- Journal of Clinical Lipidology

Journal of Clinical Lipidology (2014) 8, 61–68
Nutraceutical approach to moderate cardiometabolic risk:
Results of a randomized, double-blind and crossover study
with Armolipid Plus
Massimiliano Ruscica, PhD, Monica Gomaraschi, PhD, Giuliana Mombelli, MD,
Chiara Macchi, PhD, Raffaella Bosisio, MD, Franco Pazzucconi, MD,
Chiara Pavanello, PhD, Laura Calabresi, PhD, Anna Arnoldi, PhD,
Cesare R. Sirtori, MD, PhD*, Paolo Magni, MD, PhD
Centro Dislipidemie, A. O. Ospedale Niguarda C
a Granda, Milano, Italy (Drs Ruscica, Gomaraschi, Mombelli, Bosisio,
Pazzucconi, Pavanello, Calabresi, Arnoldi, Sirtori, and Magni); Dipartimento di Scienze Farmacologiche e Biomolecolari,
Universit
a degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy (Drs Ruscica, Gomaraschi, Macchi, Pazzucconi,
Calabresi, Sirtori, and Magni); and Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Milano, Milano,
Italy (Dr Arnoldi)
KEYWORDS:
Cardiovascular risk;
HDL-cholesterol;
LDL-cholesterol;
Berberine;
Monacolin K
BACKGROUND: Primary cardiovascular prevention may be achieved by lifestyle/nutrition improvements and specific drugs, although a relevant role is now emerging for specific functional foods and
nutraceuticals.
OBJECTIVES: The aim of this study was to evaluate the usefulness of a nutraceutical multitarget
approach in subjects with moderate cardiovascular risk and to compare it with pravastatin treatment.
SUBJECTS: Thirty patients with moderate dyslipidemia and metabolic syndrome (according to the
Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults) were included in an 8-week randomized,
double-blind crossover study and took either placebo or a nutraceutical combination that contained
red yeast rice extract, berberine, policosanol, astaxanthin, coenzyme Q10, and folic acid (Armolipid
Plus). Subsequently, they were subjected to another 8-week treatment with pravastatin 10 mg/d.
This dosage was selected on the basis of its expected 220% efficacy in reducing low-density lipoprotein-cholesterol.
RESULTS: Treatment with Armolipid Plus led to a significant reduction of total cholesterol (212.8%)
and low-density lipoprotein-cholesterol (221.1%), similar to pravastatin (216% and 222.6%, respectively), and an increase of high-density lipoprotein-cholesterol (4.8%). Armolipid Plus improved the
leptin-to-adiponectin ratio, whereas adiponectin levels were unchanged.
CONCLUSIONS: These results indicate that this nutraceutical approach shows a lipid-lowering activity comparable to pravastatin treatment. Hence, it may be a safe and useful option, especially in conditions of moderate cardiovascular risk, in which a pharmacologic intervention may not be appropriate.
Ó 2014 National Lipid Association. All rights reserved.
* Corresponding author.
E-mail address: [email protected]
Submitted July 8, 2013. Accepted for publication November 4, 2013.
1933-2874/$ - see front matter Ó 2014 National Lipid Association. All rights reserved.
http://dx.doi.org/10.1016/j.jacl.2013.11.003
62
The approach to lipid disorders has recently developed a
keen interest in the metabolic syndrome (MetS), a clinical
condition characterized by a series of cardiovascular (CV)
risk factors, that is, dyslipidemia, arterial hypertension,
hyperglycemia, and central adiposity, which involves .25%
adults in Europe.1 Despite the still ongoing debate about the
factors that lead to the MetS and on the appropriateness of
the diagnosis, correction of the associated risk factors by
lifestyle changes and eventually medications appears to be
of potential value in reducing the rates of morbidity and
mortality in affected subjects.2
The interest for a nutraceutical approach to metabolic
disorders is growing either because few new drugs in this
area are currently reaching the market3 or because patients
with metabolic conditions suitable for a nutraceutical
approach seem to appreciate a therapeutic management
that does not involve drug treatment.4 This is particularly
the case of hyperlipidemias, largely treated with drugs
(eg, statins) of proven efficacy but plagued, in fact, by a
relatively high incidence of clinical side effects, such as
myalgia and myopathy.5
Extracts of red yeast rice (RYR), Monascus purpureus,
have been widely used for therapy of patients with CV disorders in China for centuries, because they contain a family
of naturally occurring statins (monacolins), one of which is
monacolin K/lovastatin, a well-known inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. The
use of RYR extracts in the treatment of hypercholesterolemia is currently well established worldwide.6 Comparative
studies between RYR and statins observed a reduced incidence of muscular side effects with the former treatment.7,8
In view of the moderate cholesterol-lowering effect of
RYR, the addition of berberine has been suggested.9
Berberine is a natural compound from the Chinese folk
medicine, generally indicated for intestinal conditions, but
recently shown to exert a cholesterol-lowering activity.10,11
It is an isoquinoline alkaloid extracted from many herbal
plants (Coptidis rhizoma, Hydrastis canadensis, Berberis
vulgaris) which exerts its lipid-lowering effect by
increasing the hepatic expression of the low-density lipoprotein (LDL) receptor (LDLR) gene at the posttranscriptional level by stabilizing its mRNA,9 in association with
reduced expression of proprotein convertase subtilisin/
kexin type 9.12 Moreover, berberine is able to reduce hepatic total cholesterol (TC) and triglyceride (TG) synthesis
through the activation of adenosine monophosphate–activated protein kinase that leads to the inactivation of
HMG-CoA and acetyl-CoA carboxylase enzymes.13 Combinations of these products are available on the market
and are approved for the management of hyperlipidemia
in different countries.14 Policosanols are also added to
some of these products, although their activity on lipids is
still a matter of debate.15,16 They are a mix of aliphatic alcohols derived from sugar cane (Saccharum officinarum L).
The clinical pharmacology of policosanols is not fully
understood, but findings suggest suppression of HMGCoA reductase and increased LDL cholesterol (LDL-C)
Journal of Clinical Lipidology, Vol 8, No 1, February 2014
degradation via enhanced hepatic binding and internalization.17 Another nutraceutical compound proposed in this
area is astaxanthin, which is a xanthophyll carotenoid
pigment found in marine animals. It inhibits lipid peroxidation and LDL-C oxidation.18
The main objective of the present study was the
evaluation of the effect of treatment with Armolipid Plus
(Rottapharm S.p.A., Monza, Italy), a nutraceutical combination that contains RYR extract (with 3 mg of monacolin
K), berberine, policosanols, folic acid, coenzyme Q10, and
astaxanthin on a set of biomarkers associated with the
cardiometabolic risk in patients with moderate MetS and
the comparison of its efficacy with pravastatin 10 mg/d, a
standard low-dose statin treatment. Studied biomarkers
include both lipid and glucometabolic profiles, as well as
circulating adipokines and proinflammatory molecules.
Methods
Study design and population
The study was performed at the Centro Dislipidemie
(A. O. Ospedale Niguarda Ca’Granda, Milan, Italy) in the
period from September 2011 to May 2012 and was designed
for a randomized, double-blind, placebo-controlled, crossover trial. The study was conducted in accordance with the
guidelines of the Declaration of Helsinki, and the study
protocol was approved by the ethics committee of A. O.
Ospedale Niguarda Ca’Granda. Written informed consent
was obtained from each subject. After a run-in period of
2 weeks, patients were randomly assigned to receive either
Armolipid Plus (1 pill/d, containing 200 mg of RYR
[equivalent to 3 mg of monacolin k], 500 mg of berberine,
10 mg of policosanols, 0.2 mg of folic acid, 2.0 mg of
coenzyme Q10, and 0.5 mg of astaxanthin; RYR contained
in Armolipid Plus was citrinine and aflatoxins free; the
amount of heavy metals [nickel, arsenic, lead, mercury,
selenium] was below the total amount of 10 ppm) or placebo
(1 pill/d, identical in taste and appearance to the Armolipid
Plus pill and containing microcrystalline cellulose, iron
oxide brown 70, Compritol E ATO (Gattefosse, Saint-Priest,
Lyon, France), magnesium stearate) for 8 weeks. After a 4week break, the second phase was initiated. After a further
4-week washout period, all patients received pravastatin 10
mg/d for 8 weeks. This dosage was selected according to its
expected 220% efficacy in reducing LDL-C.19 Thirty patients, 23 men and 7 women with 3 (n 5 20) or 4 (n 5 10)
of the 5 MetS criteria as listed by the Third Report of the
National Cholesterol Education Program Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults,2 were selected and completed the study. Nobody met all 5 of the MetS criteria. The inclusion criteria
were patients of both sexes, age . 18 years, diagnosis of
MetS, and LDL-C within the range of 130 to 170 mg/dL.
The exclusion criteria were pregnancy; presence of chronic
liver disease, renal disease, or severe renal impairment
Ruscica et al
Nutraceutical approach to cardiovascular risk
treated with antidiabetic medications or insulin; untreated
arterial hypertension; obesity (body mass index; calculated
as weight divided by height squared; kg/m2] $ 30); pharmacologic treatments known to interfere with the study treatment; and patients who were enrolled in another research
study in the past 90 days. All patients were in primary prevention and free from liver/kidney disorders potentially
affecting the response to treatment and were not on any
drug that affected lipid/lipoproteins or glycemic profile,
including thiazolidinediones or corticosteroids. At the time
of the study entry, 16 of 30 patients were on standard antihypertensive treatment, which was maintained for the entire
duration of the study, including washout and pravastatin
periods (Table 1). At the screening visit, subjects were instructed to follow a normocaloric/low-lipid diet (approximately 2000 kcal, consisting of 55% carbohydrates, 20%
proteins, and 25% lipids). Clinical and biochemical evaluations were performed at the beginning and at the end of each
treatment period. At all visits, patients underwent a fasting
blood sampling and a full clinical examination, including
the evaluation of height, body weight, abdominal and hip circumferences, heart rate, and arterial blood pressure. Plasma
samples were immediately separated by centrifugation, and
aliquots were immediately stored at 220 C for subsequent
assays. Primary end point of the study was the reduction
of LDL-C in the Armolipid Plus arm. Secondary end points
were the reduction of total cholesterol and the changes of
other cardiometabolic and inflammatory biomarkers related
to cardiometabolic risk. Data retrieval, analysis, and manuscript preparation were solely the responsibility of the
authors.
63
Table 1 Concomitant medications (unchanged over the
entire study duration)
Medication
Patients, %
ACE-I/ARB
b-Blockers
Diuretics
Calcium antagonists
Allopurinol
Proton-pump inhibitors
Other drugs
46.7
20
20
6.7
23.3
10
46.3
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin
receptor blockers.
AST, and alanine aminotransferase, log-transformations
were used to achieve normality. The effect of either placebo
or Armolipid Plus on the different biomarkers was calculated as follows: mean of intermediate (after 4 weeks)
and final (after 8 weeks) measures minus the baseline measure [ie, mean (LDL4weeks, LDL8weeks) 2 LDLbaseline], and
the differences (expressed as D) were then compared. The
effect of pravastatin on the different variables was evaluated as the absolute variation from baseline and compared
with the effect of Armolipid Plus. Continuous variables
are indicated as mean 6 SD, if normally distributed, or
as median (interquartile range), if not. All differences
were assessed by paired Student’s t test, whereas comparisons between arms were evaluated by 2-sample t test. All
tests are 2-sided, and P values , .05 are considered as statistically significant. Statistical analysis was performed by
using the SAS Software version 9.2 (SAS Inc, Cary, NC).
Biochemical and immunometric assays
TC, TGs, HDL-C, glucose, aspartate aminotransferase
(AST), alanine aminotransferase, gamma-glutamyltranspeptidase, and creatine phosphokinase isoenzymes were
measured by standard enzymatic techniques. LDL-C was
calculated according to the Friedewald formula. Commercial
enzyme-linked immunosorbent assay kits were used according to manufacturer’s specifications to quantify plasma
leptin, adiponectin, resistin, high-sensitivity interleukin-6,
soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, C-reactive protein (all
from R&D System, Minneapolis, MN), and insulin (Millipore, Billerica, MA). The homeostasis model assessment of
insulin resistance (HOMA-IR) index was calculated as
follows: HOMA-IR 5 [fasting glucose (mmol/L) ! insulin/22.5].
Statistical analysis
Assuming a drop-out rate of up to 20%, a sample size of
30 patients will provide a 90% power to deem as significant, with an a level of 0.05 and a within-subject reduction
in LDL-C of 12% 6 20% (mean 6 SD), which is one-half
of the estimated effect of pravastatin 10 mg/d.20 For TGs,
Results
Study population
The main baseline clinical and biochemical data,
including adipokines and inflammatory molecules
(Table 2), indicate that the study subjects showed moderate
dyslipidemia and mild MetS (3/5 or 4/5 MetS criteria), no
relevant insulin resistance, and no relevant systemic lowgrade inflammation. Armolipid Plus and pravastatin treatments were well tolerated by all patients, who did not
report any significant side effects, including gastrointestinal
tract or neuromuscular symptoms. Treatment with Armolipid Plus resulted in an overall reduction of MetS criteria in
21 of 30 subjects (70%), which resulted in ,3 criteria after
intervention in 10 subjects, who thus did not fall within the
MetS definition anymore (data not shown).
Effect of Armolipid Plus treatment on lipid,
metabolic, and inflammatory biomarkers
Primary and secondary end points at baseline did not
differ between the placebo and Armolipid Plus groups
64
Journal of Clinical Lipidology, Vol 8, No 1, February 2014
Table 2 Main baseline clinical and biochemical
characteristics of the study population
Characteristics
Value
No. of participants (men/women)
Age, years
Smokers, n (%)
Weight, kg
BMI
Waist circumference, cm (men;
n 5 23)
Waist circumference, cm (women;
n 5 7)
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Heart rate, bpm
Total cholesterol, mmol/L
LDL-C, mmol/L
HDL-C, mmol/L
TGs, mmol/L
Fasting glucose, mmol/L
Insulin, mU/L
HOMA-IR
Uric acid, mg/dL
CRP, mg/dL
AST, U/L
ALT, U/L
GGT, U/L
CPK, U/L
Leptin, ng/mL
Adiponectin, mg/mL
Resistin, ng/mL
IL-6, pg/mL
sICAM-1, ng/mL
sVCAM-1, ng/mL
30 (23/7)
55.4 6 9.7
11 (36.7)
77.5 6 9.2
26.8 6 2.4
96.3 6 7.9
91.7 6 5.1
123.0 6 12.3
80.7 6 5.7
68.4 6 6.9
6.11 6 0.76
3.83 6 0.57
1.04 6 0.18
2.46 (1.76, 3.39)
4.57 6 1.06
6.1 6 4.1
1.2 6 0.8
5.3 6 1.1
0.21 6 0.23
21.0 (20.0, 23.3)
23.5 (18.8, 32.3)
32.7 6 23.4
106.4 6 36.5
16.5 6 13.1
6.3 6 4.2
8.8 6 3.7
1.4 6 1.2
256.6 6 66.5
969.1 6 276.9
ALT, alanine aminotransferase; AST, aspartate aminotransferase;
BMI, body mass index (calculated as weight divided by height squared;
kg/m2); CPK, creatine phosphokinase; CRP, high-sensitivity C-reactive
protein; GGT, gamma glutamyl transpeptidase; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; IL-6, interleukin 6; IQR, interquartile range; LDL-C,
low-density lipoprotein cholesterol; sICAM-1, soluble intercellular
adhesion molecule-1; SVCAM-1, soluble vascular cell adhesion
molecule-1; TG, triglyceride.
Values are mean 6 SD or median (interquartile range).
(Table 3) or between the Armolipid Plus and pravastatin
groups (Table 4), except for HDL-C, which was slightly
lower at baseline in the Armolipid Plus group, and uric
acid, which was higher at baseline in the pravastatin group.
Clinical parameters (body weight, waist circumference,
systolic blood pressure, diastolic blood pressure, heart
rate) were not affected collectively by treatment with either
placebo or Armolipid Plus (not shown). In the placebo arm,
no significant variation in the biochemical parameters was
observed. Armolipid Plus treatment resulted in a highly significant decrease of TC (–12.8%; P 5 .0001) and LDL-C
(221.1%; P 5 .0001) (Fig. 1) and a significant increase
of HDL-C (4.8%; P , .05), whereas TG levels were
unchanged (Table 3). A small, but significant average increase of AST (5.2%; P , .05) was observed with Armolipid Plus treatment, although it did not exceed the reference
values in any patient. Armolipid Plus treatment reduced
plasma leptin (28.5%; P , .05) and did not affect plasma
adiponectin, producing a trend toward reduction of the
leptin-to-adiponectin ratio (217.8%; P 5 .158). No
changes were found in plasma concentrations of insulin, resistin, interleukin-6, soluble vascular cell adhesion
molecule-1, and sICAM-1 (Table 3). No significant difference in the principal end point was observed between the
crossover arms (Fig. 1), thus ruling out a carry-over effect.
Effects of pravastatin treatment and comparison
with Armolipid Plus treatment
Treatment with pravastatin reduced TC (216%; P 5
.0001), LDL-C (222.6%; P 5 .0001), and uric acid
(25.2%; P 5 .013) (Table 4). A TG reduction (213.4%)
was also observed, although it was not statistically significant (P 5 .08). Pravastatin treatment was also associated
with a significant reduction of plasma adiponectin levels
(211.1%; P 5 .008), increased the leptin-to-adiponectin ratio (12.1%; P 5 .036), and reduced sICAM-1 concentration
(25.2%; P , .015) (Table 4). Armolipid Plus and pravastatin effects were similar on all biochemical parameters,
including a significant reduction of TC and LDL-C, except
for uric acid and AST (both reduced by pravastatin; P ,
.05) and the leptin-to-adiponectin ratio (increased by pravastatin; P , .05).
Discussion
This randomized, placebo-controlled, crossover study in
patients with moderate dyslipidemia and mild MetS
features attempted to explore the potential of Armolipid
Plus, a nutraceutical combination that contains RYR,
berberine, and other components, on TC, LDL-C, and
inflammatory/metabolic markers associated with CV risk.
The treatment was quite effective in reducing TC and LDLC levels, with an efficacy comparable to that of 10 mg of
pravastatin, a standard statin therapy used in our study as a
reference treatment. In addition, Armolipid Plus treatment
had the advantage to reduce leptin concentrations, leaving
adiponectin unchanged, whereas pravastatin treatment produced a reduction of both adiponectin and the leptin-toadiponectin ratio. Treatment with Armolipid Plus also
resulted in an overall reduction of MetS criteria in 21 of
30 subjects.
Armolipid Plus, containing a daily dose of RYR extract
equivalent to approximately 3 mg of monacolin K (lovastatin), in the present report showed comparable or better
results than a series of Chinese randomized controlled
studies,21 based on RYR administration corresponding to
daily intakes of approximately 5 to 10 mg of monacolin
K. In addition, in 2 secondary prevention studies in the
Ruscica et al
Summary of primary and secondary end points (Armolipid Plus and placebo)
Armolipid Plus
Total cholesterol, mmol/L
LDL-C, mmol/L
HDL-C, mmol/L
TGs, mmol/L
Fasting glucose, mmol/L
Insulin, mU/L
HOMA-IR
Uric acid, mg/dL
CRP, mg/dL
AST, U/L
ALT, U/L
GGT, U/L
CPK, U/L
Leptin, ng/mL
Adiponectin, mg/mL
Leptin-to-adiponectin
ratio
Resistin, ng/mL
IL-6, pg/mL
sICAM-1, ng/mL
sVCAM-1, ng/mL
Placebo
Baseline
After 8 wk
P value for withingroup difference*
6.2 6 0.8
3.91 6 0.62
1.04 6 0.23
2.44 (1.93, 3.21)
4.88 6 0.9
6.0 6 4.0
1.3 6 0.9
5.4 6 1.1
0.2 6 0.1
21.0 (19.0, 22.0)
24.5 (16.0, 32.0)
32.2 6 22.6
114.5 6 40.0
16.4 6 13.1
6.3 6 4.4
3.3 6 2.9
5.4 6 0.7
3.09 6 0.66
1.09 6 0.25
2.21 (1.81, 3.17)
4.86 6 0.82
5.4 6 3.3
1.2 6 0.8
5.7 6 1.5
0.2 6 0.1
22.0 (19.0, 24.0)
23.5 (18.0, 30.0)
31.9 6 21.4
117.3 6 53.4
15.0 6 11.3
6.3 6 4.1
2.8 6 2.0
.0001
.0001
.0497
.726
.783
.389
.355
.239
.449
.012
.252
.244
.151
.048
.73
.158
6.2 6 1
3.88 6 0.76
1.07 6 0.19
2.60 (1.95, 3.47)
4.76 6 1.02
6.4 6 4.4
1.3 6 1.0
5.5 6 1.3
0.2 6 0.3
21.0 (20.0, 24.0)
23.5 (18.0, 29.0)
32.8 6 21.8
116.3 6 73.2
16.9 6 13.8
6.4 6 4.5
3.1 6 2.4
.205
.526
.069
.222
9.2
1.6
249.7
973.7
8.7
1.6
249.4
944.1
6
6
6
6
3.6
1.1
65.7
254.4
8.9
1.6
242.1
904.6
6
6
6
6
4.0
1.2
58.9
249.2
Baseline
6
6
6
6
4.0
1.4
59.9
297.9
After 8 wk
P value for withingroup difference* (P)
P value for Comparison
of D Armolipid Plus vs
D placebo
6.3 6 0.9
3.73 6 0.87
1.07 6 0.24
2.42 (1.99, 2.70)
4.79 6 0.81
5.4 6 2.5
1.1 6 0.5
5.7 6 1.3
0.2 6 0.2
20.5 (18.0, 22.0)
22.0 (15.0, 30.0)
30.9 6 19.5
117.4 6 62.7
15.4 6 11.5
6.4 6 4.9
3.0 6 2.3
.904
.617
.756
.973
.784
.068
.266
.679
.764
.205
.201
.997
.768
.377
.926
.158
.0001
.0001
.293
.751
.669
.378
.767
.255
.978
.017
.198
.686
.305
.781
.403
.403
.998
.774
.226
.212
.400
.948
.079
9.2
1.5
255.3
937.7
6
6
6
6
4.5
1.5
66.0
285.9
Nutraceutical approach to cardiovascular risk
Table 3
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; CRP, high-sensitivity C-reactive protein; GGT, gamma glutamyl transpeptidase; HDL-C, high-density
lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; IL-6, interleukin 6; LDL-C, low-density lipoprotein cholesterol; sICAM-1, soluble intercellular adhesion molecule-1;
SVCAM-1, soluble vascular cell adhesion molecule-1; TG, triglyceride.
Values are mean 6 SD or median (interquartile range); n 5 30.
*D 5 mean of intermediate (after 4 weeks) and final (after 8 weeks) measures minus the baseline measure.
65
66
Journal of Clinical Lipidology, Vol 8, No 1, February 2014
Table 4
Summary of primary and secondary end points (10 mg of pravastatin)
P value for
comparison of D
(pravastatin vs
Armolipid Plus)
P value for differences
between baseline of
Armolipid Plus vs
baseline of pravastatin
(pravastatin)
.313
.974
.219
.269
.511
.167
.208
.046
.17
.02
.944
.512
.617
.241
.123
.038
.864
.639
.423
.073
.18
.66
.03
.59
.89
.17
.81
.01
.06
.63
.73
.67
.82
.90
.86
.99
.82
.55
.98
.83
Pravastatin
Total cholesterol, mmol/L
LDL-C, mmol/L
HDL-C, mmol/L
TG, mmol/L
Fasting glucose, mmol/L
Insulin, mU/L
HOMA-IR
Uric acid, mg/dL
CRP, mg/dL
AST, U/L
ALT, U/L
GGT, U/L
CPK, U/L
Leptin, ng/mL
Adiponectin, mg/mL
Leptin-to-adiponectin ratio
Resistin, ng/mL
IL-6, pg/mL
sICAM-1, ng/mL
sVCAM-1, ng/mL
Baseline
After 8 wk
P value for D
from baseline
pravastatin
6.41 6 0.63
3.97 6 0.61
1.10 6 0.23
2.55 (2.18, 3.82)
4.82 6 0.78
6.7 6 5.2
1.5 6 1.3
5.8 6 1.1
0.24 6 0.22
22.0 (19.0, 23.0)
21.0 (18.0, 29.0)
34.4 6 24.3
112.8 6 40.9
16.3 6 13.8
6.3 6 4.5
3.3 6 3.2
8.8 6 3.7
1.6 6 1.3
249.6 6 56.3
951.0 6 312.3
5.38 6 0.63
3.07 6 0.70
1.11 6 0.20
2.43 (1.83, 2.81)
4.68 6 0.9
7.2 6 4.9
1.5 6 1.1
5.5 6 1.3
0.20 6 0.23
20.5 (18.0, 23.0)
23.0 (17.0, 30.0)
32.1 6 24.5
123.8 6 82.9
16.5 6 12.4
5.6 6 3.8
3.7 6 3.2
9.1 6 4.2
1.5 6 1.1
236.7 6 52.5
966.4 6 266.5
.0001
.0001
.767
.08
.462
.363
.224
.013
.205
.399
.964
.686
.870
.805
.008
.036
.232
.605
.015
.562
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; CRP, high-sensitivity C-reactive protein; GGT, gamma
glutamyl transpeptidase; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; IL-6, interleukin 6;
LDL-C, low-density lipoprotein cholesterol; sICAM-1, soluble intercellular adhesion molecule-1; SVCAM-1, soluble vascular cell adhesion molecule-1; TG,
triglyceride.
Values are expressed as mean 6 SD or median (interquartile range) as appropriate; n 5 30.
Chinese population, the investigators used either 2 capsules
of Xuezhikang, containing approximately 2.5 to 3.2 mg of
monacolin K, in the case of a randomized study in middleaged patients with coronary disease22 or 2 capsules of
Xuezhikang, each containing 2.5 to 3.2 mg of monacolin
LDL-C (mmol/L)
4.0
group A
group B
3.5
3.0
2.5
Armolipid Plus
0
4
8
Armolipid Plus
12
16
20
weeks
Figure 1 Time course of LDL-C in the 2 crossover arms (group
A [n 5 14] and B [n 5 16]). Armolipid Plus treatment period is
indicated by the dotted (group B) and the solid (group A) lines.
Data are expressed as mean 6 SD. LDL-C, low-density lipoprotein cholesterol.
K and a small quantity of lovastatin hydroxy acid, in
another study of elderly patients with coronary disease.23
In both studies, LDL-C reduction was comparable, and
remarkable reductions of coronary heart disease incidence
and deaths were observed. The relative decrease of the primary CV end point in the former study was 45% with a
reduction of CV and total mortality of 30% and 32%,
respectively.22 In the latter study, the product reduced the
risk of death from coronary heart disease by 29.2%.23 Other
clinical studies in the Chinese population have reported
daily intakes equivalent to up to 10 or more milligrams
of monacolin K.21 In the United States, RYR daily doses
equivalent to up to 18 mg of monacolin K are allowed by
the Food and Drug Administration as a ‘‘drug’’ treatment,
and reports from the United States indicate daily doses up
to 10 mg of lovastatin are equivalent.7,8 As a general
consideration, it appears necessary to introduce a better
regulation of RYR manufacturing methods.6 In addition
to this well-known lipid-lowering activity of RYR, mainly
related to HMG-CoA reductase inhibition, the concomitant
presence of other nutraceutical ingredients contributes to
the lipid-lowering activity of Armolipid Plus. In particular,
berberine is known to increase the expression of LDLR and
to act as an insulin sensitizer.9,10 LDLR up-regulation
Ruscica et al
Nutraceutical approach to cardiovascular risk
possibly gives a major contribution to the remarkable
cholesterol-lowering activity of Armolipid Plus, which are
equivalent to that of pravastatin 10 mg/d. A recent metaanalysis has evaluated the clinical trials published on
berberine.24 Although the methodologic quality of those
studies was generally low, the final analysis showed that
administration of berberine produced a significant reduction in TC, TGs, and LDL-C, with a remarkable increase
in HDL-C. Thus, the observed 4.8% increase of HDL-C
by Armolipid Plus treatment might possibly depend on
the presence of berberine as well as on that of astaxanthin.
The latter was reported to raise HDL-C and adiponectin
concentrations in subjects with mild hyperlipidemia,18
with a 12% HDL-C increase at the lower dosage tested (6
mg/d).
In addition to the lipid profile, adipose-derived molecules are known to affect CV risk assessment. Armolipid
Plus treatment reduced plasma leptin and did not affect
plasma adiponectin, with an improved (217.8%) leptin-toadiponectin ratio, whereas pravastatin reduced adiponectin
and increased the leptin-to-adiponectin ratio. Interestingly,
reduced adiponectin levels25 and increased leptin-toadiponectin ratios are considered potentially major risk
factors for CV disease. More in detail, the leptin-toadiponectin ratio was found directly correlated with the
intima-media thickness,26 with MetS features,27 and with
prediction of the first CV event in men.28 Among Armolipid
Plus components, it is relevant to observe that RYR negatively affects adipocyte differentiation through the downregulated expression of several adipocyte-specific genes,
including leptin.29 In experimental animals, RYR extracts
were shown to significantly reduce circulating leptin and
to increase adiponectin.30 Clinical evidence indicates that
RYR treatment results in reduced leptin and increased adiponectin plasma levels.31 In patients with MetS, berberine
(300 mg three times daily) was found to reduce plasma leptin and the leptin-to-adiponectin ratio, with a moderate and
nonsignificant increase of adiponectin levels.32 Berberine
has indeed been shown to inhibit adipogenesis in vitro
and to promote the assembly of high molecular weight adiponectin, thus increasing the high molecular weight-to-total
adiponectin ratio, which results in greater insulin
sensitivity.31
Armolipid Plus and nutraceuticals with similar composition, in addition as a treatment alternative to specific
drugs (ie, statins, ezetimibe), might also be useful as add-on
therapy to achieve a greater LDL-C–lowering response as
well as an HDL-C–raising response. Some data with the use
of single components of Armolipid Plus in addition to
statins are already present in the literature. Berberine
improved the lipid-lowering efficacy of simvastatin10; the
effect of policosanols on the lipoprotein profile remains
controversial because recent trials with policosanols in
combination with statins failed in replicating the beneficial
findings observed in the early trials.17 The combination of
RYR/berberine/policosanols and ezetimibe was found
more effective than each treatment alone in reducing
67
LDL-C in subjects with heterozygous familial hypercholesterolemia.33 For the concern about the potential advantages
of such combination on the adipokine profile, it should be
noted that statins have been reported to inconsistently affect
plasma adiponectin levels, possibly because of the specific
compound tested and the different study populations,34,35
making complex the otherwise interesting evaluation of
such combined therapy. To our knowledge, no data are
available on this combination therapy; hence, this issue
needs to be further addressed.
Conclusion
In conclusion, the present report shows that a small dose
of RYR associated with berberine and other nutraceutical
compounds (Armolipid Plus) improves the lipid profile in
an equivalent way to a low dose of a standard statin. In
addition, Armolipid Plus, possibly because of the presence
of astaxanthin, also increases HDL-C levels and improves
the leptin-to-adiponectin ratio. In view of the high interest
of physicians and patients for innovative well-tolerated
treatments for moderate dyslipidemia/MetS, Armolipid
Plus is potentially of significant clinical value in the
management of cardiometabolic risk.
Acknowledgments
The study was supported by an unrestricted grant to
Centro Dislipidemie (A. O. Ospedale Niguarda Ca Granda,
Milano, Italy) from Rottapharm S.p.A. (Monza, Italy). The
expert statistical contribution of Dr. Fabrizio Veglia is
gratefully acknowledged. All authors have seen and have
approved the present study. No authors have any conflict
of interest.
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