of a stanol-
enriched diet on plasma cholesterol and
triglycerides in patients treated with sta-
tins. J Am Diet Assoc. 2006; 106:1564-9.
41. Goldberg AC, Ostlund RE, Bateman JH.
Effect of plant stanol tablets on low-
density lipoprotein cholesterol lowering
in patients on statin drugs. Am J Cardiol.
2006; 97:376-9.
42. De Jong A, Plat J, Lutjohann D et al. Ef-
fects of long term plant sterol or stanol
ester consumption on lipid and lipo-
protein metabolism in subjects on statin
treatment. Br J Nutr. 2008; 100:937-41.
43. Jones P, Kafonek S, Laurora I et al.
Comparative dose efficacy study of ator-
1172 Am J Health-Syst Pharm—Vol 67 Jul 15, 2010
vastatin versus simvastatin, pravastatin,
lovastatin, and fluvastatin in patients
with hypercholesterolemia (the CURVES
study). Am J Cardiol. 1998; 81:582-7.
[Erratum, Am J Cardiol. 1998; 82:128.]
44. Gylling H, Miettinen TA. LDL cholesterol
lowering by bile acid malabsorption dur-
ing inhibited synthesis and absorption
of cholesterol in hypercholesterolemic
coronary subjects. Nutr Metab Cardiovasc
Dis. 2002; 12:19-23.
45. Nigon F, Serfaty C, Beucler I et al. Plant
sterol enriched margarine lowers plasma
LDL in hyperlipidemic subjects with low
cholesterol intake: effect of fibrate treat-
ment. Clin Chem Lab Med. 2001; 39:634-
40.
46. Jakulj L, Trip MD, Sudhop T et al. Inhi-
bition of cholesterol absorption by the
combination of dietary plant sterols and
ezetimibe: effects on plasma lipid levels. J
Lipid Res. 2005; 46:2692-8.
47. Gylling H, Miettinen TA. Serum cho-
lesterol and cholesterol and lipoprotein
metabolism in hypercholesterolemic
NIDDM patients before and during sito-
stanol ester margarine treatment. Diabe-
tologia. 1994; 37:773-80.
48. Zaiken K, Raval KD. Treatment of hyper-
cholesterolemia in pregnancy: risks
versus benefits. J Pharm Technol. 2005;
21:258-61.
49. Latinen K, Isolauri E, Kaipiainen L et
al. Plant stanol ester spreads as compo-
nents of a balanced diet for pregnant
and breast-feeding women: evaluation of
clinical safety. Br J Nutr. 2009; 101:1797-
804.
50. Becker M, Staab D, Von Bergmann K.
Treatment of severe familial hypercho-
lesterolemia in childhood with sitosterol
and sitostanol. J Pediatr. 1993; 122:292-6.
51. Williams CL, Bollella MC, Strobino B et
al. Plant stanol ester and bran fiber in
childhood: effects of lipids, stool weight,
and stool frequency in preschool chil-
dren. J Am Coll Nutr. 1999; 18:572-81.
52. Tammi A, Ronnemaa T, Gylling H et
al. Plant stanol ester margarine lowers
serum total and low density lipoprotein
cholesterol concentrations of healthy
children: the STRIP project. J Pediatr.
2000; 136:503-10.
53. McCrindle BW, Urbina EM, Dennison
BA et al. Drug therapy of high-risk lipid
abnormalities in children and adoles-
cents. Circulation. 2007; 115:1948-67.
54. Gylling H, Siimes M, Miettinen TA.
Sitostanol ester margarine in dietary
treatment of children with familial hy-
percholesterolemia. J Lipid Res. 1995;
36:1807-12.
55. Bhattacharya S. Therapy and clinical tri-
als: plant sterols and stanols in manage-
ment of hypercholesterolemia: where are
we now? Curr Opin Lipidol. 2006; 17:98-
100.
56. Nguyen TT. Reducing cholesterol with
plant stanol esters. Sci Med. 2002; 8(1):28-
35.
57. McPherson TB, Ostlund RE, Goldberg
AC et al. Phytostanol tablets reduce hu-
man LDL-cholesterol. J Pharm Pharma-
col. 2005; 57:889-96.
58. Plat J, Mensink RP. Plant stanol and sterol
esters in the control of blood cholesterol
levels: mechanism and safety aspects. Am
J Cardiol. 2005; 96(suppl):15D-22D.
59. Grundy SM. Stanol esters as a compo-
nent of maximal dietary therapy in the
National Cholesterol Education Program
Adult Treatment Panel III report. Am J
Cardiol. 2005; 96(suppl):47D-50D.
60. Plat J, van Onselen RN, van Heugten M et
al. Effects on serum lipids, lipoproteins,
and fat soluble antioxidant concentra-
tions of consumption frequency of mar-
garines and shortenings enriched with
plant stanol esters. Eur J Clin Nutr. 2000;
54:671-7.
61. Noakes M, Clifton P, Ntanios F et al. An
increase in dietary carotenoids when
consuming plant sterols or stanols is ef-
fective in maintaining plasma carotenoid
concentration. Am J Clin Nutr. 2002;
75:79-86.
62. Raeini-Sajarz M, Ntanios FY, Vanstone
CA et al. No changes in serum fat-soluble
vitamin and carotenoid concentrations
with the intake of plant sterol/stanol
esters in the context of a controlled diet.
Metabolism. 2002; 51:652-6.
63. Law M. Plant sterol and stanol marga-
rines and health. BMJ. 2001; 320:861-4.
64. Richelle M, Ensien M, Hager C et al. Both
free and esterified plant sterols reduce
cholesterol absorption and bioavailability
of beta carotene and alpha tocopherol
in normocholesterolemic subjects. Am J
Clin Nutr. 2004; 80:171-7.
65. Jansen PJ, Lütjohann D, Abildayeva K et
al. Dietary plant sterols accumulate in
the brain. Biochim Biophys Acta. 2006;
1761:445-53.
66. Schiepers OJ, DeGroot RH, vanBoxtel
M et al. Consuming functional foods
enriched with plant stanol or sterol esters
for 85 weeks does not affect neurocogni-
tive functioning or mood in statin treated
hypercholesterolemic individuals. J Nutr.
2009; 139:1360-73.
67. De Jong A, Plat J, Mensink RP. Plant sterol
or stanol consumption does not change
osmotic fragility of the enterocyte. Ath-
erosclerosis. 2004; 5:115s. Abstract.
68. Kozlowska-Wojciechowska M, Jastrzeb-
ska M, Naruszewicz M et al. Impact of
margarine enriched with plant sterols
on blood lipids, platelet function, and fi-
brinogen level in young men. Metabolism.
2003; 52:1373-8.
69. Miettinen TA, Gylling H. Effect of statins
on noncholesterol sterol levels: implica-
tions for use of plant stanols and sterols.
Am J Cardiol. 2005; 96(suppl):40D-46D.
70. Sudhop T, Gottwald BM, von Bergmann
K. Serum plant sterols as a potential risk
factor for coronary heart disease. Metabo-
lism. 2002; 51:1519-21.
71. Fassbender K, Lutjohann D, Dik MG et al.
Moderately elevated plant sterol levels are
associated with reduced cardiovascular
risk—the LASA study. Atherosclerosis.
2008; 196:283-8.
 clinical Consultation  Phytosterols

72. Salen G, Patel S, Batta AK. Sitosterolemia.

Cardiovasc Drug Rev. 2002; 20:255-70.
73. Ostlund RE Jr, McGill JB, Zeng CM
et al. Gastrointestinal absorption and
plasma kinetics of soy-phytosterols and
phytostanols in humans. Am J Physiol
Endocrinol Metab. 2002; 282:E911-6.
74. Burck PJ, Thakkar AL, Zimmerman RE.
Antifertility action of a sterol sulphate in
the rabbit. J Reprod Fertil. 1982; 66:109-
12.
75. Ling WH, Jones PJ. Dietary phytosterols:
a review of metabolism, benefits and side
effects. Life Sci. 1995; 57:195-206.
76. Plat J, Mensink RP. Vegetable oil based
versus wood based stanol ester mixtures:
effects on serum lipids and hemostatic
factors in non-hypercholesterolemic sub-
jects. Atherosclerosis. 2000; 148:101-12.
77. Nguyen T, Dale L. Plant stanol esters
and vitamin K. Mayo Clin Proc. 1999;
74:642-3. Letter.
78. Electronic Code of Federal Regulations.
Title 21, subsection 101.83: health claims:
plant sterol/stanol esters and risk of coro-
nary heart disease (CHD). http://ecfr.
gpoaccess.gov/cgi/t/text/text-idx?c=ecfr
&rgn=div8&view=text&node=21:2.0.1.
1.2.5.1.14&idno=21 (accessed 2010 Mar
18).

Am J Health-Syst Pharm—Vol 67 Jul 15, 2010 1173