European Journal of Internal Medicine 25 (2014) 592–599

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review Article

Nutraceuticals for the treatment of hypercholesterolemia

Massimo R. Mannarino ⁎, Stefano Ministrini, Matteo Pirro
Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Hypercholesterolemia is a well-established modifiable cardiovascular risk factor and its treatment is an essential
Received 13 December 2013 aim in preventing cardiovascular disease. Current guidelines highlight lifestyle intervention as a primary issue in
Received in revised form 7 April 2014 the treatment of the patient with hypercholesterolemia. Therapeutic lifestyle changes are often insufficient to
Accepted 10 June 2014
achieve desirable cholesterol levels. This is particularly true for high risk patients; however, also low risk patients,
Available online 2 July 2014
whose cholesterol levels are not necessarily far from recommended targets, have either sub-optimal or even sig-
Keywords:
nificantly increased lipid levels. Nutraceuticals are borderline devices between nutrients and drugs providing a
Nutraceuticals supplementation of particular nutrients with beneficial effects on health. Several nutraceuticals have been sug-
Hypercholesterolemia gested to improve plasma lipid profile. The literature counted over 40 nutraceutical substances with a supposed
Red yeast rice beneficial effect on lipid metabolism; for some of them a number of clinical trials highlighted a cholesterol low-
Phytosterols ering effect and a possible positive influence on cardiovascular prognosis.
Berberine The aim of this article is to review the main evidences supporting or denying the efficacy and safety of some of the
most commonly used nutraceuticals with supposed cholesterol lowering activity.
© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction adults treated for cardiovascular prevention, hypercholesterolemia is

Cardiovascular disease (CVD) is the foremost cause of death and dis-
ability in the Western countries [1]. Hypercholesterolemia is a well-
established modifiable cardiovascular risk factor and its treatment is
pivotal in preventing CVD. A meta-analysis by Baigent et al. estimated
that every 1.0 mmol/L (38.67 mg/dL) low density lipoprotein cholester-
ol (LDL-C) reduction is associated with a corresponding 22% reduction
in CVD morbidity and mortality [2].
Although the latest AHA/ACC Guidelines on the Treatment of Blood
Cholesterol suggested to abandon the use of risk based cholesterol tar-
gets [3], we have learned from clinical trials and outstanding guidelines
that optimal fasting cholesterol levels change accordingly to the theo-
retical cardiovascular risk of each individual [4]; thus, even average cho-
lesterol levels, when associated with other risk factors, may significantly
increase CVD risk [5].
Low risk patients usually have fasting cholesterol levels slightly
above the recommended therapeutic target. In a population of dyslipid-
emic outpatients, the average distance to the therapeutic goal of
patients at low cardiovascular risk was about 20 mg/dL [6]. This not-
withstanding, most of the low risk individuals presenting non-optimal
levels of fasting cholesterol are undertreated or not treated at all. The
National Health and Nutrition Survey (NHANES) revealed that among
⁎ Corresponding author at: Unit of Internal Medicine, Angiology and Arteriosclerosis
Diseases, University of Perugia, Hospital “Santa Maria della Misericordia”, Piazzale
Menghini, 1-06129, Perugia, Italy. Tel.: +39 075 5783172; fax: +39 075 5784022.
E-mail address: massimo.mannarino@unipg.it (M.R. Mannarino).
the most common risk factor treated in a sub-optimal way [7].
Several reasons might suggest why this group of patients is so poorly
treated. Cholesterol targets are frequently underrated by health care
professionals, drug uptitration is rarely performed, patient's compliance
to drug prescription is limited, and drug intolerance and side effects are
not uncommon; accordingly, a number of patients do not tolerate
statins because of myalgias, muscular or liver toxicity [8,9]. The limited
burden of CV risk of low risk patients with sub-optimal cholesterol
levels and the possible occurrence of adverse reactions, make treatment
of low risk patients with statins a matter of intense debate [10,11].
Current guidelines highlight the key role of lifestyle intervention in
the treatment of patients with increased cholesterol levels [3]. This is
particularly true in patients whose therapeutic targets are reachable
with non-pharmacological measures. Reduction in the amount of nutri-
ents which negatively affect lipid profile is the cornerstone of diet mod-
ification: total fat intake should not exceed 35% of total caloric intake
[12]; intake of saturated fatty acids (SFAs) should be reduced below
6% of total caloric intake and trans-saturated fatty acids below 1%; die-
tary cholesterol intake b200 mg/day is still far to be accepted as a strong
recommendation [3].
Also consumption of foods which favorably affect lipid metabolism
should be encouraged. A number of dietary components are supposed
to improve cholesterol metabolism. These nutrients may be naturally
taken with the diet by increasing the consumption of foods such as
fish, nuts, vegetables and fruits. To achieve a “therapeutic” intake of
healthy nutrients, it could be useful to supplement our diet with either
artificially enriched foods or nutraceuticals; indeed a common diet con-
tains only a modest amount of these nutrients.

http://dx.doi.org/10.1016/j.ejim.2014.06.008
0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
 M.R. Mannarino et al. / European Journal of Internal Medicine 25 (2014) 592–599 593

The term nutraceuticals is a chimerical word, resulting from the fu-
sion of “nutrition” and “pharmaceutical”; it was first formulated by Ste-
phen Defelice in 1989 and according to his definition “nutraceuticals are
food or part of a food that provides medical or health benefits including
the prevention and/or treatment of a disease” [13].
According to the Food and Drugs Administration (FDA) a “dietary
supplement” is a product intended to supplement one or more nutri-
ents, with the intent of increasing their total daily intake [14]. A “func-
tional food” is instead defined as a food product to be taken as a part
of the usual diet in order to have beneficial effects that go beyond
basic nutritional function. Functional foods can be enriched with ingre-
dients that usually are not present in that particular food, or contain an
amount of a specific nutrient larger than usual. FDA regulates dietary
supplements to ensure their safety, wholesomeness and their labeling
to be truthful and not misleading [15].
Similarly, the European Commission regulates the nutraceutical
market through the European Food Safety Authority (EFSA), which
authorizes the labeling of food products with health claims. Basical-
ly a health claim must be based on accepted scientific evidences,
which demonstrate a significant effect in humans and a cause-and-
effect relationship between the consumption of the food and
claimed effect on humans. Producers must declare the target popu-
lation for the intended health claim and the recommended quantity
of nutrient, necessary to obtain the claimed beneficial effect; they
must declare if there are categories of persons who should avoid
using the nutrient [16].
Official position statements and qualified opinions expressed by
EFSA and FDA about the main nutraceuticals used for the treatment of
hypercholesterolemia are summarized in Table 1.
2. Role of nutraceuticals in the treatment of hypercholesterolemia
The literature counted over 40 nutraceuticals with a supposed ben-
eficial effect on lipid metabolism [17]. Some of these substances have
proven efficacy in reducing both serum lipids and CV risk; in addition,
some of them have been demonstrated to affect beneficially surrogate
markers of vascular damage, such as arterial intima-media thickness
(IMT), endothelial dysfunction and arterial stiffness [18].
However many trials investigating the effect of nutraceuticals on
lipid metabolism have important methodological drawbacks in terms
of study design, population characterization and outcome selection.
We tried to select and display the results that appeared, in our opinion,
most reliable; the results that we present are not intended as guidelines
for clinical practice and this article has to be intended rather as an infor-
mative paper.
In Table 2, cholesterol-lowering efficacy of some of the most com-
monly used nutraceuticals is reported.
2.1. Soy derivates
Soybeans contain substances which could have a positive effect in
reducing cardiovascular risk. Soy protein and isoflavones have been in-
tensively studied in the last 30 years because they are supposed to be
responsible of the main beneficial effects of the soy products.
Major isoflavones of soybeans are genistein, daidzin and glycitin and
they are structurally similar to 17-beta estradiol. They bind estrogen A
and B receptors acting as incomplete estrogenic agonists [19].
Most of the studies about the lipid lowering effect of soy derivates,
utilized a variety of soy products, differing amounts of soy protein,

Table 1
Official position statements and qualified opinions expressed by the European Food Safety Authority (EFSA) and U.S. Food and Drugs Administration (FDA) about the main nutraceuticals
used for the treatment of hypercholesterolemia.

Substance EFSA FDA

Soy A cause and effect relationship has not been established between the consumption The addition of soy protein to a diet that is low in saturated fat and
of isolated soy protein and a reduction in blood LDL-cholesterol concentrations. cholesterol may help to reduce the risk of CHD.
[92] The food product shall contain at least 6.25 g of soy protein per
reference amount customarily consumed of the food product.
[93]
Dietary fibers No established cause and effect relationship between the consumption of dietary The addition of soluble fiber to a diet that is low in saturated fat and
fiber and blood cholesterol concentration. cholesterol may help to reduce the risk of CHD.
[94] Dietary intake levels associated with reduced risk of CHD are:

– ≥3 g/day of [beta]-glucan soluble fiber from either whole oats or

barley, or a combination of whole oats and barley.
– ≥7 g/day of soluble fiber from psyllium seed husk.
[95]
Plant sterols & stanols A daily intake of 3 g (range: 2.6–3.4 g) in matrices approved by the Regulation Plant sterol/stanol esters may reduce the risk of CHD.
(EC) No. 376/2010 (yellow fat spreads, dairy products, mayonnaise and salad Plant sterol/stanol esters in the diet help to lower blood total and LDL
dressings) lowers LDL-cholesterol by 11.3% (95% CI: 10.0–12.5). The minimum cholesterol levels.
duration required to achieve the maximum effect on LDL-cholesterol lowering is 2 Daily dietary intake levels associated with reduced risk of CHD are:
to 3 weeks.
– ≥1.3 g/day of plant sterol esters.
[96]
– ≥3.4 g/day of plant stanol esters.
[97]
Policosanol Inconsistent effects on total and LDL-cholesterol concentrations; there is no This product is not intended to diagnose, treat, cure, or prevent any
evidence of a mechanism by which policosanols from sugar cane wax could exert disease.
the claimed effect. [99]
A cause and effect relationship has not been established between the consumption
of policosanols from sugar cane wax and maintenance of normal blood
LDL-cholesterol concentrations.
[98]
Red yeast rice A cause and effect relationship has been established between the consumption of The red yeast rice powder contains greater than 0.4% lovastatin
monacolin K from red yeast rice and maintenance of normal blood LDL cholesterol (monacolin K).
concentrations. The U.S. District Court for the District of Utah affirmed that red yeast rice
Daily dietary intake levels associated with the claimed effect: 10 mg of monacolin products that contain significant amounts of lovastatin are subject to
K from fermented red yeast rice preparations. regulation as drugs and are not dietary supplements.
[100] [101]
Berberine No publication available. This product is not intended to diagnose, treat, cure, or prevent disease.
[102]
 594
Table 2
Lipid-lowering efficacy and proposed cardiovascular and additional effects of some of the most commonly used nutraceuticals.

Substance Mechanism of action Lipid-lowering effect Effects on cardiovascular events/mortality Additional proposed effects

M.R. Mannarino et al. / European Journal of Internal Medicine 25 (2014) 592–599

Soy • Incomplete estrogenic agonists (isoflavones). • ↓TC: 9% Soy products Isoflavones
• Substitute for animal protein. • ↓LDL-C: 12.9% Ischemic stroke: −34% ↑ BMD in post-menopausal osteoporosis
• ↓TGs: 10.5% [21] Myocardial infarction: −45% [26] Relieve of vasomotor symptoms of menopause
Isoflavones Prevention of breast, endometrium and prostate cancer
Ischemic stroke: −65%
Myocardial infarction: −63% [26]
Dietary fibers • Bile acid sequestrants. • ↓TC: 1.75 mg/dL per 1 g of intake Coronary events: −14% ↓ Body weight
• Up-regulation of LDLR. • ↓LDL-C: 2.2 mg/dL per 1 g of intake [29] Coronary deaths: −27% [34] ↓ Waist circumference
• Increased clearance of LDL. ↓ Blood pressure
• Inhibition of hepatic fatty acids synthesis. ↓ Fasting glucose
• Reduced absorption of macronutrients. (in high-risk subjects with either type 2 diabetes or
• Improved intestinal motility. at least 3 CVD risk factors)
• Improved insulin sensitivity.
• Increase satiety with an overall lower energy intake.
Plant sterols & stanols • Inhibition of cholesterol absorption. • ↓TC: 18.8 ± 4.8 mg/dL [45] Unknown Anti-inflammatory
• Up-regulation of sterol transporters ABCG5 & ABCG8. • ↓LDL-C: Activation of cellular stress responses
– 32.5 ± 5.8 mg/dL [45] Reduction of apoB-48 secretion from intestinal and hepatic cells
– 10–11% [46] Reduction of cholesterol synthesis
– 23% [48]
Policosanol • Inhibition of HMG-CoA reductase expression (?). • ↓TC: 0–23% Unknown ↓ LDL oxidation
• ↓LDL-C: 0–28.1% ↓ Platelet aggregation
• ↓TGs: 0–17.4% ↓ Smooth muscle cell proliferation
• ↑HDL-C: 0–29% [58–61]
Red yeast rice • HMG-CoA reductase inhibition (monacolin K). • ↓TC: 16–31% Total mortality: −33% Suppression of adipogenesis by regulating a transcription
• Contains beta-sitosterol and capesterol, unsaturated • ↓LDL-C: 22–32% Cardiovascular deaths: −30% [68] factor in 3T3-L1 cells
fatty acids, fiber and niacin. • ↓TGs: 0–36% Coronary revascularization: −33% Decreasing glycerol-3-phosphate dehydrogenase activity
• ↑HDL-C: 0–20% [66]
Berberine • Increased expression and half-life of LDLR (activation on • ↓TC: 24 mg/dL Unknown Inhibition of hepatic cholesterol and TGs synthesis through
c-jun/JNK and ERK pathways; down-regulation of PCSK-9) • ↓LDL-C: 25 mg/dL the activation of AMP-activated protein kinase (AMPK)
• ↓TGs: 44 mg/dL
• ↑HDL-C: 2 mg/dL [80]
 M.R. Mannarino et al. / European Journal of Internal Medicine 25 (2014) 592–599
differing criteria for selecting subjects, and a variety of protocols. A
meta-analysis of 29 controlled trials by Anderson et al. [20] showed
that an average soy protein consumption of 47 g/day reduced total cho-
lesterol (TC) by 9%, LDL-C by 12.9% and triglycerides (TGs) by 10.5%
with a non-significant effect on high density lipoprotein cholesterol
(HDL-C).
In 22 randomized trials reviewed by the American Heart Association
(AHA) in 2006, dietary supplements containing isolated soy protein with
isoflavones decreased LDL-C levels by about 3%, this small reduction
being minimal compared with the large amount of soy protein tested
in these studies, approximately 50 g (about 50% of the total daily protein
intake). No significant effect was evident on HDL-C, TGs, lipoprotein(a)
or blood pressure [21]. Thus, the AHA Nutrition Committee released a
scientific advisory, which partially attenuated the former opinion on
soy derivates.
Some evidences show that the cholesterol-lowering effect of soy
derivates is about completely due to soy proteins, isoflavones having
only a marginal effect on blood lipids [22]; thus, use of isoflavone sup-
plements in food or pills is not currently recommended by AHA. Indeed,
soy proteins, washed with alcohol to remove isoflavones, were com-
pared with various animal proteins and they were found to reduce
LDL-C by 2% to 7% [23].
Also, products containing whole soybeans might be beneficial be-
cause of their content of polyunsaturated fatty acids, fibers, vitamins,
and minerals and their low content of saturated fat; thus, replacing
foods rich in animal protein and SFAs with soy products might have
beneficial effects on LDL-C [23]. The latter hypothesis has been support-
ed by the results of a wide epidemiological Japanese trial, the Japan Pub-
lic Health Center-Based (JPHC) Study [24], which recruited a cohort of
Japanese subjects without cardiovascular disease. Women eating soy
products more than 5 times per week had a 34% reduced risk of ische-
mic stroke and 45% reduced risk of myocardial infarction compared to
those eating soy products twice per week or less. Such a significant re-
duction has been observed only among women. In the same study, the
dietary intake of isoflavones was related, in a dose-dependent manner,
with a significant reduction of both ischemic stroke and myocardial in-
farction in women (65% and 63%, respectively). This relationship is even
more evident among post-menopausal women. Therefore, the debate
about soy isoflavones remains open.
2.2. Dietary fibers
Dietary fibers are classified into 2 major groups depending on their
solubility in water: lignins, cellulose and some hemicelluloses are insol-
uble, whereas pectins, gums and mucilages are soluble [25].
More than 50 years ago Keys et al. [26] observed that some type of
dietary fibers can decrease plasma cholesterol in humans. The lipid low-
ering mechanism of dietary fibers is still unclear. It has been suggested
that they may act as bile acid sequestrants; also, they may up-regulate
LDL hepatic receptors, increase LDL clearance, inhibit hepatic fatty acid
synthesis, reduce intestinal macronutrient absorption, and improve in-
testinal motility and insulin sensitivity; finally fibers might increase sa-
tiety and reduce overall energy intake [27].
The degree of cholesterol reduction caused by dietary fibers is still
controversial because of the lack of homogeneity in trial design and re-
sults. Brown et al. [27] reviewed 67 controlled trials including 2990 sub-
jects to quantify the cholesterol lowering effect of soluble dietary fibers.
An intake of 2 up to 10 g/day of soluble fiber reduced TC by 1.75 mg/dL
per 1 g of fibers and LDL-C by 2.2 mg/dL per 1 g of fibers, with no signif-
icant difference between the types of soluble fibers.
Several studies support the theory of soluble fibers being able to ac-
tively reduce total and LDL-cholesterol, whereas water-insoluble fibers
have no cholesterol lowering effect, but increase satiety and promote
bowel motility [28,29].
The effect of fibers in reducing the cardiovascular risk has been
assessed. The Health Professionals Follow-up Study, demonstrated
595
that only cereal fiber, not fruit or vegetable fiber, is inversely associated
with total cardiovascular risk [30]. In particular the Iowa Women's
Health Study highlighted that the beneficial effects of wholegrain are
more evident than any other source of fiber [31].
In a pooled analysis of 11 prospective cohorts, a 10 g/day increase in
total dietary fiber intake was associated with a 14% decrease in the risk
of coronary events and a 27% decrease in the risk of coronary death [32].
In a high-risk cohort of subjects with either type 2 diabetes or at least 3
CVD risk factors [33], the PREDIMED feeding trial sub-study showed
that the increase of dietary fiber intake associates with significant re-
ductions in body weight, waist circumference, blood pressure, and
fasting glucose and with an increase in HDL-cholesterol levels.
Based on the cumulative data, the U.S. Dietary Reference Intakes rec-
ommended an intake of 38 g/day of fiber for males and 25 g/day for
females [34].
There are many functional foods enriched both with soluble and in-
soluble fibers available on trade, such as juices, yogurt, and cereal bars.
Concentrate soluble fibers derived from algae, such as psyllium, nori or
kombu, are available as over-the-counter products. In a meta-analysis
of 8 studies, consumption of 10.2 g psyllium/day lowered serum total
cholesterol by 4% and LDL cholesterol by 7% [35].
2.3. Plant sterols and stanols
Phytosterols and their saturated derivatives stanols, are naturally oc-
curring substances found in plants [36]. They are structurally similar to
human cholesterol, but they are poorly absorbed in the intestinal tract.
More than 40 plant sterols have been identified.
They have a higher affinity than cholesterol for mixed micelles, thus
competing with cholesterol for intestinal absorption [37]; furthermore,
they upregulate the sterol transporters ATP-binding cassette subfamily
G member 5 (ABCG5) and ABCG8 [38], thus further reducing cholesterol
absorption.
Other possible effects of phytosterols include reduction of apoB se-
cretion from enterocytes and hepatocytes [39], reduction of cholesterol
synthesis, activation of cellular stress responses and modulation of the
inflammatory cascade [40].
The cholesterol lowering effect of plant sterols is known since the
1950s [41]. In 1977 Mattson et al. [42] suggested the esterification pro-
cess to make plant sterols soluble in dietary fat; esterified phytosterols
have been added to margarines, sauces, yogurt, cream cheese and cereal
bars.
In a multicenter controlled trial, a 6 week treatment with a
phytosterol-enriched dairy product significantly reduced TC by
32.5 ± 5.8 mg/dL and LDL-C by an average of 18.8 ± 4.8 mg/dL,
with a greater reduction in individuals with higher LDL-C levels [43].
A meta-analysis of 41 trials showed that intake of 2 g/day of sterols
or stanols may reduce LDL-C concentrations by about 10%, with a negli-
gible additional effect at doses higher than 2.5 g/day [44]. A more recent
meta-analysis by Amir Shaghaghi et al. [45] showed a reduction of LDL
cholesterol by 12 mg/dL by using plant sterols/stanols with a dose rang-
ing from 1.0 to 3.0 g/day.
Several studies performed on children with familial hypercholester-
olemia (FH) showed that phytosterol supplementation may achieve a
reduction in LDL-C comparable to that experienced in adults [46,47].
The use of phytosterol enriched foods is not advised for children
under 6 years [48].
The combination of phytosterols with statin therapy has been tested
in adults with different forms of dyslipidemia obtaining a further reduc-
tion in LDL-C by 10 to 16% [49–51].
Though the effects of treatment with plant sterols and stanols on lipid
metabolism are well established, whether phytosterol consumption is
associated with a reduction in the risk of CVD needs to be elucidated.
Several studies investigated the effects of a plant sterol and stanol
supplemented diet on markers of early atherosclerosis such as carotid
596 M.R. Mannarino et al. / European Journal of Internal Medicine 25 (2014) 592–599
intima media thickness [52], flow mediated dilation [53], and arterial
stiffness [54], obtaining conflicting results.
Although there are no randomized, controlled clinical trial data with
hard end-points to establish clinical benefit from the use of plant sterols
or plant stanols, the European Atherosclerosis Society consensus panel
on Phytosterols [48] has recently stated that functional foods with
plant sterols/stanols may be considered in individuals with high choles-
terol levels at intermediate or low global cardiovascular risk in whom
pharmacological therapy is not indicated. Moreover, they may be asso-
ciated with pharmacologic therapy in high and very high risk patients
who fail to achieve LDL-C targets on statins or are statin-intolerant,
and finally as a potential adjunct to lifestyle advice and diet in adults
and children (N 6 years) with familial hypercholesterolemia.
A possible disturbance in the absorption of fat-soluble vitamins dur-
ing phytosterol treatment was claimed. Vitamins A, D and K do not seem
to be affected by the use of sterols, whereas the circulating levels of ca-
rotenoids, alpha-tocopherol and lycopene are reduced [55]. Reduced
circulating levels of carotenoids might be associated with a higher inci-
dence of CVD, certain cancers and macular degeneration [56]; however,
no evidence of increased CVD risk, cancer and macular degeneration,
has been described after phytosterol enriched foods were consumed.
2.4. Policosanol
Policosanol is the common name used to address a mixture of 8
long-chain aliphatic alcohols derived from fermentation of sugarcane,
rice, wheat germ or sunflower seed [17]. Lipid lowering properties
were described in 1991 in a Cuban study and, until 2004, medical liter-
ature on this topic was mainly produced in Havana [57]. In these studies
a comparable lipid lowering efficacy of policosanol and statins has been
described, with an even greater efficacy in raising HDL-C and a lower
rate of side effects for policosanol. Reported reductions in TC, LDL-C
and TGs were 14.8–23%, 11.3–28.1% and 5.2–17.4%, respectively; HDL-C
was increased by 2.2–29% [58]. The mechanism of action of policosanol
is still unclear; the down-regulation of cellular expression of hydroxy-
methyl-glutaryl coenzyme A (HMG-CoA) reductase was proposed [59].
Lipid lowering is not the only hypothesized beneficial effect of
policosanol; other effects have been proposed, such as slowing of
LDL oxidation, inhibition of platelet aggregation and smooth muscle
cell proliferation [58].
More recently, studies performed outside Latin America have dem-
onstrated a lack of efficacy of policosanol in reducing cholesterol. In par-
ticular 3 placebo-controlled trials failed to demonstrate any significant
lipid-lowering effect of different doses of policosanol, independently
from its dosage [59–62]. Thus, policosanol is not recommended as
monotherapy for the treatment of hypercholesterolemia.
2.5. Red yeast rice
Red yeast rice (RYR) is a fermented product of rice used for centuries
in China to make rice wine, as a flavor enhancer, as a food colorant and
to “promote digestion and circulation” [63]. In 1895 the yeast Monascus
purpureus was isolated from RYR [64] and in 1979 Endo [65] discovered
a substance produced by M. purpureus, named monacolin K, which in-
hibits cholesterol synthesis with a statin-like mechanism of action.
Lipid lowering properties of RYR have been well documented by
many randomized trials. Placebo-controlled studies demonstrated a
dose-dependent effect on plasma serum lipids, with a 16% to 31% reduc-
tion in TC, a 22% to 32% reduction in LDL-C, and a 0% to 36% reduction in
TGs. HDL-C was variably affected with a null up to 20% increase [66].
This effect might be only partially attributable to monacolin K con-
tent of RYR. Indeed, RYR contains about 10 different monacolins, all
having a supposed inhibitory activity on HMG-CoA reductase. Further-
more, RYR contains beta-sitosterol and campesterol, and it might sup-
press adipogenesis by regulating a transcription factor in 3T3-L1 cells
and decreasing glycerol-3-phosphate dehydrogenase activity. RYR also
contains unsaturated fatty acids, fiber, and vitamin B3 (niacin), all of
which are thought to play a role in reducing serum cholesterol levels
[67].
The China Coronary Secondary Prevention Study explored the possi-
ble role of RYR in reducing cardiovascular risk [68]. This trial recruited
4870 patients with a history of acute myocardial infarction and hyper-
cholesterolemia. Patients were randomized to receive Xuezhikang, a
partially purified extract of RYR, or placebo for an average period of
4.5 years. Treatment with RYR significantly decreased total mortality
by 33%, cardiovascular deaths by 30% and the need for coronary revas-
cularization by 33%. Not only numerous important prognostic data but
also ethical and methodological concerns were derived from this
study. Indeed, high risk patients did not receive during the trial lipid
lowering drugs approved for secondary prevention, such as a statin. Fur-
thermore only Chinese patients were recruited in this multicenter
study; thus, results could not be applicable either to different ethnic
groups or to patients living in different geographical areas [69].
A placebo-controlled randomized trial by Becker et al. [70] on 62 pa-
tients in primary prevention who had discontinued at least one statin
because of myalgias showed no difference in recurrence of myalgias be-
tween the group treated with RYR and that receiving placebo. This re-
sult is relevant if compared with the 57% recurrence rate of myalgias
in patients that were challenged with a second statin [71].
In a meta-analysis of 93 clinical trials with 3 different RYR prepara-
tions, myalgia was not reported as a possible side effect, and a small pro-
portion of participants suffered from slightly increased ALT levels [72]. It
is unclear why RYR may be better tolerated than statins in patients with
statin-associated myalgia (SAM). Incidence of SAM is dose-related;
usual doses of RYR do not exceed 3.6 g/day, equivalent to 6 mg of
monacolin K and far below the established therapeutic dose of lovastat-
in (20–40 mg/day). It is therefore probable that doses of monacolin K
usually contained in RYR derivates are below the threshold necessary
to cause SAM. All this evidence has raised the interest on RYR as a wor-
thy therapeutic tool in patients with SAM.
Safety of different commercial preparations containing RYR prod-
ucts is still a matter of debate. There is, indeed, a wide variability of com-
position among commercial products containing RYR. For instance, a
study by Gordon et al. [73] analyzed the amount of monacolins in 12
commercially available products; although commercial preparations
were labeled as containing 600 mg of RYR per capsule, the authors re-
ported a high variable monacolin K content ranging from 0.31 to
11.15 mg/capsule.
Furthermore, some RYR products were found to contain citrinin [74],
a mycotoxin produced by several Monascus, Penicillium and Aspergillus
species, which can cause kidney failure in animals and whose effects
on human health are still unknown [75]. A strict control by regulatory
authorities on manufacturing and production workflow is needed to as-
sure patients' safety and wellness.
2.6. Berberine
Berberine is an isoquinoline alkaloid extracted from many herbal
plants (i.e. Coptis chinensis, Cortex phellodendri, Caulis mahoniae).
Beneficial metabolic effects of berberine have been intensively stud-
ied both in vitro and in vivo. Anti-diabetic, anti-obesity and lipid lower-
ing properties of berberine have been described [76]. The mechanism of
action of berberine is still debated: an increased expression and half-life
of the LDL receptor (LDLR) on the surface of hepatocytes have been de-
scribed [77]. Activating JNK/c-jun pathway, berberine increased the
transcriptional activity of the LDLR promoter and, acting on ERK signal-
ing pathway, it stabilizes LDLR mRNA [78]. The net result is an increased
expression of the LDLR.
In vitro studies in human hepatoma-derived cell lines (HepG2 and
Huh7 cells) showed that BBR decreased the expression of proprotein
convertase subtilisin/kexin type 9 (PCSK9); since PCSK9 mediates
LDLR lysosomal degradation, berberine inhibition of PCSK9 should
 M.R. Mannarino et al. / European Journal of Internal Medicine 25 (2014) 592–599
thus enhance LDL clearance [79]. Also, berberine may reduce plasma
lipids inhibiting hepatic cholesterol and TG synthesis through the acti-
vation of AMP-activated protein kinase, which in turn inactivates
HMG-CoA reductase [80].
Lipid lowering effects of berberine have been reviewed by Dong et al.
[81] in a meta-analysis of 11 randomized controlled trials involving 874
patients with hypercholesterolemia, type 2 diabetes mellitus or both
conditions. Berberine intake ranged between 0.5 g and 1.5 g/day. The
pooled results showed a significant difference between the berberine
treated groups and the control groups with an average decrease in TC,
LDL-C and TGs of 23.5 mg/dL, 25.1 mg/dL and 43.8 mg/dL respectively.
HDL-C was significantly increased by 1.93 mg/dL in average. Adding
berberine to simvastatin produced an additional reduction of total cho-
lesterol, LDL-C and TGs, with no effect on HDL-C when compared to sim-
vastatin alone [82]. These results have been observed in patients with
primary hypercholesterolemia treated with simvastatin 20 mg/day
plus berberine 1 g/day, suggesting that berberine might strengthen
in vivo the reduction of plasma LDL-C induced by the statin treatment.
The effect of berberine in reducing the risk of CVD needs to be
explored.
Side effects of berberine have been reported; these might include
constipation, diarrhea, abdominal distension and bitter taste in the
mouth [81]. Since repeated oral administration of berberine decreases
CYP2D6, CYP2D9 and CYP3A4 activities in healthy subjects [83], possi-
ble herb–drug interactions should be taken into account.
2.7. Nutraceutical combinations
The combination of different nutraceuticals is often used in commer-
cial products in order to exploit potential synergistic effects of different
agents on cholesterol metabolism. Important limitation of studies inves-
tigating the effect of nutraceutical combination on lipids should be
taken into consideration, since most of the trials were short, conducted
by single centers, often in open and on a not very large number of pa-
tients. Nevertheless, the results of these studies reveal interesting
data. In a single center, single blind study, Cicero et al. [84] showed
that a 4 week treatment with an association of red yeast rice, berberine
and policosanol (RR/BBR/P) in patients with mild hypercholesterolemia
reduced LDL-C by 25%, with significant reduction also in apoprotein B
and triglyceride levels compared to placebo controls.
In a single center, randomized, double-blind, placebo-controlled
study Affuso et al. [85] reported that the RR/BBR/P combination reduced
TC, LDL-C and TGs in hypercholesterolemic patients and a statistically
significant reduction of insulin-resistance was described (HOMA index
reduction from 3.3 at baseline to 2.5). A possible LDL-C reduction up
to 20–30% has been observed in other trials performed with RR/BBR/P
[85–87].
The lipid lowering efficacy of the RR/BBR/P combination was com-
pared to a pharmacological treatment with ezetimibe in a single center,
unblinded trial, involving subjects with polygenic hypercholesterol-
emia, who were previously found intolerant to statins [88]. Treatment
with RR/BBR/P permitted the achievement of the LDL-C target of
130 mg/dL in a larger number of patients than that with ezetimibe
(28.9% vs 11.8%).
RR/BBR/P was tested also in patients with heterozygous familial hy-
percholesterolemia on top of a standard treatment with statin or statin
plus ezetimibe; adding the nutraceutical combination allowed these pa-
tients to further reduce TC, LDL-C, non-HDL-C and TG levels by 8.1%,
10.5%, 9.7% and 5.4% respectively.
Guardamagna et al. [89] tested a combination of RYR and policosanol
vs placebo in children with heterozygous familial hypercholesterolemia
and familial combined hyperlipidemia obtaining a reduction in LDL-C by
25.1%, with no detected alteration in liver and muscular enzymes.
Becker et al. [90] observed no significant difference in LDL-C reduc-
tion, by using an association of high-dosage RYR and fish oil or simva-
statin 40 mg/day in patients with hypercholesterolemia.
597
A placebo-controlled trial failed in demonstrating a further benefit in
adding phytosterols 900 mg/day to RYR 1800 mg bid [91].
Some small, single center trials investigated the effect of RR/BBR/P
combination on markers of subclinical atherosclerosis. Hypercholester-
olemic patients treated with RR/BBR/P underwent a reduction in aortic
pulse wave velocity, a marker of arterial stiffness. Such a reduction was
correlated with the reduction in LDL-C [85]. Radial flow-mediated dila-
tion, was increased by 3% in patients with polygenic hypercholesterol-
emia [84] treated with RR/BBR/P.
3. Potential clinical use of cholesterol lowering nutraceuticals
Non-pharmacological treatment should be the basis of therapy in
each patient with dyslipidemia. Similarly, all patients with dyslipidemia
may obtain a theoretical beneficial effect in assuming dietary supple-
ments or functional foods which positively affect the lipid profile, in
combination with a lipid lowering lifestyle. Although no trial has current-
ly demonstrated a beneficial effect of nutraceutical enriched diets on car-
diovascular events, there is strong evidence that reducing cholesterol by
different mechanisms may contribute to reduce cardiovascular risk. On
the basis of this assumption, cholesterol-lowering nutraceuticals may
find a place in the clinical management of hypercholesterolemic patients.
Some categories of patients are candidates to obtain a greater bene-
ficial effect from a lipid lowering treatment including nutraceuticals. Di-
etary supplements and functional foods could be an intermediate step
of treatment in patients for whom pharmacological therapy is not rec-
ommendable as first line treatment, for example in patients at low car-
diovascular risk. Furthermore, they can be a worthy alternative for those
patients who cannot receive a first line pharmacological treatment, for
instance patients intolerant to statins, even in association with other
pharmacological treatments. At last, they might be useful, as additional
treatment, for those patients who cannot achieve acceptable serum lipid
levels in spite of a maximal pharmacological treatment, such as hetero-
zygote adults for familial hypercholesterolemia.
Nutraceutical agents, alone or in combination, have been often used
in children with familial hypercholesterolemia, with an efficacy and
safety profile similar to that observed in adults.
4. Conclusions
Nutraceutical dietary supplements have different levels of efficacy in
modifying the plasma lipid profile.
While contrasting results on the lipid lowering effects of soy deriva-
tives, dietary fibers and policosanols were presented in this review, the
cholesterol lowering effect of phytosterols and RYR (alone or in combi-
nation with other nutraceuticals) appeared to be more convincing.
Available data on these products show significant and repeatable 10 to
20% cholesterol reduction in patients with polygenic hypercholesterol-
emia or heterozygous familial hypercholesterolemia, in patients with
statin-associated myopathy and in children. Moreover, some evidence
suggests that the cholesterol lowering effect of RYR is paralleled by a
positive influence on surrogate cardiovascular endpoints. Most of the
reviewed nutraceutical supplement preparations have been tested in a
large number of hyperlipidemic patients, allowing ascertaining a funda-
mental safety of these products. Thus, RYR and phytosterol preparations
might represent a valuable tool for the management of patients with
hypercholesterolemia.
Although the standards of the evidence based medicine do not allow
definitive conclusions on the use of such nutraceuticals in the clinical
practice, possible areas of use of nutraceuticals have been delineating
in the last years. However long-term cholesterol lowering effect, influ-
ence on hard cardiovascular endpoints and reliability of manufacturing
processes are all relevant issues that need to be further addressed to de-
fine a clear indication to start a treatment with a cholesterol lowering
nutraceutical.
598 M.R. Mannarino et al. / European Journal of Internal Medicine 25 (2014) 592–599
Learning points
• Non-pharmacological treatment is the first line therapy for hypercho-
lesterolemia. Several nutraceuticals have been shown to positively in-
fluence blood cholesterol with negligible side effects.
• Among different nutraceutical substances presented, cholesterol low-
ering effects of plant sterols/stanols and red yeast rice appear the most
convincing.
• The use of nutraceutical products could be considered in hypercholes-
terolemic patients in whom statin therapy is not indicated, e.g. pa-
tients at low cardiovascular risk.
• The influence on cardiovascular endpoints, clinical safety and reliabil-
ity of manufacturing processes of nutraceutical products need to be
addressed by further study to define a clear indication to start a treat-
ment with a cholesterol lowering nutraceutical.
Conflict of interests
None of the authors has any conflict of interest.
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