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Beneficial effects of artichoke leaf extract supplementation on increasing HDL-cholesterol in subjects with primary mild hypercholesterolaemia: A double-blind, randomized, placebo-controlled trial

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  • University of Pavia, Azienda di Servizi alla Persona

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The aim of this study was to evaluate the effects of artichoke leaf extract (ALE) supplementation (250 mg, 2 b.i.d.) on the lipid pattern. A randomized, double-blind, placebo-controlled clinical trial was performed on 92 overweight subjects with primary mild hypercholesterolaemia for 8 weeks. Forty-six subjects were randomized to supplementation (age: 54.2 ± 6.6 years, body mass index (BMI): 25.8 ± 3.9 kg/m(2), male/female: 20/26) and 46 subjects to placebo (age: 53.8 ± 9.0 years, BMI: 24.8 ± 1.6 kg/m(2), male/female: 21/25). Verum supplementation was associated with a significant increase in mean high-density lipoprotein (HDL)-cholesterol (p < 0.001) and in mean change in HDL-cholesterol (HDL-C) (p = 0.004). A significantly decreased difference was also found for the mean change in total cholesterol (p = 0.033), low-density lipoprotein (LDL)-cholesterol (p < 0.001), total cholesterol/HDL ratio (p < 0.001) and LDL/HDL ratio (p < 0.001), when verum and placebo treatment were compared. These results indicate that ALE could play a relevant role in the management of mild hypercholesterolaemia, favouring in particular the increase in HDL-C, besides decreasing total cholesterol and LDL-cholesterol.
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Beneficial effects of artichoke leaf extract supplementation on increasing
HDL-cholesterol in subjects with primary mild hypercholesterolaemia:
a double-blind, randomized, placebo-controlled trial
MARIANGELA RONDANELLI
1
, ATTILIO GIACOSA
2
, ANNALISA OPIZZI
1
,
MILENA ANNA FALIVA
1
, PATRIZIO SALA
1
, SIMONE PERNA
1
, ANTONELLA RIVA
3
,
PAOLO MORAZZONI
3
, & EZIO BOMBARDELLI
3
1
Section of Human Nutrition, Health Sciences Department, Azienda di Ser vizi alla Persona, University of Pavia, Pavia, Italy,
2
Department of Gastroenterology, Policlinico di Monza, Milan, Italy, and
3
Indena S.p.A., Milan, Italy
Abstract
The aim of this study was to evaluate the effects of artichoke leaf extract (ALE) supplementation (250mg, 2 b.i.d.) on the
lipid pattern. A randomized, double-blind, placebo-controlled clinical trial was perfor med on 92 overweight subjects with primary
mild hypercholesterolaemia for 8 weeks. Forty-six subjects were randomized to supplementation (age: 54.2 ^6.6 years,
body mass index (BMI): 25.8 ^3.9 kg/m
2
, male/female: 20/26) and 46 subjects to placebo (age: 53.8 ^9.0 years, BMI:
24.8 ^1.6 kg/m
2
, male/female: 21/25). Verum supplementation was associated with a significant increase in mean high-density
lipoprotein (HDL)-cholesterol ( p,0.001) and in mean change in HDL-cholesterol (HDL-C) ( p¼0.004). A signifi-
cantly decreased difference was also found for the mean change in total cholesterol ( p¼0.033), low-density lipoprotein
(LDL)-cholesterol ( p,0.001), total cholesterol/HDL ratio ( p,0.001) and LDL/HDL ratio ( p,0.001), when verum and
placebo treatment were compared. These results indicate that ALE could play a relevant role in the management of mild
hypercholesterolaemia, favouring in particular the increase in HDL-C, besides decreasing total cholesterol and LDL-cholesterol.
Keywords: artichoke leaf extract, chlorogenic acid, cholesterol, dietary supplement, HDL cholesterol, luteolin
Introduction
Cardiovascular diseases (CVDs) continue to be the
leading cause of morbidity and mortality in the
industrialized world (Lloyd-Jones et al. 2010).
Although there are many causes for the high
prevalence of CVD, it appears that nutritional factors,
notably high saturated fat consumption, play an
important role in promoting atherosclerosis (Keys
1997). However, one apparent paradox is that the low
saturated fat consumption recommended by several
organizations, including the American Heart Asso-
ciation, the American Diabetes Association and the
American Dietetics Association, often results in
decreasing high-density lipoprotein (HDL) cholesterol
levels (Mensink et al. 2003). This result is not a
favourable one, because epidemiological studies, as
well as studies in animal models of atherosclerosis,
support the cardioprotective role of HDL-cholesterol
(HDL-C) (Gordon et al. 1977; Berliner et al. 1995;
Andersson 1997; Haffner et al. 1998; Turner et al.
1998; Eriksson et al. 1999; Kawahiri et al. 2000;
Mooradian 2003). In addition, interventional trials,
notably the Veterans Affairs High-Density Lipoprotein
Cholesterol Intervention Trial, showed that the
rate of coronary heart disease (CHD) is reduced
by raising HDL-C levels (Rubins et al. 1999; Boden
2000; Goldenberg et al. 2009).
Low-density lipoprotein (LDL)-cholesterol-lowering
drugs and dietary supplements currently used to
ISSN 0963-7486 print/ISSN 1465-3478 online q2012 Informa UK, Ltd.
DOI: 10.3109/09637486.2012.700920
Correspondence: Mariangela Rondanelli, Endocrinology and Nutrition Unit, Section of Human Nutrition and Dietetics, Department of
Applied Health Sciences, Faculty of Medicine, ASP, University of Pavia, Pavia, Italy. Tel: þ39 0382381749. Fax: þ39 0382381218.
E-mail: mariangela.rondanelli@unipv.it
International Jour nal of Food Sciences and Nutrition,
2012; Early Online: 1–9
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improve the serum lipid profile are not effective in
raising HDL-C (Sirtori et al. 2009). Therefore, a great
deal of attention is now dedicated to the study of
bioactive molecules that could increase HDL-C, in
addition to decreasing LDL-cholesterol (LDL-C).
This effect could be achieved by some bioactive
molecules present in artichoke leaves. The pharmaco-
logical properties of artichoke leaf extract (ALE) are
well documented in several studies, and the Cochrane
Database reports that ALE has potential in lowering
cholesterol levels in humans (Wider et al. 2009). The
bioactivity displayed by ALE is strictly related to its
polyphenolic content and this justifies its wide
phytopharmaceutical use (Wegener and Fintelmann
1999; Thompson Coon and Ernst 2003). Chlorogenic
acid, 1,5 and 3,4-di-O-caffeoylquinic acid and cynarin
are the predominant polyphenolic compounds among
hydroxycinnamates of ALE, while the main flavonoids
are apigenin and luteolin, and their glycosides
(Pandino et al. 2010). The cholesterol-lowering effect
of ALE has been demonstrated in animal models
(Ku
¨sku
¨-Kiraz et al. 2010; Qiang et al. 2011) as well
as in humans (Englisch et al. 2000; Lupattelli et al.
2004; Bundy et al. 2008).
Given this background, the aim of the present
randomized, placebo-controlled study was to assess
the efficacy of 8 weeks ALE supplementation on the
HDL-C increase, as the primary end-point, in subjects
with mild hypercholesterolaemia. As secondary end-
points, the decrease in total cholesterol (T-C) and
LDL-C is considered.
Methods
Subjects
The experimental protocol was approved by the
Ethics Committee of the University of Pavia and
volunteers gave their written, informed consent.
Subjects were recruited from Pavia county by
advertisement in a local newspaper and were screened
through a procedure involving a clinical assessment,
an interview and total HDL- and LDL-cholesterol
serum evaluation. Ninety-two subjects, aged 1860
years, with body mass index (BMI) ranging between
19 and 30 kg/m
2
, with mild hypercholesterolaemia
(5.4 –7.0 mmol/l) and no history of CVD, volunteered
for the trial. None of the subjects had ever taken any
medication likely to affect lipid metabolism, and all
of them were free of overt liver, kidney and metabolic
diseases, such as diabetes and thyroid disease. The
screening excluded subjects who smoked or drank
more than two standard alcoholic beverages/day
(20 g of alcohol/day) as well as those who were preg-
nant or lactating, or if they had entered menopause.
Subjects were also excluded if they were taking
medications for weight loss. Physical activity was
recorded and patients were asked to maintain their
usual habit throughout the study period.
Before the beginning of the study (BoS), energy and
nutrient intakes were assessed using the food record
method over a period of 3 days (Forster-Coull et al.
2004). Once the data were collected, the food intake
was converted into energy and nutrients, using the
Dieta Ragionata version 7.0 (Sintesi Informatica,
Milan, Italy). A senior dietician delivered advice to all
the subjects in order to suggest a personalized
isocaloric diet, according to the Step 1 American
Heart Association diet (American Heart Association
1988). The energy and nutrient intakes of all the
volunteers were also assessed after 8 weeks of
intervention, using the food record method over
3 days. Blood pressure was measured at the beginning
and at the end of the study.
Nutritional status
At the beginning and at the end of the study, body
weight was assessed and BMI was calculated. Skinfold
thicknesses (biceps, triceps, suprailiac and subscapu-
lar) were measured twice using a Harpenden Skinfold
Caliper at 5-min intervals in each site following a
standardized technique (Frisancho 1984). Sagittal
abdominal diameter at the L
4–5
level in the supine
position and waist girth was also measured on day 0
and after 8 weeks of intervention. Anthropometric
parameters were always collected by the same
investigator.
Dietary supplement
As subjects were enrolled, they were assigned a
progressive subject number. Identical products for
each treatment group were assigned to a subject
number according to a coded (AB) block randomiz-
ation table prepared by an independent statistician.
Investigators were blinded to the randomization table,
the code assignments and the procedure. Indepen-
dently of the treatment (ALE supplement or placebo),
the subjects followed a similar personalized isocaloric
energy diet. The dietary treatment was associated with
two daily oral assumptions (before lunch and dinner)
of film-coated tablets of 250 mg of standardized ALE
(.20% caffeoylquinic acids, .5% flavonoids and
.5% cynaropicrin, according to WO 2010083968) or
placebo. The tablets were provided by Indena, Milan
and Italy. The supplementation period was 8 weeks.
Compliance to the supplementation regimen was
defined as the number of tablets actually taken by each
subject, divided by the number of tablets that should
have been taken over the course of the study.
Analyses
Fasting blood samples were collected between 07.45
and 10.00 am on day 0 and after 8 weeks in both study
arms for the evaluation of LDL-C, T-C, HDL-C,
triglycerides (TG) and glucose. Moreover, the fasting
M. Rondanelli et al.2
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blood HDL-C was evaluated 8 weeks after the end
of the intervention. The study design is shown in
Figure 1.
In order to avoid venipuncture stress, blood samples
were obtained through an indwelling catheter inserted
in an antecubital vein. Blood samples were immedi-
ately centrifuged and stored at 2808C until assayed.
Fasting blood glucose, T-C, LDL-C, HDL-C and TG
levels were measured by an automatic biochemical
analyser (Hitachi 747, Tokyo, Japan). All assays were
carried out on Cobas Mira Plus
w
(Roche Diagnostic
Systems, Welwyn Garden City, UK) equipment using
a standard control serum to ensure accuracy of
measurements. Finally, for the assessment of safety,
routine blood biochemistry parameters (blood cell
count, serum protein electrophoresis, serum creati-
nine, liver and thyroid function) were evaluated with
routine methods at the beginning and at the end of
the intervention.
Statistical methods
All statistical analyses were carried out by the SAS
w
System version 9.2, choosing 5% ( p#0.05) as the
threshold value of statistical significance.
A 0.2 mmol/l standard deviation of changes in
HDL-C after 8 weeks of intervention has been drawn
from our unpublished data, in absence of published
data on the effect of ALE on HDL-C in humans.
A difference of 0.12 mmol/l at least in HDL-C
between the intervention and the placebo group at
the end of the treatment was considered clinically
relevant. Assuming a 5% type I error (two tailed
alpha ¼0.05), the sample size of 45 subjects per
group will have 80% power to detect this difference.
The primary efficacy end-point of this study was the
change in HDL-C levels between the baseline and the
end of treatment (EoT). The primary end-point did
not contemplate multiple comparisons. As far as the
secondary end-points are concerned, no adjustment
of the 5% significance level was made for multiple
comparisons, due to their descriptive nature. Second-
ary efficacy end-points were the changes in glycaemia
and in the other parameters of lipidic metabolism
between the baseline and the EoT.
The HDL-C was also evaluated at the end of the
follow-up (EoF), which is 8 weeks after the end of
treatment (Figure 1). Differences in gender distri-
bution between the two groups were assessed by the
Chi-square test. Parametric tests were adopted to
analyse the discrete or continuous data due to the
relative largeness of the sample size and the not
statistically significant departure from normality of
data distribution of baseline values of glycaemia and
main lipid parameters. At each assessment time, the
comparison of the raw data of the two groups was done
by the unpaired t-test (t). The changes within groups
and percent changes from baseline were analysed
by the paired t-test (pt). Due to the incomplete
baseline homogeneity of the two experimental groups,
the comparisons of the changes between groups and
percent changes from baseline were done by the
analysis of covariance (ANCOVA) with the baseline
value as a covariate. With regard to T-C, HDL-C,
LDL-C and TG, the comparison between groups was
also done after stratifying by gender. A within gender
stratified descriptive and comparative analysis of
HDL-C data was also carried out choosing the median
of baseline values as cut-off point. An additional within
gender stratification of HDL-C data by the quartiles
of baseline values was presented only by descriptive
statistics and graphics, due to the small number of
observations per stratum.
Safety
Safety was assessed by the measurement of blood
pressure and by assessing routine blood biochemistry
parameters at baseline and EoT and by recording
all the adverse events (AEs). AEs were based on
spontaneous reporting by subjects as well as open-
ended enquiries by members of the research staff.
T0:
Assessment of:
Fasting blood glucose (FBG),
total cholesterol (TC),
low-density lipoprotein-cholesterol
(LDL-C), high-density
lipoprotein-cholesterol (HDL-C)
and triglyceride (TG), BMI,
blood pressure,
routine blood biochemistry
parameters
End of treatment (EoT):
Assessment of:
Fasting blood glucose (FBG),
total cholesterol (TC),
low-density lipoprotein-cholesterol
(LDL-C), high-density
lipoprotein-cholesterol (HDL-C)
and triglyceride (TG), BMI,
blood pressure, routine blood
biochemistry parameters
8 weeks 8 weeks
Treatment No treatment
T0 EoT EoF
End of Follow-up (EoF):
Assessment of: HDL-C
Figure 1. Study design.
Beneficial effects of artichoke leaf extract 3
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Results
All the 92 subjects completed the 8-week intervention
trial (Figure 2) and their demographic characteristics
at the baseline are shown in Table I. Forty-six subjects
were randomized to ALE supplements and 46 to
placebo. The supplemented and placebo groups were
homogeneous for all parameters. Table II shows the
baseline characteristic of lipid parameters in the two
studied groups. Table III shows the least squares
means (LSM) of changes from baseline at EoT, as well
as the difference in the LSM between the two groups
and their comparison by ANCOVA. As regards blood
pressure, all patients had normal values, either at the
beginning or at the end of the study (supplemented
group: BoS 123.75 ^10.93/84.31 ^8.24 mm Hg,
EoT 125.46 ^11.21/85.51 ^9.33 mm Hg; placebo
group: BoS 122.46 ^9.97/82.44 ^9.65 mm Hg,
EoT 126.01 ^9.11/86.04 ^9.21 mmHg). The diet
composition at screening and at the end of the trial is
shown in Table IV. BMI remained stable in both
groups. BMI at screening was 25.36 ^3.03 kg/m
2
and
at EoT was 25.82 ^2.01 kg/m
2
. In the supplemented
group, BMI at screening was 25.86 ^3.96 kg/m
2
and
at EoT was 25.46 ^3.11 kg/m
2
, while that in the
placebo group was 24.87 ^1.16 kg/m
2
at screening
and 26.01 ^2.08 kg/m
2
at EoT.
Primary end-point
The mean HDL-C significantly increased in the
supplemented group ( p,0.001), while it did not
show any significant change in the placebo
group. These differences in the patterns of two groups
were statistically significant in the whole sample
(p¼0.004), as well as in m ales ( p¼0.001).
The results of the analyses carried out on HDL-C
data stratified by gender and the median of baseline
values reported the following statistically significant
changes from baseline observed in the supplemented
group:
.the HDL-C values were higher than baseline at
EoT ( p¼0.010 and p¼0.009, respectively, for
changes and per cent changes from baseline) and
EoF ( p¼0.005 and p¼0.006, respectively, for
changes and per cent changes from baseline) in
the females belonging to the stratum ‘#median’;
.the HDL-C values were higher than baseline at EoT
in the males belonging to both strata ( p¼0.003
for changes from baseline p¼0.006 for per cent
changes from baseline in the stratum ‘#median’ and
p¼0.002 for both changes and per cent changes
from baseline in the stratum ‘.median’);
.the HDL-C values were higher than baseline at EoF
in the males belonging to the stratum ‘#median’
(p¼0.027 and p¼0.019, respectively, for changes
and per cent changes from baseline).
The following statistically significant differences
between the groups were found:
.females belonging to the stratum #median’ at
EoT ( p¼0.007 and p¼0.004, respectively, for
changes and per cent changes from baseline) as well
as at EoF ( p¼0.006 and p¼0.003, respectively,
for changes and per cent changes from baseline);
46 allocated
to the supplementation
with Cynara scolimus (Cs)
Followed up at
week 8: n = 46
92 eligible: fulfilled inclusion criteria
46 allocated
to placebo
46 analysed 46 analysed
101 subjects assessed for eligibility
92 randomized
9 excluded:
3 refused to participate
6 with laboratory abnormalities
Followed up at
week 8: n = 46
Figure 2. Flow diagram of a trial of supplementation versus placebo in the treatment of healthy overweight subjects.
M. Rondanelli et al.4
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.males belonging to the stratum ‘ .median’ at EoT
(p¼0.002 for both changes and per cent changes
from baseline);
.males belonging to the stratum ‘ #median’ at EoF
(p¼0.021 for per cent changes from baseline).
Figure 3 shows the mean values and 95% CI by
treatment and gender.
Secondary end-point
Glycaemia showed no statistically significant changes
within groups from baseline nor differences between
groups.
With regard to the whole sample, T-C significantly
decreased in both supplemented group ( p,0.001)
and pla cebo group ( p,0.010), but the effect of the
supplemented group was significantly higher than
that of the placebo group ( p¼0.012). The lowering
of baseline values was found statistically significant
in both females ( p,0.050) and males ( p,0.050) of
the supplemented group, whereas it was not statis-
tically significant in the placebo group. However, the
differences between groups in the changes from
baseline within each gender were not statistically
significant.
Table II. Baseline values of lipid metabolism.
Supplemented (N¼46) Placebo (N¼46) Total (N¼92)
F M Total F M Total F M Total
Total cholesterol (mmol/l)
N 262046252146514192
Mean 6.730 6.282 6.535 6.612 6.575 6.595 6.672 6.432 6.565
SD 0.669 0.628 0.683 0.407 0.403 0.401 0.554 0.539 0.558
P(t) whole sample, p¼0.610
P(t) females, p¼0.452
P(t) males, p¼0.082
HDL-cholesterol (mmol/l)
Mean 2.321 1.795 2.092 1.999 1.886 1.948 2.163 1.841 2.020
SD 0.455 0.516 0.545 0.690 0.586 0.640 0.599 0.548 0.596
P(t) whole sample, p¼0.246
P(t) females, p¼0.054
P(t) males, p¼0.602
Total cholesterol/HDL ratio
Mean 3.005 3.785 3.344 3.683 3.763 3.719 3.337 3.773 3.532
SD 0.650 1.085 0.941 1.240 0.982 1.118 1.032 1.021 1.045
P(t) whole sample, p¼0.085
P(t) females, p¼0.017
P(t) males, p¼0.946
LDL-cholesterol (mmol/l)
Mean 3.866 3.811 3.843 4.021 4.086 4.050 3.942 3.952 3.946
SD 0.746 0.613 0.684 0.506 0.416 0.463 0.638 0.533 0.590
P(t) whole sample, p¼0.091
P(t) females, p¼0.393
P(t) males, p¼0.100
LDL/HDL ratio
Mean 1.761 2.336 2.011 2.334 2.394 2.361 2.042 2.366 2.186
SD 0.594 0.879 0.778 1.080 0.824 0.961 0.905 0.841 0.887
P(t) whole sample, p¼0.058
P(t) females, p¼0.022
P(t) males, p¼0.826
Triglycerides (mmol/l)
Mean 1.179 1.469 1.305 1.298 1.314 1.306 1.238 1.390 1.305
SD 0.455 0.810 0.643 0.637 0.511 0.577 0.549 0.670 0.607
P(t) whole sample, p¼0.960
P(t) females, p¼0.444
P(t) males, p¼0.495
Note: t, unpaired t-test.
Table I. Demographic characteristics at the baseline of the subjects
studied.
Variable
Supplemented
(N¼46)
Placebo
(N¼46)
Total
(N¼92)
p
(test)
Gender
F 26 (56.5%) 25 (54.3%) 51 (55.4%) p¼0.834
M 20 (43.5%) 21 (45.7%) 41 (44.6%) (
x
2
)
Age (years)
Mean 54.2 53.8 54.0 p¼0.823
SD 6.6 9.0 7.8 (t)
BMI (kg/m
2
)
Mean 25.86 24.87 25.36 p¼0.120
SD 3.96 1.61 3.03 (t)
Note:
x
2
, Chi-square; t, unpaired t-test.
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The ratio between T-C and HDL-C significantly
decreased from baseline in the supplemented
group (whole sample, females and males: p,0.001).
The values of the placebo group did not show any
significant changes from baseline. The between-
group differences in the changes from baseline were
statistically significant in the whole sample
(p,0.001) as well as in females ( p¼0.002) and
males ( p¼0.001).
LDL-C levels significantly decreased in both the
supplemented group (whole sample: p,0.001;
females: p,0.001; males: p,0.010) and in the
whole sample ( p,0.050) an d females ( p,0.050) of
placebo group. The between-group differences in the
changes from baseline were statistically significant for
the whole sample ( p,0.001) as well as for females
(p¼0.001).
The LDL/HDL ratio significantly decreased in the
supplemented group (whole sample: p,0.001;
females: p,0.001; males: p,0.001) but not in the
placebo group. The between-group differences in the
changes from baseline were statistically significant for
the whole sample ( p,0.001) as well as for females
(p¼0.002) and males ( p¼0.005).
TG showed a not statistically significant decrease in
the supplemented group and a not statistically
significant increase in the placebo group. These
opposite patterns of the two groups were statistically
significant in females ( p¼0.013).
Safety
Treatment was well tolerated by all subjects, with
excellent compliance. The fact that there were no study
dropouts further indicates the tolerability of the study
treatments. No AEs were reported. The routine blood
biochemistry parameters (blood count, serum protein
electrophoresis, creatinine, liver and thyroid function)
were within the normal range at the beginning and
at the end of treatment (data not shown).
Discussion
In this double-blind, randomized, placebo-controlled
trial, carried out on subjects with primary mild
Table IV. Dietary intake (by food record method for 3 days) at
screening and at the end of treatment (mean ^SD).
Energy (kJ) 11,019.69 (^688.47) 10,972.3 (^391.63)
Protein (g) 88.95 (^6.55) 85.81 (^6.89)
% Energy 13.38 (^0.71) 12.95 (^0.79)
Fat (g) 80.60 (^3.53) 78.29 (^3.39)
% Energy 27.32 (^1.35) 26.65 (^1.73)
Carbohydrate (g) 397.96 (^34.04) 406.24 (^31.38)
% Energy 56.03 (^1.59) 57.44 (^1.53)
Complex (g) 305.73 (^41.93) 302.44 (^33.20)
% Energy 42.16 (^2.59) 42.72 (^2.76)
Simple (g) 98.16 (^8.60) 103.79 (^8.48)
% Energy 13.87 (^1.35) 14.72 (^1.35)
Dietary fibre (g) 25.70 (^3.38) 27.33 (^3.29)
Cholesterol (mg) 286 (^92) 280 (^95)
Table III. LSM of changes from baseline at EoT, difference in the LSM of the two groups and their comparisons by ANCOVA.
LSM (95% CI)
Parameter Supplemented Placebo Difference in LSM (95% CI) pbetween groups (ANCOVA)
Glycaemia (mmol/l)
All 0.016 (20.085 to 0.117) 20.086 (20.187 to 0.016) 0.102 (20.041 to 0.245) p¼0.160
Total cholesterol (mmol/l)
All 20.397 (20.544 to 20.249) 20.127 (20.274 to 0.020) 20.270 (20.478 to 20.061) p¼0.012
Females 20.440 (20.661 to 20.220) 20.176 (20.401 to 0.049) 20.265 (20.581 to 0.052) p¼0.099
Males 20.292 (20.482 to 20.103) 20.114 (20.299 to 0.071) 20.178 (20.448 to 0.091) p¼0.189
HDL-cholesterol (mmol/l)
All 0.207 (0.113 to 0.302) 0.005 (20.089 to 0.100) 0.202 (0.067 to 0.337) p¼0.004
Females 0.199 (0.047 to 0.350) 0.012 (20.143 to 0.167) 0.187 (20.034 to 0.408) p¼0.095
Males 0.237 (0.129 to 0.345) (0.192) 20.020 (20.125 to 0.086) 0.257 (0.105 to 0.408) p¼0.001
Total cholesterol/HDL ratio
All 20.548 (20.696 to 20.400) 20.022 (20.171 to 0.126) 20.526 (20.737 to 20.314) p,0.001
Females 20.499 (20.693 to 20.305) 20.039 (20.237 to 0.159) 20.460 (20.744 to 20.175) p¼0.002
Males 20.608 (20.855 to 20.362) 20.006 (20.247 to 0.235) 20.602 (20.947 to 20.258) p¼0.001
LDL-cholesterol (mmol/l)
All 20.561 (20.709 to 20.413) 20.149 (20.297 to 20.001) 2412 (20.623 to 20.201) p,0.001
Females 20.637 (20.829 to 20.446) 20.166 (20.362 to 0.030) 20.472 (20.747 to 20.196) p¼0.001
Males 20.454 (20.697 to 20.210) 20.136 (20.374 to 0.101) 20.317 (20.663 to 0.029) p¼0.071
LDL/HDL ratio
All 20.478 (20.613 to 20.342) 20.044 (20.179 to 0.091) 20.434 (20.627 to 20.240) p,0.001
Females 20.456 (20.622 to 20.289) 20.058 (20.228 to 0.112) 20.398 (20.642 to 20.153) p¼0.002
Males 20.511 (20.747 to 20.276) 20.023 (20.253 to 0.207) 20.488 (20.818 to 20.159) p¼0.005
Triglycerides (mmol/l)
All 20.098 (20.224 to 0.029) 0.067 (20.058 to 0.193) 20.165 (20.343 to 0.013) p¼0.070
Females 20.133 (20.246 to 20.019) 0.077 (20.039 to 0.192) 20.209 (20.372 to 20.047) p¼0.013
Males 20.084 (20.332 to 0.163) 0.088 (20.147 to 0.324) 20.173 (20.516 to 0.170) p¼0.314
Note: ANCOVA, analysis of covariance; 95% CI, 95% confidence interval.
M. Rondanelli et al.6
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hypercholesterolaemia, we observed that the 8-week
supplementation with artichoke leaves extract is
associated with a significant HDL-C increase, thus
fulfilling the primary end-point of the study. This
result appears of relevant clinical interest due to the
potential preventive role of HDL-C in CVD. As a
matter of fact, long-term, follow-up studies have
demonstrated that incremental HDL-C elevation in
either absolute or percentage values can predict
cardiovascular risk. Goldenberg et al. have shown a
29% CVD risk reduction per 5 mg/dl increment in
HDL-C among patients with LDL-C levels below
130 mg/dl (Goldenberg et al. 2009). In other
cholesterol-reducing drug trials, for every 1% increase
in HDL-C, there was a 3% reduction in death or
myocardial infarction (Boden 2000). Statins represent
gold standard treatment of dyslipidaemia: anyhow
their use is associated with frequent unwanted
side effects (Kostapanos et al. 2010). Therefore,
different therapeutical strategies should be identified
at least to treat subjects with mild hypercholester-
olaemia. Although the mechanisms explaining the
HDL-cholesterol-increasing effect of ALE are not
well known, the most likely explanation could be
related to their polyphenolic content and in particular
to chlorogenic acid (Brown and Rice-Evans 1998;
Gebhardt 2002; Wider et al. 2009). This compound
could favour the increase in HDL-C through the
enhancement of the activities of paraoxonase-1
(PON-1). PON-1 is an enzyme associated with HDL
which prevents the oxidation of HDL-C, thus
favouring its anti-oxidative and anti-inflammatory
effects (Goue
´dard et al. 2004). Gugliucci et al.
demonstrated that chlorogenic acid protects PON-1
activity in HDL-C by means of an in vitro study. In this
experiment, chlorogenic acid protects PON-1 activity
in human HDLs from inactivation caused by hypo-
chlorite (HOCl), at concentrations of HOCl (50 mM)
and chlorogenic acid (2 – 10 mM) compatible with
those found in humans (Gugliucci and Bastos 2009).
Previous human studies proved that the increase in
PON-1 activity correlates strongly with the increase in
HDL-C (van der Gaag et al. 1999; Sierksma et al.
2002). Based on these data, it can be hypnotized that
chlorogenic acid, present in ALE extract, may induce
an increase in PON-1 activity and as a consequence,
may favour the increase in HDL-C in humans.
Previous intervention studies with ALE failed to
show an increase in HDL-C (Englisch et al. 2000;
Lupattelli et al. 2004; Bundy et al. 2008). This
different result could be due to the smaller sample size
and lower homogeneity of the studied population,
as compared to this study. Moreover, the different
purification and standardization, as well as the
stability, of the supplements could play a key role in
elucidating the clinical and biological effects of
artichoke extracts.
As far as the secondary end-points of the study are
concerned, a significant decrease in T-C, LDL-C,
LDL/HDL and total/HDL ratio is found in the
supplemented group, while no difference is observed
in the placebo group. The quantitative decrease in T-C
and LDL-C observed in this study is similar to those
observed in other studies carried out with ALEs in
animal models (Ku
¨sku
¨-Kiraz et al. 2010; Qiang et al.
2011) and in humans (Englisch et al. 2000; Lupattelli
et al. 2004; Bundy et al. 2008). The biological
mechanism which is involved in this effect is mainly
played by luteolin, a polyphenol contained in ALEs.
Luteolin inhibits the 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase activity, which
is a key enzyme in the liver cholesterol biosynthesis
pathway (Gebhardt 2002). Moreover, in vitro studies
showed that chlorogenic acid and luteolin may inhibit
LDL oxidation (Brown and Rice-Evans 1998), thus
reducing the critical effects of oxidized LDL-C and
reducing their atherogenic effect.
A meta-analysis published by Gould et al. on more
than 125,000 subjects confirmed that cholesterol
reduction yields clinical benefits (Gould et al. 2007).
Among all patients, for every 1 mmol/l decrease in
T-C, there was a 17.5% reduction in relative risk (RR)
for all-cause mortality; 24.5%, for CHD-related
mortality and 29.5% for any CHD event. Correspond-
ing reductions for every 1 mmol/l decrease in LDL-C
were 15.6%, 28.0% and 26.6%, respectively. Similar
relationships were observed in patients without CHD.
No significant relationship was found between lipid
reduction and non-CHD-related mortality risk.
Based on the results obtained in this study, it can
be stated that an ALE supplementation may favour
CVD prevention by acting on two different factors,
which is increasing HDL-C and decreasing LDL-C.
Therefore, ALE represents a potential treatment
option for subjects with primary mild hypercholester-
olaemia. ALE also proved to be safe and well tolerated.
Future studies are needed to confirm the present
clinical results over a longer duration with the inter-
vention with ALE, as well as to assess the PON-1
Figure 3. HDL-cholesterol (mmol/l). Mean values and 95% CI by
treatment and gender.
Beneficial effects of artichoke leaf extract 7
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behaviour in order to confirm the biological mechan-
ism that we hypothesized.
Conclusion
In conclusion, an 8-week intervention with ALE is well
tolerated and efficacious in increasing HDL-C and in
decreasing T-C and LDL-C, in subjects affected with
primary mild hypercholesterolaemia.
Declaration of interest: The authors report no
conflict of interest. The authors alone are responsible
for the content and writing of the paper.
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... After full-text review, four more studies were excluded due to the following reasons: irrelevant outcomes (n = 2), without sufficient data (n = 1), and review paper (n = 1). Finally, a total of 14 RCTs was included for the final systematic review and meta-analysis (Bundy, Walker, Middleton, Wallis, & Simpson, 2008;Englisch et al., 2000;Fallah Huseini, Kianbakht, & Heshmat, 2012;Gatmiri et al., 2019;Panahi et al., 2018;Rangboo et al., 2016;Rezazadeh et al., 2019;Khatereh Rezazadeh, Rezazadeh, & Ebrahimi-Mameghani, 2018;Roghani-Dehkordi & Kamkhah, 2009;Rondanelli et al., 2013;Rondanelli, Giacosa, Orsini, Opizzi, & Villani, 2011;Rondanelli et al., 2014;Rondanelli et al., 2020;Skarpanska-Stejnborn et al., 2008). ...
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... All included RCTs utilized a parallel-group design. The included studies had recruited subjects with hypercholesterolemia (Bundy et al., 2008;Englisch et al., 2000;Rondanelli et al., 2013), hypercholesterolemia with type 2 diabetes (Fallah Huseini et al., 2012), NASH (Rangboo et al., 2016), hypertension (Roghani-Dehkordi & Kamkhah, 2009), overweight and obesity with impaired fasting glucose (IFG) (Rondanelli et al., 2014;Rondanelli et al., 2020), NAFLD (Panahi et al., 2018), chronic kidney disease (Gatmiri et al., 2019), hypertriglyceridemia (Rezazadeh et al., 2019), metabolic syndrome (Rezazadeh, Aliashrafi, et al., 2018;, and nonhypercholestrolemic rowers (Skarpanska-Stejnborn et al., 2008). Artichoke was administered in varying doses from 50 to 2,700 mg/day for a duration of 5-12 weeks. ...
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