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The Antiseptic 2004; 101(11), 487-494
Evaluation of the clinical efficacy and safety of Diabecon in NIDDM
1
Dr. K.R. Kohli1, MD, Dr. Rangesh Paramesh2, MD(Ay)
Professor & Head, Dr. Sanjay Tamoli, MD (Scholar), Department of Kayachikitsa and Panchkarma,
R.A. Podar Medical College, Worli, Mumbai, India
2
Medical Advisor, R&D Center, The Himalaya Drug Company, Bangalore, India [*Corresponding author]
ABSTRACT
ABBREVIATIONS:
Despite
understanding
the BSL
: Blood sugar level
etiopathogenesis of NIDDM, there is an COX
: Cyclo-oxygenase
alarming rise in the insulin-resistant CRF
: Case report form
cases and failure of OHAs. Early CVA
: Cerebral vascular accident
FBSL
:
Fasting blood sugar level
diagnosis and control of NIDDM is
important in order to reduce the risk of IDDM : Insulin-dependent diabetes mellitus
: Lipopolysaccharide
later complications. Various herbs have LPS
NIDDM
: Noninsulin-dependent diabetes mellitus
been
found
beneficial
in
the
NO
:
Nitric oxide
management of NIDDM and are gaining
OHA
: Oral hypoglycemic agent
considerable
recognition
in
the
PG
: Prostaglandin
management of NIDDM worldwide. The PPBSL : Postprandial blood sugar level
present study was planned to evaluate
the clinical efficacy and safety of
Diabecon as a monotherapy and also as an adjunct with other OHAs, in the management of
NIDDM.
This was a prospective, open, non-randomized, phase III clinical trial. A total of 50 patients of
either sex, between 30-60 years of age, in whom the diagnosis of NIDDM was confirmed, and
who were willing to give informed consent were included in the study. Insulin-dependent
diabetes mellitus patients and NIDDM patients with acute complications of diabetes, pregnant
and lactating women, patients with concomitant severe illness necessitating other
medications, patients with severe hypertension, history of severe unstable angina, myocardial
infarction, CVAs, renal failure, and those patients, who were not willing to give informed
consent were excluded from the study. All enrolled patients were categorized into 2 groups.
The 1st group included 25 freshly diagnosed cases of NIDDM who were not consuming any
OHA, while the 2nd group included 25 patients of NIDDM, who were already consuming
some OHAs. Patients from the both the groups were advised to consume 2 tablets of
Diabecon, twice daily, for 3 months.
In all the patients, BSL was assessed at the time of enrollment and thereafter every month, for
3 months. All the patients had to undergo biochemical laboratory investigations. The
improvement in the NIDDM symptoms were rated using a predefined symptom score scale
ranging from 0-3.
The predefined primary efficacy end points were PPBSL control and reduction in the dose of
other OHAs. The predefined secondary safety endpoints were reduced incidence of adverse
reactions and overall compliance to the drug therapy. All the patients were followed up for 3
months (during the treatment period). All adverse events reported or observed by patients
were recorded with information about severity, date of onset, duration and action taken
regarding the study drug. Statistical analysis was done according to intention-to-treat
principles.
This study observed a significant reduction in the FBSL and PPBSL in the newly diagnosed
patients of NIDDM and a highly significant reduction in FBSL in those patients who
consumed Diabecon along with other OHAs. Similarly, there was significant improvement in
general symptoms, in both the groups after treatment with Diabecon, after a month. There
were no clinically significant changes in the hematological and biochemical parameters.
There were no clinically significant adverse reactions and overall compliance to the treatment
was excellent. Therefore, it may be concluded that Diabecon is clinically effective and safe in
the management of NIDDM, as a monotherapy in newly diagnosed patients and as an adjunct
in patients on conventional OHAs.
INTRODUCTION
Despite understanding the etiopathogenesis of NIDDM, there is an alarming rise in the
insulin-resistant cases and failure of OHAs. The past 2 decades have seen an explosive global
increase in the number of people diagnosed as NIDDM. In India, it is estimated that 19.4
million individuals are affected by NIDDM, which is likely to go up to 57.2 million by the
year 2025. India leads the world today with the largest number of diabetics in any given
country. In the 1970s, the prevalence of diabetes among urban Indians was reported to be 2.1
per cent and this has now risen to 12.1 per cent. Moreover, there is an equally large pool of
individuals with impaired glucose tolerance (IGT), many of who will eventually develop
NIDDM in the coming future.1
Diabetes can affect almost every physiological system in the body and the chronic
hyperglycemia of diabetes is associated with long-term dysfunction, damage and failure of
various organs (eyes, kidneys, nerves, heart and blood vessels). Individuals with undiagnosed
NIDDM are also at higher risk for cardiovascular disease, coronary artery disease and
peripheral vascular disease as compared with non-diabetics. They also have a greater
likelihood of having dyslipidemia, hypertension and obesity. Early diagnosis and control of
NIDDM is important in order to reduce the risk of later complications, which includes
cardiovascular events, visual loss, renal failure and limb amputations.2
Various herbs have been found beneficial in the management of NIDDM and are gaining
considerable recognition in the management of NIDDM worldwide.3 The analysis of available
data indicates that the use of herbs is increasing during the last several years.4,5 Recently,
guidelines for investigation of herbs have been developed and herbal extracts have been
clinically studied in detail for their pharmacodynamic and pharmacotherapeutic properties.6
Diabecon is a polyherbal formulation which contains extracts of Balsamodendron mukul,
Gymnema sylvestre, Pterocarpus marsupium, Glycyrrhiza glabra, Casearia esculenta,
Eugenia jambolana, Asparagus racemosus, Boerhaavia diffusa, Sphaeranthus indicus,
Tinospora cordifolia, Swertia chirata, Tribulus terrestris, Phyllanthus amarus, Gmelina
arborea, Gossypium herbaceum, Berberis aristate, Aloe vera, Shilajeet and powders of
Momordica charantia, Piper nigrum, Ocimum sanctum, Abutilon indicum, Curcuma longa,
Rumex maritimus, Vidangadi lauham, Abhraka bhasma, Pravala bhasma, Vanga bhasma,
Akika pishtia, Shingraf, Yashada bhasma and Trikatu. The present study was planned to
evaluate the clinical efficacy and safety of Diabecon as monotherapy and also as an adjunct
with other OHAs in the management of NIDDM.
Study aim
The present study was planned to evaluate the clinical efficacy and safety (long- and shortterm) of Diabecon as monotherapy and as an adjunct with other OHAs in the management of
NIDDM.
Study design
This was a prospective, open, non-randomized, phase III clinical trial conducted at the out
patient department of M.A. Podar Hospital, Mumbai, India.
MATERIALS AND METHODS
Inclusion criteria
A total of 50 patients of either sex, between 30-60 years of age in whom the diagnosis of
NIDDM was confirmed, and who were willing to give informed consent were included in the
study. The WHO diagnosis criteria (1980) was considered for diagnosis of NIDDM (For
newly diagnosed patients: FBSL >120 mg% and after 2 hours of consuming 75 grams of
glucose: >180 mg%).
Exclusion criteria
Insulin-dependent diabetes mellitus patients and NIDDM patients with acute complications of
diabetes were excluded form the trial. Pregnant and lactating women, patients with
concomitant severe illness necessitating other medications, patients with severe hypertension,
history of severe unstable angina, myocardial infarction, CVAs, renal failure, and those
patients, who were not willing to give informed consent were also excluded from the study.
Study procedure
All the enrolled patients were categorized into 2 groups. The 1st group included 25 freshly
diagnosed cases of NIDDM who were not consuming any OHA, while the 2nd group included
25 patients of NIDDM who were already consuming some OHAs. Patients from the both
groups were advised to consume 2 tablets of Diabecon, twice daily, for 3 months. Patients
with mild to moderate NIDDM were advised to consume 2 tablets of Diabecon before
breakfast followed by another 2 tablets before lunch, while patients with severe NIDDM were
advised to consume an additional 2 tablets before dinner.
In all the patients, BSL was done at the time of enrollment and thereafter every month, for 3
months. All patients were investigated for urine (routine and microscopic), hemogram, total
leucocyte count, differential leucocyte count, serum creatinine, blood urea, serum albumin,
serum globulin and lipid profile. The improvement in the NIDDM symptoms was assessed
using a predefined symptom score scale from 0 to 3 (0=absent, 1=mild, 2=moderate and
3=severe).
Primary and secondary endpoints
The predefined primary efficacy end points were PPBSL control and reduction in the dose of
other OHAs. The PPBSL control was graded as: excellent : upto 130 mg%, good : upto 150
mg%, fair : upto 180 mg%, poor : upto 250 mg% and treatment failure : >250 mg%. The
predefined secondary safety endpoints were reduced incidence of adverse reactions and
overall compliance to the drug therapy.
Follow-up and assessment
All patients were followed up for 3 months (during the treatment period) and at each followup visit, the patient’s response to the study drug was recorded in a structured CRF. The
subjective symptomatic relief and changes in the symptom score scale for each symptom were
recorded during each follow-up visit.
Adverse events
All adverse events reported or observed by patients were recorded with information about the
severity, date of onset, duration and action taken regarding the study drug. Relation of adverse
events to study medication was predefined as “Unrelated” (a reaction that does not follow a
reasonable temporal sequence from the time of administration of the drug), “Possible”
(follows a known response pattern to the suspected drug, but could have been produced by the
patient’s clinical state or other modes of therapy administered to the patient), and “Probable”
(follows a known response pattern to the suspected drug that could not be reasonably
explained by the known characteristics of the patient’s clinical state).
Patients were allowed to voluntarily withdraw from the study, if they had experienced serious
discomfort during the study or sustained serious clinical events requiring specific treatment.
For patients withdrawing from the study, efforts were made to ascertain the reason for
dropout. Non-compliance (defined as failure to take less than 80% of the medication) was not
regarded as treatment failure, and reasons for non-compliance were noted.
Statistical analysis
Statistical analysis was done according to intention-to-treat principles. The changes in various
parameters from baseline values and the values after 1st, 2nd and 3rd month were analyzed by
“Paired “t” Test”. The minimum level of significance was fixed at 95% confidence limit and
a 2-sided p value of <0.05 was considered as significant.
RESULTS
There was a significant reduction in the FBSL in the newly diagnosed patients of NIDDM
from 170 ± 40.47 mg% to 161.51 ± 52.13 mg%. Similarly, there was a significant reduction in
the PPBSL from 247.66 ± 70.65mg% to 223.13 ± 79.22 mg% (Figure 1).
In those patients who consumed Diabecon along with OHAs, there was highly significant
reduction in FBSL from 174.69 ± 55.77 mg% to 148.66 ± 35.49 mg%, after a month and there
was further reduction to 145.40 ± 39.43 mg%, at the end of the study. In eleven (22%)
patients the dose of other OHAs was reduced to 50% (Figure 2).
There
was
a
significant
improvement in the general
symptoms of NIDDM (Tables 1
and 2) such as polyuria (Figure 3),
generalized weakness (Figure 4)
and there was an improvement in
the appetite (Figure 5). The study
also observed a reduction in leg
cramps and burning sensation in
hands and soles (Figure 6) in both
the groups after a month of
treatment with Diabecon.
There were no clinically significant
changes in the hematological and
biochemical parameters. There
were no clinically significant
adverse reactions, either reported
Figure 1: Reduction in blood sugar level in newly diagnosed
patients of NIDDM on treatment with Diabecon alone
by patients, or observed by the investigators and the overall compliance to the treatment was
excellent.
DISCUSSION
This study observed a significant
reduction in the FBSL and PPBSL
in the newly diagnosed patients of
NIDDM and a highly significant
reduction in FBSL and PPBSL also
in those patients who consumed
Diabecon along with OHAs.
Similarly, there was significant
improvement in general symptoms,
in both the groups after treatment
with Diabecon, after a month.
These beneficial effects of
Diabecon in NIDDM might be due
to the synergistic action of its
ingredients, which are well
documented.
Figure 2: Reduction in blood sugar level in patients
consuming conventional OHAs on treatment with Diabecon
Table 1: Symptomatic improvement in NIDDM patients treated with Diabecon alone
Symptom
Baseline
1st month
2nd month
3rd month
Polyuria
Weakness
Loss of
appetite
Burning
sensation in
hands and
soles
Mean
S.D.
SEM
t value
p value
p value
summary
Mean
S.D.
S.E.M.
t value
p value
p value
summary
Mean
S.D.
S.E.M.
t value
p value
p value
summary
Mean
S.D.
S.E.M.
t value
p value
p value
summary
1.63
1.25
2.04
1.25
0.40
0.79
1.09
1.06
1.04
0.84
0.13
4.43
<0.001
Highly
significant
1.00
0.69
0.11
8.45
<0.001
Highly
significant
0.22
0.61
0.10
1.70
>0.1
0.90
0.92
0.18
3.88
<0.001
Highly
significant
0.68
0.56
0.15
8.45
<0.001
Highly
significant
0.04
0.21
0.15
2.34
<0.05
0.59
0.66
0.19
5.50
<0.001
Highly
significant
0.45
0.59
0.19
9.31
<0.001
Highly
significant
0.04
0.21
0.15
2.34
<0.05
Not significant
Significant
Significant
0.95
0.89
0.11
1.21
>0.1
0.81
0.73
0.18
1.5
<0.05
0.68
0.77
0.24
1.67
<0.05
Not significant
Significant
Significant
Table 2: Symptomatic improvement with Diabecon treatment in NIDDM patients consuming
conventional OHAs
Symptom
Baseline
1st month
2nd month
3rd month
Mean
1.40
0.81
0.59
0.59
S.D.
1.06
0.66
0.50
0.50
S.E.M.
0.10
0.11
0.11
Polyuria
t value
5.35
6.95
6.95
p value
<0.001
<0.001
<0.001
p value
Highly
Highly
Highly significant
summary
significant
significant
Mean
1.86
1.04
0.5
0.40
S.D.
0.88
0.72
0.59
0.59
S.E.M.
0.13
0.16
0.18
Weakness
t value
6.15
8.04
7.97
p value
<0.001
<0.001
<0.001
p value
Highly
Highly
Highly significant
summary
significant
significant
Mean
0.90
0.54
0.36
0.31
S.D.
1.15
0.73
0.78
0.64
S.E.M.
0.10
0.17
0.16
Loss of
t
value
3.46
3.19
3.48
appetite
p value
<0.01
<0.01
<0.01
p value
Significant
Significant
Significant
summary
Mean
0.86
0.54
0.40
0.31
S.D.
1.08
0.91
0.59
0.47
Burning
S.E.M.
0.13
0.12
0.15
sensation in
t
value
2.30
3.57
3.46
hands and
p value
<0.005
<0.01
<0.01
soles
p value
Significant
Significant
Significant
summary
Curcuminoids
from
Curcuma longa have an
ameliorating influence
on
diabetic
nephropathy, possibly
by their ability to lower
blood cholesterol levels.
Analysis of documented
data on enzymuria,
albuminuria, activity on
renal ATPases and fatty
acid composition of
renal membranes in
diabetic
condition
indicate
that
curcuminoids
significantly arrest the
progression of diabetic
nephropathy.7
Figure 3: Improvement in the symptom score of polyuria in the
NIDDM patients with Diabecon treatment
The active ingredients of Gymnema sylvestre are the gymnemic acids and Gymnema sylvestre
has been studied extensively for its beneficial action in diabetes mellitus.8 Gymnema sylvestre
appears to correct the metabolic derangements in diabetic liver, kidney and muscle and
reverses the hepatic pathological changes during the hyperglycemic phase by controlling
hyperglycemia. Results from studies show that extracts of Gymnema sylvestre exert a
stimulatory effect on insulin release by increasing the cellular permeability.
In one study, the extract
of Gymnema sylvestre
was found to suppress the
elevation
of
blood
glucose
level
by
inhibiting
glucose
absorption
in
the
9
intestine. Some studies
have also shown that
Gymnema sylvestre helps
in the regeneration or
revitalization of residual
beta cells in NIDDM and
IDDM patients, resulting
in
enhancement
of
10-12
endogenous insulin,
which is supported by the
raised insulin levels in the Figure 4: Improvement in the symptom score of weakness in the
NIDDM patients with Diabecon treatment
serum after Gymnema
sylvestre
supplementation. In one
experimental study, the
administration
of
Gymnema
sylvestre
regulated the BSL in
alloxan diabetic rabbits. It
has also been documented
that Gymnema sylvestre
not only produces blood
glucose homeostasis but
also increases the activity
of enzymes, affording
better
utilization
of
glucose
by
insulin
dependent pathways (it
controls the levels of Figure 5: Improvement in the symptom score of loss of appetite in the
phosphorylase,
NIDDM patients with Diabecon treatment
gluconeogenic enzymes
and sorbitol dehydrogenase). It was also observed that Gymnema sylvestre increases the
uptake and incorporation of glucose into glycogen and proteins (hepatic, renal and
muscular).13
The active ingredient of Pterocarpus marsupium is epicatechin and several studies have
documented the antihyperglycemic activity of Pterocarpus marsupium.14,15 In one study,
which assessed the effect of administration of Pterocarpus marsupium on the glycogen
content, there was a decrease in BSL by 38% and 60% on 15th and 30th day and there was
decrease in the hepatic and renal weight. Similarly, the renal glycogen content increased by
10-fold, while the hepatic and skeletal muscle glycogen content decreased by 75% and 68%.
Pterocarpus marsupium also renormalized the activities of hexokinase, glucokinase and
phosphofructokinase.16 Pterocarpus marsupium also has been shown to exhibit alphaglucosidase inhibitory activity comparable to that of metformin.17,18 Epicatechin increases the
cAMP content of the islets, which is associated with the increased insulin release, conversion
of proinsulin to insulin and cathepsin B activity.19
In one study, the
administration
of
Eugenia
jambolana
significantly decreased
the levels of blood
glucose, blood urea, and
cholesterol,
with
increased
glucose
tolerance and the levels
of total proteins and
liver glycogen. It also
decreased the activities
of
glutamate
oxaloacetate
transaminase
and
glutamate
pyruvate
transaminase and the Figure 6: Improvement in the symptom score of burning soles in the
hypoglycemic efficacy NIDDM patients with Diabecon treatment
was comparable to
glibenclamide.20 Amelioration of experimental diabetic neuropathy and gastropathy following
oral administration of Eugenia jambolana has also been documented.21 In another study,
administration of Eugenia jambolana resulted in the enhancement in serum insulin levels in
normoglycemic and diabetic rats and the incubation of isolated islets of langerhans with
Eugenia jambolana was found to stimulate insulin secretion in normal and diabetic animals,
accompanied by the inhibition of hepatic and renal insulinase activity.22
In one study, the effects of daily oral administration of Boerhaavia diffusa was investigated;
and a significant decrease in blood glucose with significant increase in plasma insulin levels
were observed in normal and diabetic rats. Treatment with Boerhaavia diffusa resulted in a
significant reduction of glycosylated hemoglobin and an increase in the total hemoglobin
level. Boerhaavia diffusa has been shown to exert influence on the activities of the hepatic
enzymes (hexokinase, glucose-6-phosphatase and fructose-1, 6-bisphosphatase); as
hexokinase activity is significantly increased and activities of glucose-6-phosphatase,
fructose-1, 6-bisphosphatase are significantly decreased in diabetic rats. Boerhaavia diffusa
also improved the oral glucose tolerance test and the effect was more prominent when
compared to glibenclamide.23
Significant inhibition of gluconeogenesis by Tribulus terrestris, along with the reduction in
the levels of plasma triglycerides have been documented.24,25 The antihyperglycemic activity
of the extracts of Aloe vera have been extensively documented and the hypoglycemic effect of
Aloe vera might be mediated through the stimulation of synthesis and/or release of insulin
from the beta cells of langerhans.26,27
Piperine, the active alkaloid of Piper nigrum has been evaluated for its glucose regulatory
efficacy and daily oral administration for 15 days lowered blood glucose concentrations and
hepatic glucose-6-phospatase enzyme activity.28
Various studies have elucidated the antihyperglycemic potential of Ocimum sanctum. Ocimum
sanctum renormalizes the glycogen content in various tissues and in a study, administration of
Ocimum sanctum was found to bring about a significant reduction in FBSL, uronic acid, total
amino acids, total cholesterol, triglycerides, phospholipids and total lipids. There was also a
significant reduction in the hepatic total cholesterol, triglycerides and total lipids and a similar
significant reduction in the renal total lipids. There was a significant reduction in the total
cholesterol content in cardiac tissue and of phospholipids.29-31
Oxidative stress has a critical role to play in the initiation of hyperglycemia; and it is also
responsible for tissue damage and vascular endothelial dysfunction, leading to the diabetic
complications. Many of the herbs used in Diabecon act as powerful antioxidants. The
antioxidant activity of Glycyrrhiza glabra, Eugenia jambolana, Curcuma longa, Casearia
esculenta, Asparagus racemosus, Tinospora cordifolia, Boerhaavia aristata, Phyllanthus
amarus, Swertia chirata, Aloe vera and Curcuma longa has a contributory role in the
antihyperglycemic activity of Diabecon.32-35
As observed in various studies, Diabecon helps in improving the glycogen stores in the liver
and prevents the oxidative damage of beta cells by increasing the islet cell superoxide
dismutase activity. Diabecon stimulates insulin secretion by stimulating cell membrane
permeability, and also helps in the regeneration and revitalization of islet cells. Diabecon also
enhances the peripheral utilization of glucose. By exerting effective control over
hyperglycemia, Diabecon thus prevents complications due to uncontrolled hyperglycemia. In
one study, Diabecon attenuated the progression of diabetic nephropathy and also improved
diabetic retinopathy.36 In another study, Diabecon resolved retinal and vitreal hemorrhages,
with subsequent prevention of the same and also enhanced the absorption of hard and soft
exudates by its anti-inflammatory properties. In a clinical study, Diabecon caused the
retardation of microaneurysmal and proliferative changes in the retina.37
CONCLUSION
Despite understanding the etiopathogenesis of NIDDM, there is an alarming rise in the insulin
resistant cases and failure of OHAs. Early diagnosis and control of NIDDM is important in
order to reduce the risk of later complications. Various herbs have been found beneficial in
the management of NIDDM and are gaining considerable recognition in the management of
NIDDM worldwide. The present study was planned to evaluate the clinical efficacy and
safety of Diabecon as a monotherapy and also as an adjunct with other OHAs in the
management of NIDDM. This study observed significant reduction in the FBSL and PPBSL
in the newly diagnosed patients of NIDDM and a highly significant reduction FBSL in those
patients who consumed Diabecon along with OHAs. Similarly, there was a significant
improvement in general symptoms in both the groups, after treatment with Diabecon, after a
month. There were also no clinically significant changes in the hematological and
biochemical parameters. There were no clinically significant adverse reactions, either reported
by patients, or observed by the investigators and the overall compliance to the treatment was
excellent.
Diabecon helps in improving the hepatic glycogen stores and prevents the oxidative damage
of beta cells by increasing the islet cell superoxide dismutase activity. Diabecon stimulates
insulin secretion and also helps in the regeneration and revitalization of islet cells. Diabecon
also enhances the peripheral utilization of glucose. Further, the antioxidant activity of various
ingredients has a contributory role in the antihyperglycemic activity of Diabecon. Therefore,
it may be concluded that Diabecon is clinically effective and safe in the management of
NIDDM, as a monotherapy in newly diagnosed patients and as an adjunct in patients on
conventional OHAs.
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