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Abstract
Aim: Once considered a
problem of developed
countries, obesity and
obesity-related
complications (such as
metabolic syndrome) are
rapidly spreading around
the globe. The purpose
of the present study was
to investigate the use
of a Cissus
quadrangularis
formulation in the
management of metabolic
syndrome, particularly
weight loss and central
obesity.
Methods: The study was a
randomized,
double-blind,
placebo-controlled
design involving 123
overweight and obese
persons (47.2% male;
52.8% female; ages
19–50). The 92 obese
(BMI >30)
participants were
randomized into three
groups; placebo,
formulation/no diet, and
formulation/diet
(2100–2200
calories/day). The 31
overweight participants
(BMI = 25–29) formed a
fourth (no diet)
treatment group. All
participants received
two daily doses of the
formulation or placebo
and
remained on a normal or
calorie-controlled diet
for 8 weeks.
Results: At the end of
the trial period,
statistically
significant net
reductions in weight and
central
obesity, as well as in
fasting blood glucose,
total cholesterol,
LDL-cholesterol,
triglycerides, and
Creactive
protein were observed in
participants who
received the
formulation, regardless
of diet.
Conclusion: Cissus
quadrangularis
formulation appears to
be useful in the
management of weight
loss and metabolic
syndrome.
Background
Although still defined
in diverse terms,
metabolic syndrome
is a common disorder
arising as a result of
the
increased prevalence of
obesity throughout the
world [1].
Metabolic syndrome, also
known as insulin
resistance
syndrome and Syndrome X,
has 3 main potential
etiologic
categories: obesity and
disorders of adipose
tissue; insulin
resistance; and a
constellation of
independent factors
(e.g., molecules of
hepatic, vascular, and
immunologic
origin) that mediate
specific components of
the metabolic
syndrome [2].
In the United States,
over 60% of the adult
population is
now overweight or obese
[3] and 47 million
people have
metabolic syndrome,
which will soon overtake
cigarette
smoking as the number
one risk factor for
heart disease
[4,5]. Globally, the
disorder has become a
major public health
challenge. (In Cameroon,
approximately 25% of
the population is now
considered obese.)
Obesity has been shown
to contribute to high
serum cholesterol,
low HDL cholesterol and
hyperglycemia, all of
which increase the
chances of
cardiovascular disease
(CVD) [6-8].
Correlations between
central obesity and
high blood pressure,
high blood cholesterol,
low levels of
high density
lipoprotein-cholesterol,
and high fasting
blood glucose levels
have been shown for both
sexes in
various racial and
ethnic groups [6-10].
Since it has been
determined that
abdominal fat poses a
greater health risk than
fat stored in the lower
half of the
body [11], waist
circumference has become
a major factor
in body-fat assessment
[12,13]. A large waist
circumference
(>88 cm in women and 102
cm in men) is associated
with an increased risk
for type 2 diabetes,
dyslipidemia,
hypertension and CVD in
patients with a body
mass index
(BMI) 25–34 [8].
Moreover, for obese
patients with metabolic
complications, changes
in waist circumference
are
useful predictors of CVD
risk factors [13,14].
Thus, in
addition to weight (kg),
fat (%) and BMI, changes
in waist
measurement (cm) was one
of the primary endpoints
in
this study.
Because of its links
with obesity, it is
difficult to identify a
unique role for insulin
resistance in patients
with metabolic
syndrome. Although
insulin resistance
generally
rises with increasing
body fat content, one
finds a broad
range of insulin
sensitivities at all
levels [6]. Although
most people with BMI ≥
30 have postprandial
hyperinsulinemia
and relatively low
insulin sensitivity,
there is
variation in insulin
sensitivity even within
the obese population
[6,7]. Overweight
persons (BMI 25–29) also
exhibit a spectrum of
insulin sensitivities,
which seems to
suggest an inherited
component to insulin
resistance.
The increased chance of
CVD and type 2 diabetes
require
therapeutic
consideration for the
vast numbers of
overweight/
obese persons now at
high risk for these
diseases
[1]. The current
International Diabetes
Foundation
recommendations
for preventing or
delaying the development
of diabetes include both
primary and secondary
interventions. The
former emphasizes
lifestyle changes
such as calorie
restriction and
increased physical
activity,
and the latter (for
people at high risk for
CVD) uses
pharmacological
agents [15] that
specifically target
individual
components of metabolic
syndrome [15-20]. When
used
by obese patients in
combination with dietary
regimes,
these agents can produce
some weight loss and
some
reversal of accompanying
complications. The role
of pharmacotherapy,
however, has been
compromised by safety
issues leading to the
withdrawal of some
medications
from the market [21,22].
The combination of
safety concerns
and high costs have
forced many populations
to
continue to rely on
traditional healing
methods using the
indigenous
pharmacopoeia.
Cissus quadrangularis,
for example, is used by
common
folk in India to hasten
the fracture healing
process [23-
28]. In Cameroon, the
whole plant is used in
oral rehydration,
while in Africa and Asia
the leaf, stem, and root
extracts are utilized in
the management of
various ailments
[29-33]. Phytochemical
analyses of Cissus
quadrangularis
reveal a high content of
ascorbic acid, carotene,
phytosterol substances
and calcium [34,35], and
there
have also been reports
of the presence of
β-sitosterol, δ-
amyrin and δ-amyrone
[36]. All these
components have
potentially different
metabolic and
physiologic effects
[37,38]. Although
researchers have
investigated several
uses of Cissus
quadrangularis, its
potential application
against metabolic
syndrome has not yet
been reported.
Several other dietary
supplements (green tea,
soy, chromium,
selenium, B-vitamins)
have only marginal
effects
in treating obesity but
they address other
metabolic syndrome
symptoms and thus were
included in the
formulation.
Green tea (Camellia
sinensis) extracts
contain high
concentrations of
epigallocatchin gallate
and may work
with other chemicals to
increase levels of fat
oxidation
and thermogenesis
[39,40]. Numerous
studies on soy
(Glycine max) protein
show it is associated
with a reduction
in serum cholesterol and
triglyceride levels and
suggest
it may protect against
the development of
coronary
heart disease [41].
Chromium helps insulin
metabolize
fat, turn protein into
muscle, and convert
sugar into
energy [42]; thus,
chromium supplementation
can favorably
influence
glucose/insulin
metabolism, reduce
levels of
harmful LDL cholesterol,
and increase HDL
cholesterol
[43]. Both humans and
animals require selenium
for the
optimal functioning of
the selenoproteins,
which reduce the
risk of CVD by
decreasing lipid
peroxidation and
influencing
the metabolism of the
cell-signaling
prostaglandins
[44]. Lastly, B-vitamins
(B-6, B-12 and folic
acid)
regulate energy
metabolism [45], which
plays a critical
role in obesity
management; they also
maintain lower
homocysteine levels
[46], which are closely
associated
with cardiovascular
health benefits.
The purpose of the
present study was to
examine the efficacy
of a Cissus
quadrangularis
formulation (Cylaris™)
containing
the above agents in the
management of obesity
and metabolic syndrome.
Methods
The study was a
prospective, randomized,
double blind,
placebo-controlled
design conducted by the
Laboratory
for Nutrition and
Nutritional Biochemistry
at the University
of Yaoundé I, Cameroon,
Africa. The Cameroon
National Ethics
Committee approved the
protocol.
Applicants
were advised of the
study's purpose, nature,
and
potential risks, and all
gave their written
informed consent
before participation.
The study was conducted
in
accordance with the
Helsinki Declaration
(1983 version).
Participants
Eligibility criteria
included meeting the
minimal standards
for overweight (i.e., a
BMI >25 and a waist
circumference
>85.5 cm.) and a
willingness to
participate in an 8-
week trial. Exclusion
criteria (confirmed via
an initial
interview and physical
examination) included
pregnancy/
lactatation, use of any
form of weight-reducing
medication,
participation in intense
exercise programs,
medical
conditions known to
affect serum lipids, and
a history of
drug or alcohol abuse.
For the 123 eligible
participants,
BMIs ranged from 25.5 to
45.6; waist
circumferences from
85.5 cm to 125 cm; and
weight from 62.6 kg to
142 kg.
(See Table 1 for other
baseline
characteristics.)
Ninety-two
persons qualified as
obese (BMI >30), and 31
as overweight
(BMI = 25–29). The age
range was 19 to 50;
males
= 47.2%; females =
52.8%.
Intervention
The 92 obese persons
were randomized to a
placebo or
one of two treatment
groups; the 31
overweight persons
formed a fourth group.
One obese treatment
group was
prescribed a
calorie-controlled
(2100–2200 calories/day)
diet; none of the groups
was prescribed an
exercise regimen.
Apart from the expected
lower anthropomorphic
and serological
characteristics of the
overweight group,
none of the baseline
differences between the
groups was
clinically significant.
The overweight group was
used for general
comparison
with the obese groups,
thus the results were
expressed in
percentages rather than
absolute values. The
formulation/
diet group was used to
determine if a
short-term,
caloriecontrolled
diet would significantly
increase anthropomorphic
and serological outcomes
compared to the
formulation/
non-diet group.
Materials
The Cissus
quadrangularis formula,
Cylaris™, contains a
Cissus quadrangularis
extract (supplied by
Gateway Health
Alliances, Inc,
Fairfield, California,
USA), standardized to
contain a minimum of
2.5% phytosterols and a
mini-mum of 15% soluble
plant fiber. The formula
also consists
of a soy albumin extract
(supplied by Gateway
Health
Alliances, Inc,
Fairfield, California,
USA); a green tea
extract standardized to
22% EGCG and 40%
caffeine;
niacin bound chromium
(ChromeMate™ supplied by
InterHealth
Nutraceuticals, Inc,
Benicia, California,
USA);
selenium standardized to
0.5% l-Selenomethionine;
vitamin
B6 (as pyridoxine
hydrochloride); vitamin
B12 (as
cyanocobalamin); and
folic acid (supplied by
Protein
Research, Inc,
Livermore, California,
USA). All active and
placebo capsules were
manufactured and bottled
by Protein
Research, Inc.
Participants received
two daily doses (514 mg
each) of the
Cissus formulation or
placebo for 8 weeks.
Each capsule
was taken with 8–12 oz
of water immediately
prior to
meals (preferably
breakfast and dinner).
In keeping with
the experimental design,
the capsules were
identical in
shape, color and
appearance, and neither
the participants
nor researchers knew
which capsule was
administered.
Side effects were noted
on each visit.
Body weight and
percentage of body fat
were determined
in the 12-hour- fasted
participants with a
Tanita™ BC-418
Segmental Body
Composition
Analyzer/Scale that uses
bio-electrical impedance
analysis for body
composition
analysis. Height was
measured with a
Harpended™ stadiometer,
which measures the
length of curved line
staffage
to the nearest 0.5 cm.
Blood (5 ml) samples
were collected after an
overnight
fast at the start and
end of the 8 week trial
period. The
blood was collected into
vacutainer tubes, and
the serum
was separated (via
centrifugation) and
stored (200 μl aliquots)
at -20°C until needed
for analyses. The
concentrations
of total cholesterol,
triacylglycerol,
HDL-cholesterol,
LDL-cholesterol, and
glucose were measured
using commercial
diagnostic kits
(cholesterol Infinity,
triglyceride
Infinity, EZ HDL™
cholesterol, EZ LDL™
cholesterol, Glucose
Trinder) from SIGMA
Diagnostics. C-reactive
protein
was measured using an
ELISA method (BioCheck™
hsCReactive
Protein ELISA kit,
Foster City, CA USA).
Statistical analyses
The data for each
parameter was summarized
via n, mean,
and standard deviation
for Week 0 and Week 8
and the
percent difference (Week
8 – Week 0/week 0). The
percent
change from baseline was
tested for differences
using
analysis of variance.
Contrasts were used for
testing pairwise
differences.
Results
Anthropomorphic
characteristics
Waist circumference is
an extremely important
determinant
in the diagnosis of
obesity and metabolic
syndrome.
As shown in Table 2, the
significant reduction in
this variable
across all treatment
groups was paralleled by
significant
reductions in weight and
BMI for the two obese
treatment groups.
To translate the
percentage loss over 8
weeks into actual
measurements, the mean
change in weight (kg)
for the 3
obese (BMI >30) groups
was 95.6 to 93.3
(placebo); 95.8
to 89.2 (formulation/no
diet); and 95.3 to 87.2
(formulation/
diet). The mean change
for the overweight (BMI
25 –
29) group was 76.3 to
72.6 kg (formulation/no
diet).
Thus, over a period of 8
weeks, the placebo group
lost 2.3
kg; the overweight group
lost 3.7 kg and the two
obese
groups lost 6.6 kg and
8.1 kg, respectively.
Serological
characteristics
As shown in Table 3,
there was a significant
improvement
in virtually every
measurement for the
three treatment
groups vs. placebo.
Eight-week use of the
Cissus formulation
significantly reduced
plasma total cholesterol
and LDL cholesterol in
the three treatment
groups and
increased HDL
cholesterol in the two
obese groups by
50.5 % and 43.0% The
increase in the
concentration of
circulating
HDL-cholesterol in the
three treatment groups
shows a large reduction
in the ratio of total
cholesterol to
HDL-cholesterol ratios
as well as
LDL-cholesterol to
HDLcholesterol
ratios. All three
treatment groups also
demonstrated
a significant decrease
in triglycerides, C-
reactive
protein, and fasting
blood glucose levels.
To translate the
percentage loss over 8
weeks into actual
measurements, the mean
change in Total
cholesterol (mg/
dl) for the 3 obese (BMI
>30) groups was 160.8 to
155.8
(placebo); 159.1 to
116.1 (formulation/no
diet); and
171.0 to 126.5
(formulation/diet. The
mean change for
the overweight (BMI 25 –
29) group was 152.6 to
123.9.
Thus, over a period of 8
weeks, Total cholesterol
declined
5.0 mg/dl for the
placebo group; 28.7
mg/dl for the overweight
group; and 43.0 mg/dl
and 44.5 mg/dl for the
two
obese groups.
Adverse events
Adverse events with an
incidence >5 included
headache
(12), gas (11), dry
mouth (7), diarrhea (7),
and insomnia
(6). Since the incidence
of all reported side
effects was
always higher in the
placebo group than in
any of the
treatment groups, it is
probably safe to
conclude that the
Cissus formulation had
few, if any, negative
side effects.
Discussion
Our results support the
hypothesis that the use
of a Cissus
quadrangularis
formulation has efficacy
in the management
of weight loss and
metabolic syndrome,
particularly
for central obesity. The
use of the formulation
(which also
contains green tea, soy,
chromium, selenium, and
B-vitamins)
over an 8-week period
brought about a
significant
reduction in many of the
anthropomorphic
measures:
weight, % body fat, BMI
and, especially, waist
circumference
of obese and overweight
patients, regardless of
calorie-
controlled diet (see
Table 2).
Waist circumference is a
particularly important
factor in
weight and body-fat
assessment since fat
distribution,
rather than total body
fat, is currently the
key indicator of
weight-related health
problems. The dramatic
reduction
in waist circumference
that accompanied the
8-week use
of the Cissus
quadrangularis
formulation for both the
diet
and no diet groups is
particularly important
because waist
circumference is a major
criterion in the
diagnosis of obesity
and metabolic syndrome
[2] and is generally
considered
a surrogate measure for
abdominal visceral fat
[12,13]. Moreover, not
only does the risk of
type 2 diabetes
increase with the degree
and duration of obesity
it, too,
is associated with
central obesity [6,7].
The reduction in the
primary anthropomorphic
measurements
can be attributed to the
synergistic effects of
Cylaris
™, Glycine max extract,
Camellia sinensis
extract and
ChromeMate™ ingredients
in the formula, all of
which
have previously been
shown to affect weight
loss activity
[32,35,39,41,42].
Cissus quadrangularis
phytosterols and fiber
extracts have
been shown to have
anti-lipase, and
anorexiant properties
that reduce the
absorption of dietary
fats and enhance
satiation by increasing
serum serotonin levels
[47]. In
1999, Swiss researchers
found that men who were
given a
combination of caffeine
and green tea catechin
extract
burned more calories
than those given only
caffeine or a
placebo. It was
postulated that the
catechins and caffeine
combination sustained
the effect of
norepinephrine on
thermogenesis longer
than caffeine alone
[39].
Numerous
studies on chromium
supplementation have
also demonstrated
weight loss in
overweight and obese
people
[48,49]. Grant et al.
(1997) reported that
chromium with
a moderate diet and
exercise regimen
influences weight
loss and body
composition [50].
The modification of
certain serological
characteristics
(blood parameters) (see
Table 3) by Cissus
formulation
may or may not be
dependent on weight
loss. Only the
reduction of
LDL-cholesterol followed
a similar pattern to
weight loss over the
8-week trial period. The
circulating
concentration of total
cholesterol and
triglycerides,
though reduced by the
formulation, could be
independent
of weight loss since all
treatment groups
(diet/no diet)
showed significant
cholesterol reduction.
The increase in
the concentration of
circulating
HDL-cholesterol in the
treatment groups shows a
reduction in the ratio
of total
cholesterol to
HDL-cholesterol as well
as LDL-cholesterol
to HDL-cholesterol. This
reduced ratio also
implies a
reduction in the risk of
atherosclerosis and
coronary heart
disease [51].
Although the exact
mechanisms for the
formulation's
cholesterol-
lowering ability needs
further study, the
various
ingredients might
interact in a manner
similar to statins,
fibrates, probucol,
nicotinic acid or
cholesterol absorption
inhibitors. Green tea
catechins have a number
of antioxidant
activities related to
cholesterol regulation.
For
example, the inhibition
of the oxidation of
low-density
lipoproteins and the
antithrombotic activity
both aid in
lowering total
cholesterol/LDL-cholesterol
and increasing
HDL-cholesterol levels
[52,53]. Also, the
phytochemical
constituents
(phytosterols,
β-sitosterol, δ-amyrin
and δ-
amyrone), in Cissus
quadrangularis may have
activity similar
to other plant sterols.
The molecular structure
of phytosterols,
for example, is
practically identical to
that of
cholesterol.
Recent studies show that
metabolic syndrome
causes an
inflammatory process in
the blood vessels that
leads to
arteriosclerosis. This
inflammatory process can
be gauged
by blood levels of
C-reactive protein [54]
and, as our
results showed, Cissus
formulation
significantly reduced
the circulating
concentrations of CRP
thereby inhibiting
the inflammatory process
and possibly reducing
individual
components of metabolic
syndrome [54]. In
metabolic
syndrome, the body
becomes resistant to
insulin,
and high levels of
glucose remain trapped
in the blood. In
response, the pancreas
produces more insulin.
The extra
insulin temporarily
allows glucose to enter
the cells and
also increases
cholesterol and
triglyceride levels.
In sum, Cissus
formulation administered
twice daily to
obese and overweight
persons with symptoms of
metabolic
syndrome results in both
weight reduction and an
improvement in the
symptoms associated with
metabolic
syndrome. It has also
shown efficacy in the
control and
lowering of triglyceride
concentrations, total
cholesterol,
LDL-cholesterol, and
fasting blood glucose.
The formulation
may also have
applications in other
metabolic diseases,
such as diabetes
mellitus.
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