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OBJECTIVE - To
investigate the
tolerability, efficacy,
and mode of action of
Caiapo, an extract of
white sweet potatoes, on
metabolic control in
type 2 diabetic
patients.
RESEARCH DESIGN AND
METHODS - A total of 61
type 2 diabetic patients
treated by diet were
given 4 g Caiapo (n 30;
mean age 55.2 2.1 years;
BMI 28.0 0.4 kg/m2) or
placebo (n 31; mean age
55.6 1.5 years; BMI 27.6
0.3 kg/m2) once daily
for 12 weeks. Each
subject underwent a 75-g
oral glucose tolerance
test (OGTT) at baseline
and after 1, 2, and 3
months to assess 2-h
glucose levels.
Additionally, fasting
blood glucose, HbA1c,
total cholesterol, and
triglyceride levels were
measured.
RESULTS - After
treatment with Caiapo,
HbA1c decreased
significantly (P 0.001)
from 7.21 0.15 to 6.68
0.14%, whereas it
remained unchanged (P
0.23) in subjects given
placebo (7.04 0.17 vs.
7.10 0.19%). Fasting
blood glucose levels
decreased (P 0.001) in
the Caiapo group (143.7
1.9 vs. 128.5 1.7 mg/dl)
and did not change in
the placebo group (144.3
1.9 vs. 138.2 2.1 mg/dl;
P 0.052). A decrease in
body weight was observed
in both the placebo
group (P 0.0027) and in
the Caiapo group (P
0.0001), probably due to
a bettercontrolled
lifestyle. In the Caiapo
group, body weight was
related to the
improvement in glucose
control (r 0.618; P
0.0002). Two-hour
glucose levels were
significantly (P 0.001)
decreased in the Caiapo
group (193.3 10.4 vs.
162.8 8.2 mg/dl)
compared with the
placebo group (191.7 9.2
vs. 181.0 7.1 mg/dl).
Mean cholesterol at the
end of the treatment was
significantly lower in
the Caiapo group (214.6
11.2 mg/dl) than in the
placebo group (248.7
11.2 mg/dl; P 0.05). No
significant changes in
triglyceride levels or
blood pressure were
observed, and Caiapo was
well tolerated without
significant adverse
effects.
CONCLUSIONS - This study
confirms the beneficial
effects of Caiapo on
plasma glucose as well
as cholesterol levels in
patients with type 2
diabetes. For the first
time, the long-term
efficacy of Caiapo on
glucose control was
demonstrated by the
observed decrease in
HbA1c. Thus, the
neutraceutical Caiapo
seems to be a useful
agent in the treatment
of type 2 diabetes.
The pathogenesis of type
2 diabetes involves
insulin resistance and
impaired insulin
secretion (1,2). When
diet therapy and
exercise remain
ineffective, medications
such as oral
hypoglycemic drugs or
insulin must be used
(3,4). In addition to
insulin and drugs that
stimulate insulin
release, new compounds
From the 1Department of
Medicine III, Division
of Endocrinology and
Metabolism, University
of Vienna, Vienna,
Austria; 2Via Livio 14,
Chiasso, Switzerland;
and the 3Metabolic Unit,
Institute of Biomedical
Engineering, ISIB,
National Research
Council, CNR, Padova,
Italy. Address
correspondence and
reprint requests to
Bernhard Ludvik, MD,
Department of Internal
Medicine 3, Division of
Endocrinology and
Metabolism, University
of Vienna Medical
School, Waehringer
Guertel 18–20, A-1090
Vienna, Austria. E-mail:
bernhard.ludvik@akh-wien.ac.at.
Received for publication
30 July 2003 and
accepted in revised form
15 October 2003. B.L.
receives grant support
for an ongoing study of
Caiapo from Fuji Sangyo.
G.P. received
reimbursement from Fuji
Sangyo for travel and
lodging for the American
Diabetes Association
Scientific Sessions (New
Orleans, LA, June 2003).
Abbreviations: OGTT,
oral glucose tolerance
test. A table elsewhere
in this issue shows
conventional and
Syste`me International
(SI) units and
conversion factors for
many substances. that
improve insulin
sensitivity are
currently under
investigation or are
already in clinical use
(4 –7). Recently,
attention has also been
directed to evaluate the
efficacy of natural and
neutraceutical products
on diabetes control (8
–10). As noted in a
recent meta-analysis on
neutraceuticals in
management of diabetes,
few compounds have shown
efficacy in randomized
trials (11). However, in
the absence of
thoroughly controlled
studies on effectiveness
and potential risks,
these neutraceuticals
cannot be unanimously
recommended for
management of diabetes
(12,13). A variety of
white sweet potato
cultivated
in a mountainous region
of Kagawa Prefecture,
Japan, has been eaten
raw for many years in
the belief that it is
effective therapy for
anemia, hypertension,
and diabetes. Caiapo
(Ipomoea batatas) is
commercialized
in Japan without medical
prescription as a food
additive (neutraceutical)
for the prevention and
care of
type 2 diabetes (14,15).
In a previous study, we
evaluated the efficacy
and tolerability of two
doses (2 and 4 g/day) of
Caiapo versus placebo
given orally for 6 weeks
to 18 male Caucasian
patients with type 2
diabetes treated only by
diet (16). Those results
showed that Caiapo at
the dose of 4 g/day for
6 weeks lowered total
and LDL cholesterol
levels, as well as blood
glucose, by increasing
insulin sensitivity
without affecting
insulin secretion. The
low number of subjects
and the short duration
of the prior study
prevented us from
evaluating the effect of
Caiapo on parameters of
long-term glucose
control such as HbA1c.
Thus, it seemed of
clinical and scientific
interest to verify those
findings in a wider
comparative trial. The
aim of the present study
was, therefore,
assessment of the
efficacy and
tolerability of Caiapo
(4 g/day) compared with
placebo when
administered for 12
consecutive weeks to
type 2 diabetic patients
with mild fasting
hyperglycemia
who were advised to keep
body weight, physical
activity, and diet under
RESEARCH DESIGN AND
METHODS - This
investigation
wasperformed in a total
of 61 clinically stable
type 2 diabetic patients
treated by diet only and
recruited from the
offices of general
practitioners. In five
patients, the respective
antidiabetic medication
(metformin,
glibenclamide,
glimepiride) was
withdrawn 2 weeks before
the start of the study.
All of these patients
gave informed consent to
participate in this
study, which was
approved by the Ethics
Committee of the Swiss
Federal Authorities (IKI).
All patients had no
relevant history of
renal, hepatic,
cardiovascular,
hematological,
respiratory, autoimmune,
or neurological
diseases. Apart from
diabetes, no other
endocrine dysfunction
that could interfere
with the study was
detected. Subjects were
instructed to follow a
weight-maintaining diet
(28 –32 kcal/kg body wt)
consisting of 55%
carbohydrates, 30% fat,
and 15% proteins.
Drinking alcohol and
smoking cigarettes were
allowed if patients were
in the habit of doing
so, but alcohol
consumption was limited
to 60 g/day for men and
40 g/day for women and
smoking was limited to
10 cigarettes/day. Each
subject was advised to
maintain usual physical
activity at a constant
level throughout the
entire period of the
study. The study was
placebo-controlled,
randomized, and
double-blinded. Patients
were randomly divided
into two groups: group 1
(n 30) consumed Caiapo 4
g/day, and group 2 (n
31) consumed placebo.
After disclosure of the
randomization code, data
of both groups showed no
differences in baseline
parameters, except for
glucose levels measured
2 h after dinner (Tables
1 and 2). Both Caiapo
and placebo were taken
orally once daily, in
the morning before
breakfast. Each subject
underwent a 75-g oral
glucose tolerance test (OGTT)
in the clinic at
baseline and after 1, 2,
and 3 months. Fasting
and 2-h glucose levels
were measured from
venous samples (15 ml)
by the glucose oxidase
method. Subjects
measured their blood
glucose levels at home
using a blood glucose
test system (Glucotrend;
Boehringer Mannheim,
Mannheim, Germany). All
patients were instructed
regarding use of the
glucometer, and the
subjects’ ability to
correctly use the
glucometer, as well as
instrument precision and
calibration, were
frequently checked.
Blood glucose levels
were monitored
three times per week: on
Monday before breakfast,
on Wednesday 2 h after
beginning lunch, and on
Friday 2 h after
beginning dinner. These
measurements were
averaged over 1 month.
HbA1c was measured by
immunoassay (IMX;
Abbott, North Chicago,
IL); cholesterol and
triglyceride levels were
measured by routine
laboratory methods.
Statistics
Changes in blood
glucose, total
cholesterol,
triglyceride, and HbA1c
values after treatment
were analyzed between
groups by ANOVA using
corresponding baseline
values and BMI as
covariates. Comparisons
versus baseline were
assessed within groups
with the appropriate
Student’s test corrected
by Bonferroni
adjustment. Coefficient
of correlation was
calculated for changes
in HbA1c versus changes
in weight. Unless
otherwise specified,
data are reported as
means SE. Tolerability
and safety Tolerability
scores were compared
between groups using 2
test. The safety
analysis was performed
in all randomized
patients to assess the
nature, severity, and
frequency of adverse
effects, including
laboratory values
outside the normal
range that may suggest a
clinically relevant
abnormality. The
equivalence between the
two groups concerning
occurrence of adverse
effects was assessed
using 2 test.
RESULTS
HbA1c
After treatment with
Caiapo, HbA1c
significantly decreased
after 2 and 3 months
(Table 2); no change was
observed in the placebo
group (P 0.08 after 2
months and P 0.23 after
3 months versus
baseline). At both 2 and
3 months, HbA1c values
in the Caiapo group were
lower than the
corresponding values of
the placebo
group (P 0.001). Because
both groups exhibited
significant weight loss
(Table 2), we tested the
hypothesis that the
de-crease in HbA1c in
the Caiapo group was
related to the changes
in body weight by using
ANOVA with body weight
as a covariate. The P
value was 0.041,
indicating that a
possible influence of
the change in
body weight on the
improvement of HbA1c
cannot be excluded.
Accordingly, body weight
and HbA1c changes
correlated significantly
(r 0.618; P 0.0002).
Fasting, OGTT, and
postprandial glucose
Fasting blood glucose
(Table 2, Fig. 1)
decreased at 2 months in
both groups (Caiapo
group: P 0.001; placebo
group: P 0.05), but the
decrease was greater in
the Caiapo group (P
0.0289 versus the
placebo group). No
further decrease was
observed in the placebo
group afterward, where
fasting glucose levels
in the Caiapo group
continued to decrease
(at 3 months: P 0.001
versus the placebo
group). The frequency of
achieving mean fasting
blood glucose levels
below the upper normal
limit (126 mg/dl) after
3 months of treatment
was evaluated: there
were 48.3% responders in
the Caiapo group versus
7.7% in the placebo
group
(P 0.0005, 2 test).
Figure 2 shows the
differences between the
Caiapo and placebo
groups in regard to
glucose values measured
2 h after oral
administration of
glucose (Table 2). No
significant changes from
baseline were observed
in the placebo group at
2 and 3 months. In the
Caiapo group, a
progressive
decrease occurred (P
0.005 at 1 and 2 months;
P 0.001 at 3 months
versus the placebo
group). Within the
Caiapo group, the
differences from
baseline were
statistically
significant at any data
point (P 0.001).
Blood glucose levels
measured 2 h after lunch
decreased significantly
in the Caiapo group
after 2 and 3months
(Table 2). In the
placebo group, a
nonsignificant decrease
was observed until 2
months (P 0.14), but
there was no further
change after that time.
Blood glucose levels
measured 2 h after
dinner at baseline
were more elevated in
the Caiapo group than in
the placebo group (P
0.05, Table 2). They
became virtually
identical after 2 and 3
months; however, when
evaluating the
progressive decrease in
blood glucose levels
versus baseline, we
observed a statistical
significance within the
Caiapo group after 2 and
3 months, whereas in the
placebo group, the
difference compared with
baseline was significant
only at 3 months. Body
weight, blood pressure,
and lipid levels Body
weight was similar at
baseline (P 0.8) and
decreased significantly
in both groups at 3
months, but the decrease
was more pronounced in
the Caiapo group (Table
2). In fact, despite
similar body weight at 3
months (P 0.67), the
difference versus
baseline was higher in
the Caiapo group (3.7
0.3 vs. 1.0 0.3 kg, P
0.0004). Overall, 26
subjects in the Caiapo
group and 18 subjects in
the placebo group lost
weight during the study.
Blood pressure did not
change; at the end of
the study, the mean
blood pressure was 136.2
2.0/81.6 1.2 mmHg in the
Caiapo group and 137.2
2.1/81.7 1.0 in
the placebo group (P
0.15 versus baseline,
Table 1). Mean
cholesterol at baseline
was similar in the two
groups
(P 0.276); at 3 months,
it was significantly
higher, as at baseline,
in the placebo group,
whereas it was slightly
decreased in the Caiapo
group, without reaching
statistical significance
(P 0.08). At the
end of the treatment
period, cholesterol
levels in the Caiapo
group were lower than
those in the placebo
group (P 0.05). There
were no significant
differences in
triglyceride levels
neither between nor
within the groups; P
values ranged from 0.2
to 0.8. Tolerability and
safety At the end of the
study, the patients
expressed
their opinions about
gastrointestinal
tolerability (poor,
acceptable, good,
excellent). Tolerability
was very good in the
Caiapo group, in which
only three subjects
reported a negative
opinion. Similarly, no
negative opinions were
expressed by the
subjects in the placebo
group (P 0.8181 Caiapo
versus placebo).
Regarding adverse
events, 16 were reported
in the Caiapo group and
14 were reported in the
placebo group. In six
subjects in the Caiapo
group and two subjects
in the placebo group, a
relation with the
medication could not be
excluded. These adverse
events were mainly of
gastrointestinal nature
(constipation, gastric
pain,
meteorism) and of mild
intensity.
CONCLUSIONS - In this
study, we confirmed the
beneficial effects of
Caiapo on glucose and
serum cholesterol levels
in type 2 diabetic
patients treated by diet
(16) after 3 months of
administration. This
effect was observed in
improved fasting blood
glucose levels as well
as improved glucose
levels during an OGTT
and in the postprandial
state. In addition, we
demonstrated for the
first time an
improvement in long-term
glucose control as
expressed by the
significant decrease in
HbA1c. The
glucose-lowering potency
of Caiapo has long been
recognized, and over the
past decades, it has
been commercial-ized in
Japan as an antidiabetic
medication. However,
publications on the
efficacy and safety of
this compound consisted
mainly of case reports
and uncontrolled
studies. We have
recently performed a
pilot study in 18 type 2
diabetic
patients over a period
of 6 weeks and reported
a significant decrease
in plasma glucose levels
(16). The duration of
the study, however, was
too short to allow an
evaluation of long-term
parameters of
glucose control, such as
HbA1c. Therefore, the
present study was
designed to address this
issue and to further
extend the knowledge
about the safety of
Caiapo. Regarding
glucose control, the
data of the pilot study
were confirmed, and
Caiapo can be regarded
as an effective compound
in the treatment of type
2 diabetes. After 3
months of treatment,
48.3% of patients in the
Caiapo group had fasting
blood glucose
levels 126 mg/dl, which
is diagnostic for
diabetes. HbA1c was
lowered by 0.5%, and
thus, the
glucose-lowering potency
of Caiapo is in the
range or even beyond
that of compounds such
as acarbose (17) or
nateglinide (18).
Furthermore, baseline
glucose control was
fairly good, as
indicated by an HbA1c of
7–7.2%, and one could
speculate whether Caiapo
would have proven more
efficient if patients
with higher HbA1c levels
had been studied. The
improvement of glucose
control comprised
fasting as well as
postprandial
blood glucose levels and
raises a question
regarding of the mode of
action of Caiapo. In a
previous study, we
investigated the effect
of Caiapo by performing
oral and intravenous
glucose tolerance tests
in type 2 diabetic
patients (19). The study
showed an improvement in
insulin sensitivity as
the responsible
mechanism for the
amelioration of glucose
tolerance, while any
effect on glucose
absorption or insulin
secretion was excluded.
These findings were in
accordance with a study
in obese Zucker fatty
rats (14), in which
glucose tolerance
increased in response to
100 mg/kg of Caiapo
powder per day. The
effects, demonstrated by
an enhanced [14C]glucose
uptake in isolated
adipocytes, were
comparable to treatment
with 50 mg/kg of
troglitazone per day in
a pairfed group.
Contrary to troglitazone,
no weight gain could be
seen after Caiapo
treatment in those
animals. Whereas the
active substance
responsible for the
glucose-lowering effect
in this extract of
white-skinned potatoes
is not entirely known,
an acidic glycoprotein
has been identified as
possible candidate (15)
and is currently under
thorough investigation.
Unlike in animals and in
our pilot
study, we observed a
decrease in body weight
in both groups; however,
this decrease was more
pronounced in the Caiapo
group. After further
analyzing the HbA1c data
by using body weight
change as a covariate, a
possible influence of
weight loss on the
improvement in glucose
control was shown for
the Caiapo group. We
cannot, however,
quantify the exact
contribution of weight
loss on the effects
observed. In both
groups, the decrease in
body weight may be due
partly to a change in
lifestyle under the
conditions of a
controlled study.
However, reduction of
body weight was
definitely more
sustained in the Caiapo
group, and
this raises a question
about a possible
mechanism of Caiapo in
decreasing body weight.
This issue, however,
remains unclear and
requires further
investigation. At this
stage, malabsorption can
be excluded by analysis
of safety laboratory
parameters. Because the
tolerability of Caiapo
was considered very
good, with only three
subjects reporting a
negative opinion, a
potential
gastrointestinal side
effect is unlikely to be
responsible for the
reduction of body
weight. From the time
course of weight loss
and improvement of
glucose control,
however, we hypothesize
that the continuing
decrease in glucose at a
stable body weight
during the last month
supports an intrinsic
action of Caiapo beyond
weight loss, presumably
by means of those
effects seen in previous
studies, e.g., by
increasing insulin
sensitivity. Finally, we
found in this, as well
as in the pilot study
(16), a beneficial
effect of Caiapo on
serum cholesterol
levels. Although we have
not determined LDL or
HDL cholesterol levels
in the present
investigation, the pilot
study showed that this
effect was confined only
to LDL cholesterol.
Because the improvement
in insulin sensitivity
exerted by Caiapo is not
expected to alter
cholesterol levels, a
second compound, which
is not yet identified,
could be responsible for
this effect. Weight loss
in these patients could
also contribute to the
lowering of cholesterol
levels; however, the
amount of this reduction
exceeds the extent
expected from a weight
loss of 3.7 kg. No
change in the main
safety parameters (blood
pressure and other
laboratory measurements)
was observed with Caiapo,
and the tolerability was
considered good, as also
indicated by the very
low number of adverse
events. These were
similar between the
respective groups, with
only a slightly higher
number of mild gastric
problems during
administration of Caiapo.
In conclusion, this
study confirms the
beneficial effects of
Caiapo on fasting and
postprandial plasma
glucose levels, as well
as cholesterol, in
patients with type 2
diabetes. For the first
time, we demonstrated
the long-term efficacy
of Caiapo on glucose
control by the observed
reduction of HbA1c.
Thus, the neutraceutical
Caiapo seems to be a
useful agent in the
management of type 2
diabetes.
Acknowledgments—This
multicenter study has
been performed in
Switzerland (Canton
Ticino) and has involved
antidiabetic centers (Bellinzona,
Dr. David Nicola
Alexander;
Breganzona, Dr. Giovanni
Frey; Chiasso, Dr. Luca
Heitmann; Lugano, Dr.
Fabrizio Ferretti;
Malvaglia, Dr. Valentin
Dehelan; Massagno, Dr.
Claudio Foletti;
Sementina, Dr. Renato
Milani) under the
overall clinical
responsibility of Dr.
Beatrice Neuffer, of
Chiasso. Responsible for
the entire project is
Dr. Osami Aki of Fuji
Sangyo, Japan, which
sponsored, in part, this
study, which was
monitored by Cross
Research (Arzo,
Switzerland).
Preliminary results of
this study have been
presented at the
Scientific Sessions of
the American Diabetes
Association (ADA) Annual
Meeting, New Orleans,
Louisiana, June 2003.
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