dissertation on comparison of efficacy...
TRANSCRIPT
DISSERTATION ON
“COMPARISON OF EFFICACY AND SAFETY OF EPALRESTAT
WITH METHYLCOBALAMIN IN PATIENTS WITH
DIABETIC NEUROPATHY”
Dissertation submitted to
THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY
In partial fulfillment of the requirement
For the award of the degree of
M.D. BRANCH-VI
IN
PHARMACOLOGY
Submitted By
Registration Number: 201516452
KARPAGA VINAYAGA INSTITUTE OF MEDICAL SCIENCES
AND RESEARCH CENTRE, MADURANTHAGAM
THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY, CHENNAI
TAMILNADU
MAY-2018
CERTIFICATE
This is to certify that Dr. C. Preeth, a Post Graduate student in the
Department of Pharmacology has carried out the work titled “Comparison of
efficacy and safety of Epalrestat with Methylcobalamin in patients with
Diabetic neuropathy” under the guidance of Dr.P.JACOB VERGHESE, M.D.,
PROFESSOR, Department of Pharmacology, towards the partial fulfillment of
regulations laid down by The Tamilnadu Dr. M.G.R Medical University, Guindy,
Chennai, Tamilnadu, India for the award of Doctor of Medicine (M.D.,) in
Pharmacology.
Dr.P. JACOB VERGHESE, M.D., DR. R. KAVITHA, M.D.,
PROFESSOR, PROFESSOR & HOD,
Karpaga Vinayaga Institute of Medical Karpaga Vinayaga Institute of Medical
Sciences & Research Centre, Sciences & Research Centre,
Chinnakolambakkam, Chinnakolambakkam,
MaduranthagamTk, MaduranthagamTk,
Kancheepuram District– 603 308, Kancheepuram District– 603 308,
Tamilnadu, India. Tamilnadu, India.
DR. SUFALA SUNIL VISHWASRAO,
PRINCIPAL,
Karpaga Vinayaga Institute of Medical Sciences & Research Centre,
Chinnakolambakkam,
Maduranthagam Tk,
Kancheepuram District– 603 308,
Tamilnadu, India.
DECLARATION
I declare that dissertation entitled “Comparison of efficacy and safety
of Epalrestat with Methylcobalamin in patients with Diabetic neuropathy”
submitted by me for the degree of M.D., is the record work carried out
by me under the guidance of Dr.P. JACOB VERGHESE, Professor Of
Pharmacology, Karpaga Vinayaga Institute of Medical Sciences and Research
Centre and has not formed the basis of any Degree, Diploma, Fellowship, titles
in this or any other University or other similar Institution of Higher learning.
Place: Chinnakolambakkam Signature of the Candidate
Date: DR. C. PREETH
Signature of the Guide Signature of HOD
Dr.P. JACOB VERGHESE, M.D., DR. R. KAVITHA, M.D.,
PROFESSOR, PROFESSOR & HOD,
KarpagaVinayaga Institute of Medical Karpaga Vinayaga Institute of Medical
Sciences & Research Centre, Sciences & Research Centre,
Chinnakolambakkam, Chinnakolambakkam,
MaduranthagamTk, MaduranthagamTk,
Kancheepuram District– 603 308, Kancheepuram District– 603 308,
Tamilnadu, India. Tamilnadu, India.
ACKNOWLEDGEMENTS
At the outset I express my sincere thanks to my esteemed guide
Dr.P.JACOB VERGHESE M.D., Professor in the Department of
Pharmacology, Karpaga Vinayaga Institute of Medical Sciences and Research
Centre for his encouragement and valuable guidance in the topic given from
time to time for the successful completion of study.
I am extremely thankful to the Managing Director,
Dr.R. ANNAMALAI, M.S., M.Ch., Principal Dr. SUFALA SUNIL
VISHWASRAO, M.D., Medical Director Dr. SATHIYANARAYANAN,
Karpaga Vinayaga Institute of Medical Sciences and Research Centre for
providing me all the facilities to conduct this study.
I express my deep and sincere gratitude to Dr. R. KAVITHA, M.D.,
Professor and Head, Department of Pharmacology, Karpaga Vinayaga Institute
of Medical Sciences and Research Centre for being my mentor and support at
all levels.
I profusely thank my Co-guide Dr. V. GOPAL DASS, M.D., Professor
and Head, Department of General Medicine, Karpaga Vinayaga Institute of
Medical Sciences and Research Centre for having permitted to conduct this
study and the constant support he extended throughout the study.
I thank Dr. D. SRINIVASAN, Ph.D., Professor in the Department of
Pharmacology, KarpagaVinayaga Institute of Medical Sciences and Research
Centre for his kind guidance and encouragement during the course of this
study.
I express my deep and sincere gratitude to Dr. B. PRATHAP, M.D.,
Associate Professor, Department of Pharmacology, Karpaga Vinayaga Institute
of Medical Sciences and Research Centre for his guidance and support at all
levels.
My heartfelt thanks to my Assistant Professors, Dr. E. SESHATHRI,
M.D., and Dr. SUNIL M VISHWASRAO, M.D., in guiding me through the
course of the study.
I owe my sincere thanks to Dr. N. CHANDRAN, B.V.Sc., and AH for
encouraging me towards this research.
I thank my Senior and Junior Post Graduate colleagues for their greatest
help and support through the course.
I sincerely thank our bio-statistician GLADIUS JENIFER for her
guidance during my dissertation.
I am immensely grateful to the staffs at the Department of
Pharmacology and Department of General Medicine, Karpaga Vinayaga
Institute of Medical Sciences and Research Centre for having provided me
technical support throughout the study.
Last but no means the least, I am greatly indebted to all the patients who
had taken part in this study without whom the study could not have been
completed.
Finally my dissertation would have not been accomplished without the
support of my parents Mr. Chandrasekaran& Mrs. Thiripurasundari, my
husband Dr. Chakravarthi, my sons Sibi Aathyandha& Rishi Aathreya and my
other family members.
Above all I thank my Almighty for his blessings.
PLAGIARISM CERTIFICATE
PLAGIARISM CERTIFICATE
CONTENTS
CHAPTER PARTICULARS PAGE NO.
1 INTRODUCTION 1
2 AIMS AND OBJECTIVES 4
3 REVIEW OF LITERATURE 5
4 DRUG PROFILE 33
5 PLAN OF WORK 40
6 MATERIALS AND METHODS 41
7 OBSERVATION AND RESULTS 46
8 DISCUSSION 82
9 SUMMARY 86
10 CONCLUSION 88
11 BIBLIOGRAPHY 89
12 ANNEXURES 99
LIST OF TABLES
SL.
NO
TITLE PAGE
NO.
1 Explains blood test levels for diagnosis of diabetes and
prediabetes. 20
2 Explains the study groups. 42
3 Explains the number of males and females among the study
groups A, B and C. 49
4 Shows the mean age (in years) of the patients belonging to
groups A, B and C. 51
5 Shows the mean BMI of all three groups at baseline and at
the end of 4th, 8th and 12th weeks. 53
6 Shows the mean fasting blood glucose level of all three
groups at baseline and at the end of 4th, 8th and 12th weeks. 55
7 Shows the mean post prandial blood glucose level of all
three groups at baseline and end of study. 57
8 Shows the mean glycosylated haemoglobin level of all three
groups at baseline and end of study. 59
9 Shows the mean AST concentration of groups A, B & C. 61
10 Shows the mean ALT concentration of groups A, B & C. 63
11 Shows the mean serum albumin level of groups A, B & C. 65
12 Explains the mean serum total bilirubin level of groups A, B
& C. 67
13 Explains the serum creatinine concentration of groups A, B
& C. 69
14 Shows the serum urea concentration of groups A, B & C. 71
15 Shows the urine albumin levels of groups A, B & C. 73
16 Explains the urine sugar levels of groups A, B & C. 74
17 Shows the frequency of various adverse drug reactions
between the study groups. 75
18 Shows the pain intensity scores (VAS Method). 76
19 Shows the MichiganNeuropathy Screening Instrument
(MNSI) score- Completed by the person with diabetes. 78
20 Shows the MichiganNeuropathy Screening Instrument
(MNSI) score - Completed by health professionals. 80
LIST OF FIGURES
SL.
NO
TITLE PAGE
NO.
1 Explains the synthesis, release and actions of insulin 17
2 Explains the pathogenesis of type 1 diabetes mellitus 18
3 Explains the pathogenesis of type 2 diabetes mellitus 19
4 Polyol (Sorbitol) Pathway 24
5 Polyol (Sorbitol) Pathway with accumulation of sorbitol
and fructose
25
6 Shows the percentage of males and females among the
study group A.
50
7 Shows the percentage of males and females among the
study group B.
50
8 Shows the percentage of males and females among the
study group C.
50
9 Illustration of the graphical representation of the mean age
of the study groups.
52
10 Shows the graphical representation of change in mean BMI
of all three groups during the visits.
54
11 Illustration of graphical representation of table 6. 56
12 Shows the graphical representation of table 7. 58
13 Illustration of graphical representation of table 8. 60
14 Illustration of graphical representation of table 9. 62
15 Shows the graphical representation of table 10. 64
16 Illustration of graphical representation of table 11. 66
17 Illustration of graphical representation of table 12. 68
18 Illustration of graphical representation of table 13. 70
19 Shows the graphical representation of table 14. 72
20 Shows the graphical representation of table 18. 77
21 Shows the graphical representation of table 19. 79
22 Illustration of graphical representation of table 20. 81
LIST OF ABBREVIATIONS
ACE Angiotensin-converting enzyme
ACR Albumin:Creatinine Ratio
ALA Alpha Lipoic Acid
ALT Alanine Amino Transferase-SGPT
ARBs Angiotensin Receptor Blockers
AST Aspartate Transaminase – SGOT
ATP Adenosine Triphosphate
BMI Body Mass Index
CBC Complete Blood Count
CDC Center for Disease Control
CHD Coronary heart disease
CNS Central Nervous System
DKA Diabetic Ketoacidosis
DM Diabetes Mellitus
FBS Fasting Blood Glucose
FPG Fasting Plasma Glucose
GAD Glutamic acid Decarboxylase
GFR Glomerular Filtration Rate
GIP Gastric Inhibitory Polypeptide
GLP Glucagon Like Peptide
GLUT2 Glucose Transporter 2
HbA1C Glycosylated Hemoglobin
HDL High Density Lipoprotein
HHS Hyperosmolar hyperglycaemicnonketotic
coma
HLA-DR Human Leukocyte Antigen – antigen D
Related
HNF Hepatocyte nuclear transcription factor
IDDM Insulin-Dependent Diabetes Mellitus
IDF International Diabetes Federation
IEC Institutional Ethical Committee
IM Intra Muscular
IRS Insulin Receptor Substrates
IV Intra Venous
LFT Liver Function Test
MC Methylcobalamin
MDRD Modification of Diet in Renal Disease
MI Myocardial Infarction
MNSI Michigan neuropathy screening instrument
NIDDM Noninsulin-Dependent Diabetes Mellitus
NPH Neutral Protamine Hagedorn
NRS Numeric Rating Scale
NS Non- Significant
OADs Oral Anti Diabetic Drugs
OGTT Oral Glucose Tolerance Test
PKC Protein Kinase C
PPAR-γ Peroxisome proliferator-activated receptor
gamma
PPBS Post Prandial Blood Glucose
PPG Post Prandial Glucose
PVD Peripheral Vascular Disease
PZI Protamine Zinc Insulin
RFT Renal Function Test
SC Subcutaneous
SD Standard Deviation
SEM Standard Error Mean
SIS Sleep Interference Scores
SUR Sulphonyl Urea Receptor
T2DM Type 2 Diabetes Mellitus
TZDs Thiazolidinediones
VAS Visual Analog Scale
INTRODUCTION
1
1. INTRODUCTION
DIABETES MELLITUS
Diabetes is a national as well as global epidemic disease in terms of
incidence, healthcare costs and overall complications as reported by the Center
for Disease Control (CDC)1. According to recent estimates, approximately 285
million people worldwide (6.6%) in the 20–79 year age group have diabetes in
2010 and by 2030, 438 million people (7.8%) of the adult population, is
expected to have diabetes.
The International Diabetes Federation (IDF) estimates the total number
of people in India with diabetes to be around 50.8 million in 2010, rising to
87.0 million by 20302. Globally, as of 2013, an estimated 382 million people
have diabetes worldwide, with type 2 diabetes making up about 90% of the
cases3,4. This is equal to 8.3% of the adult’s population, with equal rates in both
women and men5. Worldwide in 2012 and 2013 diabetes resulted in 1.4 to 5.1
million deaths per year, making it the 8th leading cause of death6. The number
of people with diabetes is expected to rise to 592 million by 20357,8. The
number of people with diabetes has risen from 108 million in 1980 to 422
million in 20149,10. The global prevalence of diabetes among adults over 18
years of age has risen from 4.7% in 1980 to 8.5% in 20149. Diabetes prevalence
has been rising more rapidly in middle- and low-income countries. Diabetes is
a major cause of blindness, kidney failure, heart attacks, stroke and lower limb
amputation. In 2014, 8.5% of adults aged 18 years and older had diabetes.
2
In 2015, diabetes was the direct cause of 1.6 million deaths and in 2012 high
blood glucose was the cause of another 2.2 million deaths. In 2015, an
estimated 1.6 million deaths were directly caused by diabetes. Another 2.2
million deaths were attributable to high blood glucose in 2012. Almost half of
all deaths attributable to high blood glucose occur before the age of 70 years.
WHO projects that diabetes will be the seventh leading cause of death in
203011,12. Healthy diet, regular physical activity, maintaining a normal body
weight and avoiding tobacco use are ways to prevent or delay the onset of type
2 diabetes. Diabetes can be treated and its consequences avoided or delayed
with diet, physical activity, medication and regular screening and treatment for
complications.
Epalrestat is a carboxylic acid derivative that acts as aldose reductase
inhibitor. Epalrestat is proven to have beneficial effects in diabetic neuropathy
in many controlled clinical trials. In hyperglycemia, Epalrestat significantly
reduces intracellular sorbitol accumulation by an uncompetitive aldose
reductase inhibition.
Methylcobalamin is one of the biologically active forms of vitamin B12.
It is used in the treatment of peripheral neuropathy, diabetic neuropathy, and as
a preliminary treatment for amyotrophic lateral sclerosis. Unlike
cyanocobalamin, Methylcobalamin is active in the spinal fluid. Due to this
property, it is able to help heal the damaged nerve cells and restores normal
functions.
3
Diabetic neuropathies can lead to a wide variety of sensory, motor and
autonomic symptoms. The most common is the symmetrical distal sensory
type, which is particularly evident in the feet and may slowly progress to a
complete loss of feeling. It is most prevalent in elderly patients with type 2
diabetes but may be found with any type of diabetes, at any age beyond
childhood.
Recently Epalrestat and Methylcobalamin are widely used in clinical
practice to manage diabetic neuropathy. Hence, this study was undertaken to
evaluate the efficacy and safety of Epalrestat with Methylcobalamin in patients
with diabetic neuropathy.
AIMS AND OBJECTIVES
4
2. AIMS AND OBJECTIVES
AIM:
This study was aimed to assess and compare the efficacy and safety of
Epalrestat with Methylcobalamin in patients with diabetic neuropathy.
OBJECTIVES
1. To assess the efficacy and safety of individual effect of Epalrestat and
Methylcobalamin in patients with diabetic neuropathy.
2. To assess the efficacy and safety of combined effect of Epalrestat and
Methylcobalamin in patients with diabetic neuropathy and to compare
with individual effect of Epalrestat and Methylcobalamin in patients
with diabetic neuropathy.
REVIEW OF LITERATURE
5
3. REVIEW OF LITERATURES
A literature review is a summary of previous research on a topic. The
review of literature aims to describe the ‘state of play’ in the area selected for
study. Our literature review focused on the pharmacological potential of
Epalrestat, an aldose reductase inhibitor and Methylcobalamin. Such literature
reviews describe what has been written about the area, the major research
findings across studies, and the major debates in terms of substantive and
methodological issues.
Diabetes mellitus (DM) is a group of metabolic disorders characterized
by hyperglycemia and abnormalities in carbohydrate, fat, and protein
metabolism. It results from defects in insulin secretion, insulin sensitivity, or
both13. In this condition there are high blood sugar levels over a prolonged
period14. This high blood sugar produces the symptoms of frequent urination,
increased thirst, and increased hunger. Untreated, diabetes can cause many
complications15. Acute complications include diabetic ketoacidosis and
nonketotic hyperosmolar coma16. Serious long term complications include
heart disease, kidney failure, foot ulcers and damage to eyes15.
CLASSIFICATION OF DIABETES MELLITUS
TYPE 1 DIABETES MELLITUS
It results from the body’s failure to produce insulin. This form was
previously referred to as “insulin-dependent diabetes mellitus” (IDDM) or
“Juvenile diabetes”. The cause is unknown14. It is characterized by loss of the
6
insulin-producing beta cells of the islets of Langerhans in the pancreas, leading
to insulin deficiency17. Type 1 DM is further divided into 2 subtypes:
Subtype 1A (immune-mediated) DM
It is characterized by autoimmune destruction of β-cells which usually
leads to insulin deficiency.
Subtype 1B (idiopathic) DM
It is characterized by insulin deficiency with tendency to develop ketosis
but these patients are negative for autoimmune markers18.
TYPE 2 DIABETES MELLITUS
It begins with insulin resistance, a condition in which cells fail to
respond insulin properly14. As the disease progresses a lack of insulin may also
develop19,20. This form was previously referred to as noninsulin-dependent
diabetes mellitus (NIDDM) or “adult-onset diabetes”. The primary cause is
excessive body weight and not enough exercise15. In the early stage of type 2,
the predominant abnormality is reduced insulin sensitivity. At this stage,
hyperglycemia can be reversed by a variety of measures and medications that
improve insulin sensitivity or reduce glucose production by the liver.
GESTATIONAL DIABETES
It is the third main form and occurs when pregnant women without a
previous diagnosis of diabetes develop a high blood glucose level11. About 4%
pregnant women develop DM due to metabolic changes during pregnancy.
7
Although they revert back to normal glycaemia after delivery, these women are
prone to develop DM later in their life18.
OTHER SPECIFIC TYPES OF DIABETES14
A. Genetic defect of β-cell function due to mutations in various
enzymes (maturity-onset diabetes of the younger MODY)
E.g.: Hepatocyte nuclear transcription factor—HNF Glucokinase
B. Genetic defect in Insulin action
E.g.: Type A Insulin resistance
C. Diseases of exocrine pancreas
E.g.: Chronic pancreatitis, Pancreatic tumours, Post pancreatectomy
D. Endocrinopathies
E.g.: Acromegaly, Cushing’s syndrome, Pheochromocytoma
E. Drug or Chemical induced
E.g.: Steroids, Thyroid hormone, Thiazides, Beta blockers
F. Infections
E.g.: Congenital rubella, Cytomegalovirus
G. Uncommon forms of immune mediated DM
E.g.: Stiff man syndrome, Anti insulin receptor antibodies
H. Other genetic syndromes
E.g.: Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome
8
SIGNS AND SYMPTOMS16,21
Weight loss
Polyuria
Polyphagia
Headache
Polydipsia
Blurring of vision
Fatigue
Slow healing of cuts
Prolonged high blood glucose absorption in the lens of eyes, which lead
to changes in the shape resulting in visual changes. Blurred vision is a common
complaint leading to a diabetes diagnosis. A number of skin rashes that can
occur in diabetes are collectively known as diabetic dermatomes.
RISK FACTORS FOR TYPE 2 DIABETES MELLITUS18, 19-24
1. Family history of type 2 DM
2. Obesity
3. Habitual physical inactivity
4. Race and ethnicity (Blacks, Asians, Pacific Islanders)
5. Previous identification of impaired fasting glucose or impaired
glucose tolerance
9
6. History of gestational DM or delivery of baby heavier than 4 kg
7. Hypertension
8. Dyslipidaemia (HDL level < 35 mg/dl or triglycerides > 250 mg/dl)
9. Polycystic ovary disease and acanthosis nigricans
10. History of vascular disease
COMPLICATIONS18, 25-30
As a consequence of hyperglycaemia of diabetes, every tissue and organ
of the body undergoes biochemical and structural alterations which account for
the major complications in diabetics which may be acute metabolic or chronic
systemic. Both types of diabetes mellitus may develop complications which are
broadly divided into 2 major groups:
I. Acute metabolic complications
II. Long-term diabetic complications
I. ACUTE METABOLIC COMPLICATIONS
These include diabetic ketoacidosis, hyperosmolar nonketotic coma, and
hypoglycaemia. Metabolic complications develop acutely. While ketoacidosis
and hypoglycaemic episodes are primarily complications of type 1 DM,
hyperosmolar nonketotic coma is chiefly a complication of type 2 DM.
1. Diabetic ketoacidosis (DKA)
Ketoacidosis is almost exclusively a complication of type 1 DM. It can
develop in patients with severe insulin deficiency combined with glucagon
10
excess. Failure to take insulin and exposure to stress are the usual precipitating
causes. Severe lack of insulin causes lipolysis in the adipose tissues, resulting
in release of free fatty acids into the plasma. These free fatty acids are taken up
by the liver where they are oxidized through acetyl coenzyme-A to ketone
bodies, principally acetoacetic acid and β-hydroxybutyric acid. Such free fatty
acid oxidation to ketone bodies is accelerated in the presence of elevated level
of glucagon. Once the rate of ketogenesis exceeds the rate at which the ketone
bodies can be utilised by the muscles and other tissues, ketonaemia and
ketonuria occur.
2. Hyperosmolar hyperglycaemic nonketotic coma (HHS)
Hyperosmolar hyperglycaemic nonketotic coma is usually a
complication of type 2 DM. It is caused by severe dehydration resulting from
sustained hyperglycaemic diuresis. The loss of glucose in urine is so intense
that the patient is unable to drink sufficient water to maintain urinary fluid loss.
3. Hypoglycaemia
Hypoglycaemic episode may develop in patients of type 1 DM. It may
result from excessive administration of insulin, missing a meal, or due to stress.
Hypoglycaemic episodes are harmful as they produce permanent brain damage,
or may result in worsening of diabetic control and rebound hyperglycaemia, so
called Somogyi’s effect.
11
II. LONG-TERM DIABETIC COMPLICATIONS
The long-term complications may occur in each type of diabetes, the
spectrum of incidence is different. Many patients with type 2 diabetes have had
their disease a longtime before the diagnosis, by which time many have
developed diabetic complications. Hyperglycaemia and hypertension are the
two major modifiable risk factors that influence the development of diabetic
complications.
Diabetic complications are frequently divided into macrovascular and
microvascular complications. Macrovascular complications arise from
damage to large blood vessels and microvascular complications occur from
damage to smaller vessels. The general aetiology of macro- and microvascular
complications is the same and results from atherosclerosis of the vessels, which
may lead to occlusion.
A. Macrovascular Complications
The risk of macrovascular complications, including cardiovascular
disease (coronary heart disease and stroke) and PVD, is 2–4 times higher for
people with diabetes.
1. Cardiovascular disease
The most common cause of death in people with type 2 diabetes is
cardiovascular disease which accounts for an estimated 80% of deaths in this
patient group. The risk of a person with diabetes having a myocardial infarction
(MI) is the same as someone without diabetes having a second myocardial
12
infarction. The risk of cardiovascular disease is increased further if
nephropathy is present. Other cardiovascular disease risk factors are the same
as in the non-diabetic population and include smoking, hypertension and
dyslipidaemia.
2. Hypertension
Hypertension is twice as common amongst the diabetic population
compared to the general population. It affects over 80% of those with type 2
diabetes. The treatment target ranges for people with diabetes are generally
lower than for people without diabetes, as hypertension is associated with the
development of macro- and microvascular complications.
3. Peripheral vascular disease (PVD)
PVD affects the blood vessels outside the heart. In people with diabetes,
it often affects the arteries of the legs and may give rise to intermittent
claudication, a cramping pain experienced on walking, due to reversible muscle
ischaemia secondary to atherosclerosis. The iliac vessels can be affected,
causing buttock pain and also erectile dysfunction. If PVD is present, the risk
of cardiovascular disease increases.
B. Microvascular Complications
Microvascular complications include retinopathy, nephropathy and
neuropathy.
13
1. Retinopathy
Diabetic retinopathy is the leading cause of blindness in people under
the age of 60 in industrialized countries. Twenty years from the onset of
diabetes, over 90% of people with type1, and over 60% of people with type 2,
will have diabetic retinopathy. The main problem with diagnosing retinopathy
is that it is symptom less until the disease is far advanced. Therefore, if regular
screening is not undertaken, diagnosis may not be made early enough for
successful treatment intervention. Tight glycaemic control has been shown to
prevent and delay the progression of retinopathy in patients with type 1 disease.
2. Nephropathy
In diabetic renal disease, the kidneys become enlarged and the
glomerular filtration rate (GFR) initially increases. However, if the
nephropathy progresses, the GFR starts to decline. Serum creatinine used alone
to estimate renal function has limitations. The GFR can be estimated (eGFR).
The most popular method is the modified Modification of Diet in Renal
Disease (MDRD) formula, which requires serum creatinine, age, sex and
ethnicity.
eGFR = 175× [plasma creatinine (µmol / L) 0.011312]1.154 × [age in years]0.203
× [1.212if black] × [0.742if female]
eGFR = glomerular filtration rate (mL / minper1.73m2 )
The presence of nephropathy is indicated by the detection of
microalbuminuria (small amounts of albumin present in urine). If higher
14
amounts of albumin are detected, this is termed proteinuria (or
macroalbuminuria) and signifies more severe renal damage. Microalbuminuria
is defined as an albumin:creatinine ratio (ACR) greater or equal to 2.5
mg/mmol (men) and 3.5 mg/mmol (women). Proteinuria may be defined as an
albumin:creatinine ratio greater than 30 mg/mmol or albumin concentration
greater than 200 mg/L. Proteinuria may progress to end-stage renal disease and
require dialysis. Albumin in the urine increases the risk of cardiovascular
disease, with microalbuminuria associated with 2–4 times the risk, proteinuria
with nine times the risk and end-stage renal disease increasing risk by 50 times.
Tight control of both glycaemic levels and blood pressure reduces the risk of
developing nephropathy.
3. Peripheral neuropathy30-37
Peripheral neuropathy is the progressive loss of peripheral nerve fibres
resulting in nerve dysfunction. Diabetic neuropathies can lead to a wide variety
of sensory, motor and autonomic symptoms. The most common is the
symmetrical distal sensory type, which is particularly evident in the feet and
may slowly progress to a complete loss of feeling. It is most prevalent in
elderly patients with type 2 diabetes but may be found with any type of
diabetes, at any age beyond childhood. Diabetic proximal motor neuropathy is
rapid in onset and involves weakness and wasting, principally of the thigh
muscles. Distal motor neuropathy can lead to symptoms of impaired fine
co-ordination of the hands and/or foot slapping. Autonomic neuropathy may
15
also cause dry skin and lack of sweating, both of which may contribute to
diabetic foot problems.
C. Macro- and microvascular disease combined
1. Diabetic foot problems
Infected diabetic foot ulcers account for the largest number of diabetes-
related hospital bed-days and are the most common non-trauma cause of
amputations. The rate of lower limb amputation in people with diabetes is 15
times higher than in the general population. The lifetime risk of a person with
diabetes developing a foot ulcer is around 15%.
Diabetic foot ulcers are a costly problem and are associated with
considerable morbidity. Foot problems often develop as a result of a
combination of specific problems associated with having diabetes, which are
sensory and autonomic neuropathy, PVD and hyperglycaemia.
Poor foot care and poorly controlled diabetes are also contributory
factors. Development of foot ulcers may be partly preventable by patient
education. People with diabetes learn that their feet are particularly vulnerable,
and if problems arise, they must seek immediate professional advice.
There are three main types of foot ulcers: neuropathic, ischaemic and
neuroischaemic.
Neuropathic ulcers occur when peripheral neuropathy causes loss of
pain sensation. The ulcers can be deep but are usually painless and are caused
by trauma to the foot which is not noticed until after significant damage has
16
occurred Ischaemic ulcers result from PVD and poor blood supply causing a
reduction in available nutrients and oxygen required for healing. Ischaemic
ulcers are painful and usually occur on the distal ends of the toes.
Most ulcers have elements of both neuropathy and ischaemia and are
termed as neuroischaemic.
PATHOGENESIS18,38,39
PHYSIOLOGY OF NORMAL INSULIN SYNTHESIS AND
SECRETION
The major stimulus for both synthesis and release of insulin is glucose.
The steps involved in biosynthesis, release and actions of insulin are as follows
Synthesis
Insulin is synthesized in the β-cells of pancreatic islets of Langerhans.
i) It is initially formed as pre-proinsulin which is single-chain 86-amino
acid precursor polypeptide.
ii) Subsequent proteolysis removes the amino terminal signal peptide,
forming proinsulin.
iii) Further cleavage of proinsulin gives rise to A (21 aminoacids) and B
(30 amino acids) chains of insulin, linked together by connecting
segment called C-peptide, all of which are stored in the secretory
granules in the β-cells.
17
Release
Glucose is the key regulator of insulin secretion from β-cells by a series
of steps:
i) Hypoglycaemia stimulates transport into β-cells of a glucose
transporter, GLUT2. Other stimuli influencing insulin release
include nutrients in the meal, ketones, amino acids etc.
ii) An islet transcription factor, glucokinase, causes glucose
phosphorylation.
iii) Metabolism of glucose to glucose-6-phosphate by glycolysis
generates ATP.
iv) Generation of ATP alters the ion channel activity on the membrane.
It causes inhibition of ATP-sensitive K+ channel on the cell
membrane and opening up of calcium channel with resultant influx
of calcium, which stimulates insulin release.
Action
Half of insulin secreted from β-cells into portal vein is degraded in the
liver while the remaining half enters the systemic circulation for action on the
target cells.
Figure 1: Explains the synthesis, release and actions of insulin.
18
PATHOGENESIS OF TYPE 1 DM
The basic phenomenon in type 1 DM is destruction of β-cell mass,
usually leading to absolute insulin deficiency.
MECHANISMS OF TYPE 1A DM
1. Genetic susceptibility
2. Autoimmune factors
3. Environmental factors, are involved as basic mechanism.
Figure 2: Explains the pathogenesis of type 1 diabetes mellitus.
19
PATHOGENESIS OF TYPE 2 DM
The basic metabolic defect in type 2 DM is either a delayed insulin
secretion relative to glucose load (impaired insulin secretion), or the peripheral
tissues are unable to respond to insulin (insulin resistance).
The pathogenesis factors are,
1. Genetic factors
2. Constitutional factors
3. Insulin resistance
4. Impaired insulin secretion
5. Increased hepatic glucose synthesis
Figure 3: Explains the pathogenesis of type 2 diabetes mellitus.
20
DIAGNOSIS19,40,41
• A1C test, also called hemoglobin A1C, HbA1C, or glycohemoglobin
test.
• Fasting plasma glucose (FPG) test.
• Oral glucose tolerance test (OGTT).
TABLE 1: Explains blood test levels for diagnosis of diabetes and
prediabetes
A1C
(Percent)
Fasting
Plasma Glucose
(mg/dL)
Oral Glucose
Tolerance Test
(mg/dL)
Diagnosis
About 5 99 or below 139 or below Normal
5.7 to 6.4 100 to 125 140 to 199 Prediabetes
6.5 or above 126 or above 200 or above Diabetes
MANAGEMENT OF DIABETES MELLITUS42-45
For the management of diabetes mellitus life style modification is
necessary along with pharmacological treatment
NONPHARMACOLOGICAL TREATMENT
Diet control : Avoid carbohydrates, sugar, reduction of salt
intake & to include more fiber containing
food, vegetables and fish oils
21
Moderate exercise : Include brisk walking, cycling, and restrict
alcohol consumption, avoid stress, avoid
smoking
PHARMACOLOGICAL TREATMENT
The treatment option for type 1 diabetes is insulin. Exogenous insulins
are used to control blood sugar level.
TYPES OF INSULIN
A. Rapid Acting
Insulin lispro, Insulin aspart, Insulin glulisine
B. Short Acting
Regular (soluble) insulin
C. Intermediate Acting
Insulin zinc suspension or Lente, Neutral protamine hagedorn
(NPH) or isophane insulin
D. Long Acting
Protamine zinc insulin (PZI) , Insulin glargine
Insulin preparations:
Soluble insulin : Human actrapid, Human velosulin
Biphasic insulin : Human mixtard 10, Novomix 30
22
Isophane insulin : Humulin 1, hypurinporcinisophane
Insulinzinc suspension : Human monotard, Hypurin Bovine
Lente
ORAL HYPOGLYCAEMIC AGENTS
In type 2 diabetes glycaemic control cannot be achieved by only life
style modification, along with pharmacological treatment also necessary to
control blood sugar level. These agents are used as a monotherapy or
combination therapy for the treatment of type 2 diabetes. The oral
hypoglycemic agents are;
(1) Sulfonylureas:-
These drugs enhance release of insulin by a direct secretary mechanism.
Examples: Glibenclamide, Gliclazide, Glimepiride
(2) Biguanides:-
These drugs enhance the sensitivity of insulin in liver, and reduce
gluconeogenesis and glycogenesis, and also enhance the glucose uptake.
Examples: Metformin
(3) α-glucosidase inhibitors:-
These drugs inhibit the activity of α-glucosidase enzyme which present
in intestinal brush border, and these prevent the cleavage of polysaccharides to
absorbable monosacharides. Examples: Acarbose, Voglibose, Miglitol
23
(4) Thiazolidinediones:-
These drugs increase the effect of insulin in skeletal muscle, adipose and
hepatic tissues without enhancing pancreatic secretion of insulin. Examples:
Rosiglitazone, Pioglitazone
(5) Meglitinides:-
These drugs bind to ATP sensitive potassium channels and enhance the
release of insulin from pancreatic cells. Examples: Repaglinide, Nateglinide
(6) Dipeptidyl peptidase four inhibitors:-
These drugs enhance the effect of GLP-1 and GIP, and increase glucose
mediated insulin secretion and suppresses glucagon secretion, these drugs
mostly commonly used as a combination therapy with metformin or TZDs.
Examples: Sitagliptin, Vildagliptin, Saxagliptin.
The present study mainly focused with diabetic neuropathy, which is a
common complication that develops nearly 50% of over all diabetes
population.
Diabetic neuropathy appears relatively early in the disease process. The
prevalence of up to 7% is reported in South Indian patients even at the time of
diagnosis of diabetes46. Diabetic neuropathy has widespread occurrence and
devastating effects. The precise pathogenesis of diabetic neuropathy is unclear
despite recent advances. Polyol pathway of glucose metabolism has been
considered as one of the major mechanisms in the pathogenesis of diabetic
neuropathy47-50. Conversion of glucose to sorbitol by the enzyme aldose
24
reductase is the rate limiting step of polyol pathway. Increased activity of
polyol pathway due to hyperglycemia and subsequent accumulation of excess
sorbitol explains the neuronal damage in diabetes48-50.
Figure 4: Polyol (Sorbitol) Pathway.
Epalrestat is a carboxylic acid derivative that acts as aldose reductase
inhibitor. Epalrestat is proven to have beneficial effects in diabetic neuropathy
in many controlled clinical trials. In hyperglycemia, Epalrestat significantly
reduces intracellular sorbitol accumulation by an uncompetitive aldose
reductase inhibition. Epalrestat improves motor and sensory nerve conduction
velocity and subjective neuropathy symptoms in patients with diabetic
neuropathy49-52.
25
Figure 5: Polyol (Sorbitol) Pathway with accumulation of
sorbitol and fructose.
Methylcobalamin is one of the biologically active forms of vitamin B12.
It is used in the treatment of peripheral neuropathy, diabetic neuropathy, and as
a preliminary treatment for amyotrophic lateral sclerosis. Unlike
cyanocobalamin, Methylcobalamin is active in the spinal fluid. Due to this
property, it is able to help heal the damaged nerve cells and restores normal
functions. In clinical studies, Methylcobalamin showed improvement in the
somatic and autonomic symptoms with regression of signs of diabetic
neuropathy such as pain and paresthesia53,54. With this background, this study
was undertaken to assess the efficacy and safety of Epalrestat and
Methylcobalamin alone and in combination, in diabetic patients with
neuropathy condition.
26
Our literature review focused on the pharmacological potential of
Epalrestat, an aldose reductase inhibitor and Methylcobalamin. Such literature
reviews describe what has been written about the area, the major research
findings across studies, and the major debates in terms of substantive and
methodological issues.
Ramirez MA and Boria NL., studied the effect of Epalrestat: an aldose
reductase inhibitor for the treatment of diabetic neuropathy. Unlike the
current treatment options for diabetic neuropathy, Epalrestat may affect
or delay progression of the underlying disease process. Data from six
clinical trials were evaluated, and it was determined that Epalrestat 50
mg 3 times/day may improve motor and sensory nerve conduction
velocity and subjective neuropathy symptoms as compared with baseline
and placebo. Epalrestat may serve as a new therapeutic option to prevent
or slow the progression of diabetic neuropathy. Long-term, comparative
studies in diverse patient populations are needed for clinical
application51.
Yaqub BA., et al., studied the clinical and neurophysiological effects of
Methylcobalamin on patients with diabetic neuropathy. In a double-
blind study, the active group showed statistical improvement in the
somatic and autonomic symptoms with regression of signs of diabetic
neuropathy. Motor and sensory nerve conduction studies showed no
statistical improvement after 4 months. The drug was easily tolerated by
the patients and no side effects were encountered53.
27
Hotta. N et al., evaluated and observed that the long term treatment
with Epalrestat was well tolerated and effectively delay the progression
of diabetic neuropathy in addition to that good glycemic control and
limited microangiopathy55.
Epalrestat is an aldose reductase inhibitor (ARI), the author conducted a
questionnaire based study for the effectiveness of diabetic peripheral
neuropathy in Epalrestat treated patients and the author correlated the
therapeutic benefits and responses56.
Karunanithi.P., et al., considered about the comparative study of
efficacy between Pregabalin and Epalrestat in diabetic peripheral
neuropathic pain and reported that there was rapid reduction of pain
scores in pain rating scale, biothesiometry scores and reduction of
plasma glucose post prandial (PGPP) levels are more in pregabalin
therapy when compared to Epalrestat therapy57.
The author conducted a comparative trial namely evaluation of efficacy
and safety of Epalrestat and Epalrestat in combination with
Methylcobalamin in patient with diabetic neuropathy in a randomized
comparative trial. In which the author concluded that combination of
Epalrestat and Methylcobalamin is a better option for the treatment of
diabetic neuropathy than Epalrestat alone. Combination therapy was
associated with faster onset and better symptomatic relief58.
28
Maladkar. M., et al., conducted a prospective, randomized single blind
comparative study of Epalrestat to Methylcobalamin in patient with
diabetic neuropathy. The author finally reported that Epalrestat, seems to
be a better alternative than Methylcobalamin in the treatment of diabetic
neuropathy. Epalrestat has a better efficacy and safety profile than
Methylcobalamin in the treatment of diabetic neuropathy59.
The Chinese author conducted a randomized controlled trial along with
meta analysis, entitled effects of Epalrestat combined with
Methylcobalamin on diabetic peripheral neuropathy. The
methodological quality of the trials was evaluated and the valid data for
Meta-analysis were extracted. Six randomized controlled trials (496
cases) were included. In addition to conventional basic treatments, test
group was treated with additional Epalrestat combined with
Methylcobalamin, while control group was treated with additional B
vitamins. Meta analysis showed that the patient in test group was better
than those in control group in the improvement of clinical symptoms.
The author concluded that the meta analysis on this group shows that
Epalrestat combined with Methylcobalamin can improve the clinical
symptoms in the patients with diabetic peripheral neuropathy60.
Ide H., Fujiya S., et al., conducted a study of Clinical utilization of
intrathecal injection of Methylcobalamin in patients with diabetic
neuropathy. Seven men and four women with symptomatic diabetic
29
neuropathy were treated with Methylcobalamin (2,500 micrograms in 10
ml of saline) injected intrathecally. Treatment was begun when patients
had good metabolic control, as determined by measurements of plasma
glucose and hemoglobin, and was repeated several times with a one-
month interval between injections. Three patients were re-treated one
year after the last intrathecal injection. Symptoms in the legs, such as
paresthesia, burning pains, and heaviness, dramatically improved. The
mean (+/- SD) concentration of Methylcobalamin in spinal fluid was
114 +/- 32 pg/ml before intrathecal injection (n = 5) and 4,752 +/- 2,504
pg/ml one month after intrathecal Methylcobalamin treatment (n = 11).
Methylcobalamin caused no side effects with respect to subjective
symptoms or characteristics of spinal fluid. These findings suggest that a
high concentration of Methylcobalamin in spinal fluid is highly effective
and safe for treating the symptoms of diabetic neuropathy61.
Kuwabara S, et al., studied intravenous Methylcobalamin treatment for
uremic and diabetic neuropathy in chronic hemodialysis patients. The
main objective of the study was to study the effects of the intravenous
administration of Methylcobalamin, an analogue of vitamin B12, for
uremic or uremic-diabetic polyneuropathy in patients who are receiving
maintenance hemodialysis. An ultra-high dose of vitamin B12 has been
reported to promote peripheral nerve regeneration in experimental
neuropathy. Nine patients received a 500 microg Methylcobalamin
injection 3 times a week for 6 months. The effects were evaluated using
30
neuropathic pain grading and a nerve conduction study. The author
reported that Serum concentrations of vitamin B12 were ultra-high
during treatment due to the lack of urinary excretion. After 6 months of
treatment, the patients' pain or paresthesia had lessened, and the ulnar
motor and median sensory nerve conduction velocities showed
significant improvement. There were no side effects and finally
concluded that intravenous Methycobalamin treatment is a safe and
potentially beneficial therapy for neuropathy in chronic hemodialysis
patients62.
Bhavani J and Lian LL studied a review article namely Vitamin B
supplementation for diabetic peripheral neuropathy. This review aims to
examine the existing evidence on the effectiveness of vitamin B12
supplementation for the treatment of diabetic peripheral neuropathy. A
search of PubMed and the Cochrane Central Register of Controlled
Trials for all relevant randomized controlled trials was conducted in
December 2014. Any type of therapy using vitamin B12 or its coenzyme
forms was assessed for efficacy and safety in diabetics with peripheral
neuropathy. Changes in vibration perception thresholds, neuropathic
symptoms and nerve conduction velocities, as well as the adverse effects
of vitamin B12 therapy, were assessed. Four studies comprising 363
patients met the inclusion criteria. This review found no evidence that
the use of oral vitamin B12 supplements is associated with improvement
in the clinical symptoms of diabetic neuropathy. Furthermore, the
31
majority of studies reported no improvement in the electrophysiological
markers of nerve conduction63.
Mizukami H, et al., studied the effect of Methylcobalamin on diabetic
neuropathy and nerve protein kinase C in rats. The study conducted
with back ground of methyl-base-attached cobalamin
(Methylcobalamin) (MC) has a special affinity for nerve tissues to
promote myelination and transport of axonal cytoskeleton. It is not
known, however, how MC influences on peripheral nerve in
experimental diabetic neuropathy. This study suggested that correction
of impaired neural signalling of PKC and oxidative stress-induced
damage may be a major attribute to the beneficial effects of MC on
diabetic nerve64.
Vasudevan D, et al., conducted a pilot study namely efficacy and safety
of Methylcobalamin, alpha lipoic acid and pregabalin combination
versus pregabalin monotherapy in improving pain and nerve conduction
velocity in type 2 diabetes associated impaired peripheral neuropathic
condition. The study aimed to assess whether Methylcobalamin and
alpha lipoic acid (ALA) added to pregabalin provide additional benefit
compared to pregabalin alone in type 2 diabetes mellitus associated
peripheral neuropathy. It was an open label, randomized, controlled
parallel-group pilot study. Thirty adult patients with type 2 diabetes
mellitus with symptoms of peripheral neuropathy for ≥6 months were
randomized to receive pregabalin 75 mg, Methylcobalamin 750 μg, and
32
ALA 100 mg (PMA, n = 15); or pregabalin 75 mg (PG, n = 15) for 12
weeks. Assessment variables were numeric rating scale (NRS), sleep
interference scores (SIS), response rate to pain, and global assessment
for the usefulness of therapy. Finally the author concluded that
Methylcobalamin, ALA and pregabalin combination provides pain relief
and improves sleep interference. Addition of Methylcobalamin and ALA
to pregabalin improves the nerve function65.
DRUG PROFILE
33
4. DRUG PROFILE
EPALRESTAT66-68
GENERIC NAME : EPALRESTAT
TRADE NAME :
Aldonil (Zydus Medica), India
Aldorin, Bangladesh
Alrista (marketed and not manufactured by Macleods), India
Epalrica-M (Ordain Global), India
Eparel 50 (Microlabs Ltd), India
Epimeth (Zaiva Lifesciences), India
Eplistat 150 SR (Schem), India
Letostat-SR (Amor Pharmaceuticals), India
Listap-50 (Vivid Biotek), India
Tanglin (Yangtze River Pharmaceutical Group), China
STRUCTURE :
MOLECULAR FORMULA : C15H13NO3S2
CATEGORY : Oral anti-diabetic agent: Aldose reductase
inhibitor
DOSE66 : 50mg, 150mg
34
DOSAGE FORM : Tablet
MECHANISM OF ACTION :
Epalrestat is aldose reductase inhibitor. Aldose reductase reduces
glucose to sorbitol.
Epalrestat suppresses accumulation of sorbitol in nerve by inhibiting
aldose reductase, and relieves numbness/pain of the hands and feet
and leg cramp, etc., which induced by diabetic peripheral neuropathy.
PHARMACOKINETICS:
The absorption rate and elimination rate of Epalrestat were not
changed after multiple oral administrations.
There was no accumulation of drug in plasma. No difference in
pharmacokinetics of Epalrestat in male and female gender.
Plasma Epalrestat concentrations were measured using high-
performance liquid chromatography.
PRECAUTION :
Precaution should be taken while patient with Diabetic neuropathy,
liver disease, renal impairment, pregnancy, nursing mothers, pediatric
and geriatric use.
Before using this drug, inform your doctor about your current list of
medications, over the counter products (e.g. vitamins, herbal
supplements, etc.,), allergies, pre-existing diseases, and current health
conditions (e.g. pregnancy, upcoming surgery, etc.,).
35
SIDE EFFECT :
Nausea
vomiting
diarrhea
generalized gastric discomfort
cutaneous reactions including erythema
bullae and skin blistering.
CONTRAINDICATION :
Hypersensitivity & in severe hepatic insufficiency
DRUG INTERACTION : Not Known
36
METHYLCOBALAMIN69-73
GENERIC NAME : METHYLCOBALAMIN
TRADE NAME : TRINERGIC (UNICHEM)
PREGAB (TORRENT)
LYRICA ( PFIZER)
STRUCTURE :
MOLECULAR FORMULA : C63H91CoN13O14P
CATEGORY :
Antianemic Preparations
Blood and Blood Forming Organs
Corrinoids
Vitamin B12 (Cyanocobalamin and Analogues)
Vitamin B12 and Folic Acid
37
DOSE AND DOSAGE FORMS72 :
TABLET
100mcg
250mcg
500mcg
1000mcg
1500mcg
Tablet, Extended Release
1000mcg
Tablet, Sublingual
2500mcg
Injectable Solution
1000mcg/mL
Nasal Spray
500mcg/spray
MECHANISM OF ACTION :
It's used as a dietary supplement and to treat certain anaemias.
Vitamin B12 plays an important role in helping the body make red
blood cells
Coenzyme; metabolic functions include protein synthesis and
carbohydrate metabolism
38
PHARMACOKINETICS :
Mecobalamin is the neurologically active form of vitamin B12 and
occurs as a water-soluble vitamin in the body.
Bioavailability: 6.1% (intranasal solution relative to IM)
Peak plasma concentrations after 3 hr (oral); 0.9 hr (IM); 3 min (IV).
Distributed to liver, bone marrow, and other tissues.
Protein bound: Binding to transcobalamins
Excretion Via urine.
PRECAUTION :
Intensive treatment of B12-deficient megaloblastic anemia may cause
hypokalemia and sudden death
Use with caution in patients with leber optic nerve atrophy
Injection is incompatible with some common drugs (eg, warfarin and
several phenothiazines) but is compatible with vitamins B and C
Vitamin B12 deficiency for >3 months results in irreversible
degenerative CNS lesions
Oral and intranasal route are not indicated for the treatment of
pernicious anemia until symptoms resolve
IM and SC route used to treat pernicious anemia; oral and intranasal
not indicated until hematologic remission and no signs of nervous
system involvement.
Use with caution in patients with leber’s disease; B12 treatment may
result in rapid optic atrophy
39
Parenteral product may contain aluminum; toxic aluminum
concentrations may occur with renal dysfunction, high doses, or
prolonged use
SIDE EFFECT :
Headache
Itching
Swelling
Nervousness and anxiousness
Involuntary or uncontrollable movements
CONTRAINDICATION:
Hypersensitivity to product; sensitivity to cobalt
DRUG-DRUG INTERACTION :
Leukeran (chlorambucil)
Prilosec (omeprazole)
Colcrys and Mitigare (colchicine)
The herbal supplement goldenseal
DRUG-FOOD INTERACTION :
Alcohol actually decreases levels of B vitamins in the body especially if
you drink a lot.
PLAN OF WORK
40
5. PLAN OF WORK
The present study was planned to conduct a randomized comparative
study on clinical efficacy of Epalrestat (150mg/day) versus Methylcobalamin
(1500 mcg/day) versus Epalrestat (150mg/day) with Methylcobalamin (1500
mcg/day) in diabetic neuropathy patients. The present study was conducted in
Karpaga Vinayaga Institute of Medical Sciences & Research Centre,
Chinnakolambakkam, Kanchipuram District- 603 308, Tamil Nadu.
The Plan of Work Includes:
I. Submission & design of protocol.
II. To get informed written consent from patient.
III. Select diabetic neuropathy patients for the study.
IV. Selection of efficacy and safety parameters.
V. Evaluation of collected data.
VI. Data analysis and statistical analysis was done with the help of Graph
Pad Prism Instat Version 3 (USA). Basic statistical evaluation including
Mean, Median, and Standard Deviation (SD) will be calculated from the
raw data. Efficacy variables such as diabetic neuropathy symptoms, pain
intensity were assessed by VAS (Visual Analog Scale) Pain scoring
method. Muscle strength, muscle cramps, prickling feelings, burning
pain, sensitive to touch, ulceration and ankle reflexes were assessed by
Michigan Neuropathy Screening Instrument (MNSI) score method. Chi-
square test and One way ANOVA followed by Tukey-Kramer multiple
comparison test were used where ever applicable.
MATERIALS AND METHODS
41
6. MATERIALS AND METHODS
STUDY SITE
The study was carried out in Karpaga Vinayaga Institute of Medical
Sciences & Research Centre, Chinnakolambakkam, Kanchipuram District- 603
308, Tamil Nadu.
STUDY DESIGN
A prospective randomized controlled study carried out in diabetic
neuropathy patients.
SAMPLE SIZE
A total number of 165 patients from the out- patient and in-patient
department in Karpaga Vinayaga Institute of Medical Sciences & Research
Centre, Chinnakolambakkam, Kanchipuram District- 603 308, Tamil Nadu,
who were diagnosed as Diabetic neuropathy were included.
STUDY PERIOD
The study was conducted from March 2016 to February 2017.
STUDY GROUP
For this study, about 165 diabetic patients with symptoms of neuropathy
were randomly divided into three groups by block randomization method, i.e.,
Group A (55 patients) received 150 mg of Epalrestat per day, Group B (55
patients) received 1500 mcg of Methylcobalamin per day, Group C (55
patients) received 150 mg of Epalrestat + 1500 mcg Methylcobalamin per day.
42
They were treated with drugs for a period of 12 weeks and they were followed
up on 4, 8 & 12 weeks.
TABLE 2: Explains the study groups
Group Drug treated Number of patients
A Epalrestat (150 mg/day) 55
B Methylcobalamin (1500 mcg/day) 55
C
Epalrestat (150 mg/day)
+ Methylcobalamin (1500 mcg/day)
55
A total of 165 diabetic patients with neuropathy symptoms were
enrolled in our study program. The patients were observed for age, sex, family
history, blood pressure, weight & height were recorded. The patients were
monitored for their blood glucose level, both fasting and postprandial and
glycosylated hemoglobin at the initial visit to the hospital and after 3 months of
treatment.
INCLUSION CRITERIA:
1. Diabetic patients, both type 1 & type 2 with symptoms of
neuropathy.
2. Age – 20 to 65 years.
3. HbA1C ≤ 9% ± 0.5% variation in the previous 3 months.
4. Patients on continued conventional therapy for Diabetes Mellitus.
43
EXCLUSION CRITERIA:
1. Patients having alcoholic neuropathy.
2. Patients having Foot ulcer.
3. Patients having Carpal tunnel syndrome.
4. Patients having Cerebrovascular sequelae.
5. Patients having hepatic and renal impairment.
6. Patients taking antiepileptic and anti- depressant drugs.
7. Patients on any other medications that affects symptoms of
neuropathy.
ETHICAL CONSIDERATION:
All the investigational procedures and protocols used in this study were
reviewed & approved by the Institutional Ethical Committee (IEC Reference
No: 22/2016) and were in accordance with the CONSORT guidelines.
STUDY EVALUATION:
Informed consent was obtained after a detailed explanation of the study
purpose and methods. Patients were received Epalrestat or Methylcobalamin or
Epalrestat with Methylcobalamin combination. The treatment period was 12
weeks and both the medications were administered once daily. This is a single
blind study; therefore patients were unaware of treatment given to them.
Patients were monitored on 4th, 8th and 12th weeks of the study. Patient’s
demographic data and medical history were recorded at screening visit.
Physical examinations were recorded at screening and 12th week of follow up
44
visit. Systemic examination and vital examination were recorded at every
follow up visit.
EFFICACY PARAMETERS:
1. Visual Analog Scale of pain intensity based on 10 point scoring
method - mild, moderate, severe, very severe, worst.
Score Symptoms
0 No pain
1-2 Mild pain
3-4 Moderate pain
5-6 Severe pain
7-8 Very severe pain
8-10 Worst pain
2. Loss of sensation, burning sensation, numbness, muscle cramps,
spontaneous pain, weakness, dizziness, loss of sensation of heat &
cold assessed by Michigan neuropathy screening instrument score
method. ( Patient Version and Physician Version)
3. HbA1C at baseline & at the end of treatment.
SAFETY PARAMETERS:
1. Adverse events like skin rash, hot flushes, etc.,
2. FBS at baseline & at the end of treatment.
3. PPBS at baseline & at the end of treatment.
4. LFT at baseline & at the end of treatment.
5. RFT at baseline & at the end of treatment.
6. CBC at baseline & at the end of treatment.
45
STATISTICAL ANALYSIS:
Statistical analysis was done with the help of Graph Pad Prism Instat
Version 3 (USA). Basic statistical evaluation including Mean, Median, and
Standard Deviation (SD) were calculated from the raw data. Efficacy variables
such as diabetic neuropathy symptoms, pain intensity were assessed by VAS
Pain scoring method. Muscle strength, muscle cramps, prickling feelings,
burning pain, sensitive to touch, ulceration and ankle reflexes were assessed by
Michigan neuropathy screening instrument (MNSI) score method. Chi-square
test and one way ANOVA followed by Tukey-Kramer multiple comparison test
were used where ever applicable.
OBSERVATION AND RESULTS
46
7. OBSERVATION AND RESULTS
Out of 267 patients screened, 102 were excluded and 165 were enrolled
based on the inclusion and exclusion criteria. The reasons for exclusion were:
a. Patients with Foot ulcer (31)
b. Patients having alcoholic neuropathy (33)
c. Patients having hepatic impairment (29)
d. Patients taking antidepressants (09)
The 165 recruited patients were randomized into 3 groups A, B and C
consisting of 55 patients each. Patients of group A received Epalrestat, group B
received Methylcobalamin and group C received Epalrestat combined with
Methylcobalamin.
Patients withdrawn from the study:
Group A : 3
a. 2 patients had diabetic foot ulcer complication with standard
therapy which required additional care and therapy.
b. 1 patient had abnormal laboratory parameters especially HbA1C.
Group B : 2
a. 2 patients had developed symptoms of chronic kidney failure
which requiring additional care and therapy.
Group C : 3
a. 3 patients had abnormal laboratory parameters especially
HbA1C.
47
Patient lost to follow-up :
Group A : 3 patients were failed to follow up.
Group B : 2 patients were failed to follow up.
Group C : 2 patients were failed to follow up.
Patient who completed the study:
Group A : 49
Group B : 51
Group C : 50
The results at the end of the study are as follows.
48
TRAIL FLOW CHART
49
SEX DISTRIBUTION
TABLE 3: Explains the number of males and females among the
study groups A, B and C.
GROUP MALES FEMALES TOTAL
Chi-Square
test
independence
p-value A 32 65% 17 35% 49
0.775 (NS) B 28 55% 23 45% 51
C 34 68% 16 32% 50
(NS-Not Significant)
There was no statistically significant difference in sex distribution
between all three groups.
50
Figure 6,7 & 8 :Shows the percentage of males and females
among the study groups.
65%
35%
Group A
MALES
FEMALES
55%
45%
Group B
MALES
FEMALES
68%
32%
Group C
MALES
FEMALES
51
AGE DISTRIBUTION
TABLE 4: Shows the mean age (in years) of the patients belonging
to groups A, B and C.
GROUP N
MEAN Age
in Years
SD
Chi-Square
test
independence
p-value
A 49 53.87 14.14
0.846 (NS) B 51 53.61 11.24
C 50 57.62 11.70
(NS-Not Significant)
There was no statistically significant difference between the study
groups with respect to age.
52
Figure 9 : Shows the graphical representation of the mean age
of the study groups.
MEAN AGE IN YEARS
53.87
53.61
57.62
51
52
53
54
55
56
57
58
Group A Group B Group C
Study Groups
Ag
e in
Ye
ars
Mean Age in Years
53
BODY MASS INDEX (BMI)
TABLE 5: Shows the mean BMI of all three groups at baseline and
at the end of 4th, 8th and 12th weeks.
Visit
Group A (n=49) Group B (n=51)
Group C
(n=50)
Chi-Square test
independence
p-value Mean
BMI
S.D Mean
BMI
S.D Mean
BMI
S.D
Baseline
(1)
25.49 2.34 25.65 2.52 25.78 2.89 0.750 (NS)
2 25.57 2.47 25.71 2.49 25.82 2.97 0.767 (NS)
3 25.51 2.38 25.63 2.76 25.69 2.67 0.762 (NS)
4 25.50 2.65 25.59 2.65 25.62 3.12 0.625 (NS)
(NS-Not Significant)
There was no statistically significant difference between the groups as
well within the groups at each visit.
54
Figure 10 : Shows the graphical representation of change in mean BMI of study
groups during the visits.
BODY MASS INDEX
25.49
25.65
25.78
25.57
25.71
25.82
25.51
25.63
25.69
25.5
25.59
25.62
25.3
25.4
25.5
25.6
25.7
25.8
25.9
Group A Group B Group C
Study Groups
Mean
BM
I Baseline
2nd Visit
3rd Visit
4th Visit
55
FASTING BLOOD SUGAR
TABLE 6: Shows the mean fasting blood glucose level of all three
groups at baseline and at the end of 4th, 8th and 12th weeks.
Visit
Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
One way
ANOVA –
Tukey-
Kramer
Multiple
Comparison
Test P Value
Mean
(mg/dl) S.D
Mean
(mg/dl)
S.D Mean
(mg/dl) S.D
Baseline
(1)
161.17 14.76 165.53 13.51 164.18 12.37 0.263 (NS)
2 160.76 13.34 165.37 14.52 163.41 14.28 0.262 (NS)
3 159.89 15.21 163.16 15.26 163.56 14.72 0.416 (NS)
4 157.87 14.29 161.59 14.47 162.892 13.67 0.191 (NS)
(NS-Not Significant)
There was no statistically significant difference between the groups or
within the groups at each visit.
56
Figure 11 : Shows the graphical representation of table 6.
FASTING BLOOD SUGAR
160.76
159.89
157.87
165.37
161.59
162.892
161.17
163.16
165.53
163.56
164.18
163.41
154
156
158
160
162
164
166
168
Baseline 2nd Visit 3rd Visit 4th Visit
Visits
Fasti
ng
Blo
od
Su
gar
(mg
/dl)
Fasting Blood Sugar Group A Fasting Blood Sugar Group B Fasting Blood Sugar Group C
57
POST PRANDIAL BLOOD SUGAR
TABLE 7: Shows the mean post prandial blood glucose level of all
three groups at baseline and end of study.
Visit
Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
One way
ANOVA –
Tukey- Kramer
Multiple
Comparison
Test P Value
Mean
(mg/dl) S.D
Mean
(mg/dl)
S.D Mean
(mg/dl) S.D
Baseline 271.22 21.34 275.24 13.82 274.18 12.19 0.442 (NS)
End of
Study
270.34 18.41 273.39 14.84 270.45 14.25 0.552(NS)
(NS-Not Significant)
There was no statistically significant difference between the groups or
within the groups at baseline and end of study.
58
Figure 12 : Shows the graphical representation of table 7.
59
GLYCOSYLATED HEMOGLOBIN (HbA1C)
TABLE 8: Shows the mean glycosylated haemoglobin level of all
three groups at baseline and end of study.
Visit
Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
One way
ANOVA –
Tukey- Kramer
Multiple
Comparison Test
P Value
Mean
(%) S.D
Mean
(%)
S.D Mean
(%)
S.D
Baseline 7.67 0.34 7.85 0.62 7.76 0.69 0.293 (NS)
End of
Study
7.56 0.51 7.78 0.74 7.56 0.69 0.154 (NS)
(NS-Not Significant)
There was no statistically significant difference between all the groups
at baseline and end of study.
60
Figure 13 : Shows the graphical representation of table 8.
7.67
7.85
7.76
7.56
7.78
7.56
7.4
7.45
7.5
7.55
7.6
7.65
7.7
7.75
7.8
7.85
Hb
A1C
(%
)
Baseline End of Study
Visits
Glycosylated Haemoglobin (HbA1C)
Group A Group B Group C
61
ASPARTATE TRANSAMINASE (AST) CONCENTRATION
TABLE 9: Shows the mean AST concentration of groups A, B & C.
Visit Group A
(n=49)
Group B
(n=51)
Group
C
(n=50)
One way
ANOVA,
followed by
Tukey-
Kramer
Multi
comparison
test P-Value
Baseline
Mean
(IU/L)
33.78 32.28 33.36
0.902 (NS)
S.D 19.27 17.74 13.73
End of
Study
Mean
(IU/L)
33.13 32.02 33.13
0.695 (NS)
S.D 11.65 12.89 12.46
(NS-Not Significant)
There was no statistically significant difference between and with in the
groups at baseline and at the end of study.
62
Figure 14 : Shows the graphical representation of table 9.
31
31.5
32
32.5
33
33.5
34
Baseline End of Study
33.78
33.13
32.28
32.02
33.36
33.13
Visits
ASPARTATE TRANSAMINASE (AST) CONCENTRATION
Group A
Group B
Group C
63
ALANINE AMINOTRANSFERASE (ALT) CONCENTRATION
TABLE 10: Shows the mean ALT concentration of groups A, B & C.
Visit Group A
(n=49)
Group B
(n=51)
Group
C
(n=50)
One way
ANOVA,
followed by
Tukey-
Kramer
Multi
comparison
test P-Value
Baseline
Mean
(IU/L)
34.56 35.41 35.73
0.851 (NS)
S.D 9.37 10.64 11.54
End of
Study
Mean
(IU/L)
33.13 35.12 34.59
0.669(NS)
S.D 13.65 10.89 9.46
(NS-Not Significant)
There was no statistically significant difference between and with in the
groups at baseline and at the end of study.
64
Figure 15 : Shows the graphical representation of table 10.
31.5
32
32.5
33
33.5
34
34.5
35
35.5
36
Baseline End of Study
34.56
33.13
35.41
35.12
35.73
34.59
AL
T C
on
c. IU
/L
Visits
ALANINE AMINOTRANSFERASE (ALT) CONCENTRATION
Group A
Group B
Group C
65
SERUM ALBUMIN
TABLE 11: Shows the mean serum albumin level of groups A, B & C.
Visit Group A
(n=49)
Group B
(n=51)
Group
C
(n=50)
One way
ANOVA,
followed by
Tukey-Kramer
Multi comparison
test P-Value
Baseline
Mean
(gm/dl) 3.26 3.18 3.2
0.569(NS)
S.D 0.37 0.45 0.34
End of
Study
Mean
(gm/dl) 3.29 3.22 3.25
0.802(NS)
S.D 0.52 0.49 0.57
(NS-Not Significant)
There was no statistically significant difference between and with in the
groups at baseline and at the end of study.
66
Figure 16 : Shows the graphical representation of table 11.
3.26
3.18
3.2
3.29
3.22
3.25
3.12
3.14
3.16
3.18
3.2
3.22
3.24
3.26
3.28
3.3
Alb
um
in (
gm
/dl)
Baseline End of Study
Visits
SERUM ALBUMIN
Group A
Group B
Group C
67
SERUM TOTAL BILIRUBIN
TABLE 12: Explains the mean serum total bilirubin
level of groups A, B & C.
Visit Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
Baseline
Mean
(mg/dl) 0.76 0.73 0.74
S.D 0.08 0.07 0.07
End of Study
Mean
(mg/dl) 0.75 0.74 0.75
S.D 0.07 0.06 0.05
Unpaired t test, two tail P-
value 0.512(NS) 0.125(NS) 0.413(NS)
(NS-Not Significant)
There was no statistical significance difference was observed with in the
groups at baseline and at the end of study.
68
Figure 17 : Shows the graphical representation of table 12.
0.715
0.72
0.725
0.73
0.735
0.74
0.745
0.75
0.755
0.76
Baseline End of Study
0.76
0.75
0.73
0.740.74
0.75
S. T
ota
l B
ilir
ub
in (
mg
/dl)
Visits
SERUM TOTAL BILIRUBIN
Group A
Group B
Group C
69
SERUM CREATININE
TABLE 13: Explains the serum creatinine
concentration of groups A, B & C.
Visit Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
Baseline
Mean
(mg/dl) 0.89 0.91 0.93
S.D 0.08 0.10 0.18
End of Study
Mean
(mg/dl) 0.86 0.89 0.91
S.D 0.09 0.07 0.08
Unpaired t test, two tail P-
value 0.084 (NS) 0.245 (NS) 0.475(NS)
(NS-Not Significant)
There was no statistical significance difference was observed with in the
groups at baseline and at the end of study.
70
Figure 18 : Shows the graphical representation of table 13.
0.82
0.84
0.86
0.88
0.9
0.92
0.94
Baseline End of Study
0.89
0.86
0.91
0.89
0.93
0.91
Sr.
Cre
ati
nin
e (
mg
/dl)
Visits
SERUM CREATININE
Group A
Group B
Group C
71
SERUM UREA
TABLE 14: Shows the serum urea concentration of groups A, B & C.
Visit Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
Baseline
Mean
(mg/dl) 16.23 16.75 16.54
S.D 0.17 0.12 0.18
End of Study
Mean
(mg/dl) 16.10 16.70 16.48
S.D 0.9 0.13 0.17
Unpaired t test, two tail P-
value 0.332 (NS) 0.066 (NS) 0.065(NS)
(NS-Not Significant)
There was no statistical significance difference was observed with in the
groups at baseline and at the end of study.
72
Figure 19: Shows the graphical representation of table 14.
16.23
16.1
16.75
16.7
16.54
16.48
15.6
15.8
16
16.2
16.4
16.6
16.8
Baseline End of Study
S. U
rea (
mg
/dl)
Visits
SERUM UREA
Group A
Group B
Group C
73
URINE ALBUMIN
TABLE 15: Shows the urine albumin levels of groups A, B & C.
Visit Group A
(n=49)
Group
B
(n=51)
Group
C
(n=50)
Chi-square
Test P-Value
Baseline
nil 43 45 42
0.801(NS) trace 6 6 8
present 0 0 0
End of
Study
nil 44 46 45
0.630(NS) trace 4 5 4
present 1 0 1
(NS-Not Significant)
There was no statistically significant difference between all the groups
at baseline and at the end of study.
74
URINE SUGAR
TABLE 16: Explains the urine sugar levels of groups A, B & C.
Visit Group A
(n=49)
Group B
(n=51)
Group
C
(n=50)
Chi-square
Test P-Value
Baseline
nil 43 45 40
0.054(NS) trace 4 6 9
P 2 0 0
PP 0 0 1
End of
Study
nil 43 43 46
0.240(NS) trace 5 7 3
P 1 0 1
PP 0 1 0
P- One Plus; PP- two plus by urine dipstick
(NS-Not Significant)
There was no statistically significant difference between all the groups
at baseline and at the end of study.
75
ADVERSE DRUG REACTIONS
TABLE 17: Shows the frequency of various adverse drug reactions
between the study groups.
S.No Adverse drug
reaction
Group A
(n=49) %
Group
B
(n=51)
%
Group
C
(n=50)
%
01 Diarrhoea - 0 1 1.9 - 0
02 Erythema - 0 - 0 - 0
03 Gastric
Discomfort
2 4 4 7.8 2 4
04 Head ache 1 2 - 0 - 0
05 Hepatic
Dysfunction
- 0 - 0 - 0
06 Hot flush 1 2 1 1.9 2 4
07 Itching - 0 1 1.9 - 0
08 Nausea &
Vomiting
1 2 3 5.9 3 6
09 Skin rash 1 2 - 0 1 2
10 Swelling - 0 1 1.9 - 0
In group B, 7.8% of patients suffered with gastric discomfort and 5.9%
of patients suffered with nausea and vomiting, in group A, 4% of patients
suffered with gastric discomfort. In group C, 6% of patients suffered with
nausea and vomiting.
76
VISUAL ANALOG PAIN SCORE
TABLE 18: Shows the pain intensity scores (VAS Method)
Visit Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
Baseline/ Visit
1
Mean Score
6.39∗∗∗ 6.28∗∗∗ 6.34∗∗∗
S.D 0.60 0.59 0.47
Visit 2
Mean Score
4.65 ΔΔΔ 4.75 ΔΔΔ 4.89 ΔΔΔ
S.D 0.43 0.45 0.39
Visit 3
Mean Score
4.12 ΨΨΨ 3.98 ΨΨΨ 3.09 ΨΨΨ
S.D 0.42 0.38 0.28
Visit 4
Mean Score
1.92 1.84 1.49
S.D 0.11 0.13 0.10
Data represented as mean with S.D (n=49, 51 & 50), which represents
mean VAS pain Score. ∗∗∗ denotes p<0.001, Base line (Visit 1st) compared
with visit 2nd, 3rd and 4th visit, ΔΔΔ denotes p<0.001, visit 2nd compared with
visit 3rd and 4th. ΨΨΨ denotes p<0.001, visit 3rd compared with visit 4th.
(One-way ANOVA followed by Tukey-Kramer multiple comparisons test).
77
Figure 20: Shows the graphical representation of table 18.
6.396.28 6.34
4.654.75 4.89
4.12 3.98
3.09
1.92
1.84
1.49
0
1
2
3
4
5
6
7
Mean
Pain
Sco
re
Baseline 2nd Visit 3rd Visit 4th Visit
Visits
MEAN VAS PAIN SCORE
Group A
Group B
Group C
78
MICHIGAN NEUROPATHY SCREENING INSTRUMENT (MNSI)
SCORE
TABLE 19: Shows the michigan neuropathy screening instrument (MNSI)
score- Completed by the person with diabetes.
Visit Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
Baseline/
Visit 1
Mean Points 11∗∗∗ 10∗∗∗ 11∗∗∗
S.D 1.63 1.19 1.77
End of 4th
week
Mean Points
07 06 05
S.D 0.58 0.52 0.61
Data represented as mean with S.D (n=49, 51 & 50), which represents
mean points of MNSI. ∗∗∗ denotes p<0.001, Base line (Visit 1st) compared
with visit 4th visit (One tail P value with Unpaired t test).
79
Figure 21: Shows the graphical representation of table 19.
11
7
10
6
11
5
0
2
4
6
8
10
12
Mean
Sco
re o
f M
NS
I
Group A Group B Group C
Groups
MNSI Score - Patient Version
Baseline
4th Visit
80
TABLE 20: Shows the Michigan Neuropathy Screening Instrument
(MNSI) score - Completed by health professionals
Visit Group A
(n=49)
Group B
(n=51)
Group C
(n=50)
Baseline/
Visit 1
Mean Score 7.0∗∗∗ 7.5∗∗∗ 7.0∗∗∗
S.D 0.68 0.78 0.64
End of 4th
week
Mean Score
2.0 2.5 1.0
S.D 0.17 0.19 0.92
Data represented as mean with S.D (n=49, 51 & 50), which represents
mean score of MNSI- Completed by health professional. ∗∗∗ denotes p<0.001,
Base line (Visit 1st) compared with visit 4th visit (One tail P value with
Unpaired t test).
81
Figure 22: Shows the graphical representation of table 20.
7
2
7.5
2.5
7
1
0
1
2
3
4
5
6
7
8
Mean
Sco
re o
f M
NS
I
Group A Group B Group C
Groups
Mean Score- Physician Version
Baseline
4th Visit
DISCUSSION
82
8. DISCUSSION
Diabetic neuropathies are nerve disorder; it is a common complication
of diabetes caused by hyperglycaemia which can damage nerve fibers to whole
body. Depends upon the types of nerves involved, which is categorized as
peripheral, autonomic, proximal and focal neuropathies. The exact mechanism
of diabetic neuropathy remains unknown. Several reports suggested that a
variety of molecules are involved in the development of diabetic neuropathy,
such as protein kinase C, polyol, aldose reductase, advanced glycation end
products, reactive oxygen species, cytokines. More over, some risk factors like
metabolite, autoimmune, inherited traits and life style, may contribute to the
development of diabetic neuropathy. Methylcobalamin has an extended record
as a nerve and it has been used in the treatment of neuropathy for a long time.
Epalrestat is a relatively newer addition in this category that has gained the
acceptance of the healthcare society as an effective treatment option for
diabetic neuropathy, potentially preventing or ameliorating long term diabetic
complications51.
Present study was conducted to compare the efficacy and safety of
epalrestat, methylcobalamin alone and epalrestat in combination with
methylcobalamin in treatment of patients with diabetic neuropathy. We have
evaluated most common diabetic neuropathy complications including pain
assessed by VAS scale of pain intensity based on 10 point scoring method, loss
of sensation, burning sensation, numbness, muscle cramps, spontaneous pain,
weakness, dizziness, loss of sensation of heat & cold assessed by Michigan
83
neuropathy screening instrument score method and HbA1C at baseline & at the
end of treatment.
The results of the present study reveal that combination group and
Epalrestat monotherapy group showed a very good improvement and
comparably moderate improvement respectively in diabetic neuropathy
symptoms over the baseline. All the evaluated neuropathy symptoms showed
statistically significant (P<0.001) and (P<0.01) in both groups. Despite the fact
that, in combination group symptomatic relief was achieved much earlier with
reduction in score values and was better compared to Epalrestat alone.
Improvement in diabetic neuropathy patients was investigated in terms
of VAS (Visual analog scale) pain intensity score, MNSI (Michigan
neuropathy screening instrument) score and HbA1C levels. In group C
significant (p<0.001) reduction in pain score (3.09) was observed at 8th week
onwards while compared to baseline and very good reduction in pain score
(1.49) was observed at 12th week of therapy. All three groups had significant
(p<0.001) reduction in MNSI score by patient version, especially group C were
shown to have very good reduction (Mean Score Value: 5) compared to rest
other groups. Similarly, all three groups had significant (p<0.001) reduction in
MNSI score by health professional version, especially group C were shown to
have very good reduction (Mean Score Value: 1.0) compared to rest other
groups. The MNSI diabetic patient version score was evaluated on the basis of
higher score out of maximum 13 points indicates more neuropathic symptoms
as well as MNSI physician version score grater than 2 points out of 10 point
84
scale were considered neuropathic74. With respect to HbA1C, both group A &
C were shown very slight amount (7.56%) of reductions compared to baseline,
which is not merely significant. The demographic profiles were not statistically
significant. Blood glucose profiles like FBS, PPBS, HbA1C and BMI were
measured before and after study, which also not significant. The serum profiles
like AST, ALT, serum albumin and urine albumin & urine sugar were
measured before and after study period, but which were not observed any
significant difference. Serum urea, creatinine and total bilirubin were measured
baseline and end of study, which were showed statistically not significant
difference between and with in the groups at baseline and at the end of study.
The synergistic effect of Epalrestat and Methylcobalamin may be linked
to their complementary mechanisms of neuroprotection. Epalrestat helps to
prevent neuronal degeneration by reducing the accumulation of toxic sorbitol
and decreasing the oxidative stress while Methylcobalamin helps to recover
neuronal injury. Methylcobalamin is one of the biologically active forms of
vitamin B12. It is used in the treatment of peripheral neuropathy, diabetic
neuropathy, and as a preliminary treatment for amyotrophic lateral sclerosis.
Unlike cyanocobalamin, methylcobalamin is active in the spinal fluid. Due to
this property, it is able to help heal the damaged nerve cells and restores normal
functions. In clinical studies, Methylcobalamin showed improvement in the
somatic and autonomic symptoms with regression of signs of diabetic
neuropathy such as pain and paresthesia53,54.
85
Epalrestat is a carboxylic acid derivative that acts as aldose reductase
inhibitor. Epalrestat is proven to have beneficial effects in diabetic neuropathy
in many controlled clinical trials. In hyperglycemia, Epalrestat significantly
reduces intracellular sorbitol accumulation by an uncompetitive aldose
reductase inhibition. Epalrestat improves motor and sensory nerve conduction
velocity and subjective neuropathy symptoms in patients with diabetic
neuropathy49-51. So this combination of Epalrestat and Methylcobalamin
treated patients were more efficacious and well tolerated with safety for the
management of diabetic neuropathy than monotherapy of Epalrestat and
Methylcobalamin. The combination therapy showed faster onset and quick
relief of symptoms. Apart from this as per our observation, in general people
with diabetes who smoke and drink alcohol are more likely to develop
neuropathy. Hyperglycemia promotes the synthesis of an endogenous protein
kinase C activator, diacylglycerol. This excess protein kinase C activation
induces ischemia and promotes vascular permeability and thickening of the
basement memberane and causes neuropathy75-77. So, inactivation of protein
kinase C indirectly reduces the risk of diabetic neuropathy.
The wellbeing and safety of both drugs was assessed based on the
occurrence of adverse events reported by the patients who received the
medicine. From our study, it was observed that nausea and vomiting (5.9%),
gastric discomfort (7.8%) and diarrhoea (1.9%) was reported as ADR. All three
groups were well tolerated and do not generate any safety concern.
SUMMARY
86
9. SUMMARY
The present study outcome focuses mainly with the following highlights,
The proportion of male diabetic neuropathy patients were high
[group A (65%), group B (55%), group C (68%)] compared to
female population in our study.
The over all mean age group of patients were in group A- 53.87yrs,
group B- 53.61 yrs and group C- 57.62 yrs respectively.
There was no statistically significant difference of BMI between
three groups of patients as well as within the groups at each visit.
There was no statistically significant difference of the other
laboratory parameters like FBS, PPBS, AST, ALT, serum albumin,
serum total bilirubin, serum creatinine, serum urea, urine albumin,
urine sugar between three groups of patients as well as within the
groups at each visit.
There was no statistically significant difference of HbA1C level
between three groups of patients as well as within the groups at each
visit. The mean percentage of HbA1C was 7.78% at the end of study.
Nausea and vomiting (5.9%), gastric discomfort (7.8%), diarrhoea
(1.9%), swelling (1.9%), itching (1.9%) was reported as ADR from
our patients.
From VAS method, in group C patients had significant (p<0.001)
reduction in pain score (3.09) at 8th week of therapy while compared
87
to baseline and very good reduction in pain score (1.49) was
observed at 12th week of therapy.
All three groups had significant (p<0.001) reduction in MNSI score
by patient version, especially group C were shown to have very good
reduction (Mean Score Value: 5) compared to rest of other groups.
Similarly, all three groups had significant (p<0.001) reduction in
MNSI score by health professional version, especially group C were
shown to have very good reduction (Mean Score Value: 1.0)
compared to rest of other groups.
In combination therapy (group C), the majority of the patients had
absence of muscle cramps, prickling feelings, burning pain
especially at 12 weeks of therapy, though they were having presence
of the same neurological problems at base line of therapy.
CONCLUSION
88
10. CONCLUSION
From our study, it was revealed that
Combination of Epalrestat and Methylcobalamin was more
efficacious, well tolerated and safer when compared to
monotherapy of Epalrestat and Methylcobalamin. for the
management of diabetic neuropathy.
The combination therapy showed better improvement of
symptoms with respect to MNSI patient version followed by
physician version score and VAS pain intensity score.
All the three groups had no significant difference between
baseline and end of study with respect to HbA1C levels.
There was no statistically significant change between the groups
and with in groups at base line and end of study with respect to
BMI, FBS, PPBS, AST, ALT, serum albumin, urea, creatinine,
total bilirubin, urine albumin and urine sugar.
BIBLIOGRAPHY
89
11. BIBLIOGRAPHY
1. Keecia DK, Jocelyn DJ, Jessica W. Micro vascular and macro vascular
complications of diabetes mellitus. American Journal of
Pharmaceutical education, 2005; 69: 1-8.
2. Ramachandran A, Das AK, Joshi SR, et al., Current status of diabetes in
India and need for novel therapeutic agents. Journal of the Association
of Physicians of India, 2010; 58: 7-9.
3. Melmed, Shlomo, Williams, et al., Textbook of endocrinology (12th
ed.). Philadelphia: Elsevier/Saunders: 1371–1435.
4. Shi Y, Hu FB. The global implications of diabetes and cancer. The
Lancet, 2014; 383: 1947–1948.
5. Vos T, Flaxman AD, Naghavi M, et al., Years lived with disability
(YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a
systematic analysis for the Global Burden of Disease Study. TheLancet,
2010; 380: 2163–96.
6. The top 10 causes of death Fact sheet N°310, World Health
Organization, October 2013.
7. IDF DIABETES ATLAS (6 ed.), International Diabetes Federation, 2013.
8. International Diabetes Federation: Diabetes Atlas, Retrieved 4 April
2014.
9. John WS, Diana F, Karen LG. Projections of global mortality and
burden of disease from 2002 to 2030. PLoS Medicine, 2006;
3(11):e442.
90
10. Sarwar N, Gao P, Seshasai SR, Gobin R, et al., Diabetes mellitus,
fasting blood glucose concentration, and risk of vascular disease: a
collaborative meta-analysis of 102 prospective studies. Lancet, 2010; 26
(375):2215-2222.
11. Bourne RR, Stevens GA, White RA, Smith JL, et al., Causes of vision
loss worldwide, 1990-2010: a systematic analysis. Lancet, 2013; 1: 339-
349.
12. USRDS annual data report: Epidemiology of kidney disease in the
United States. United States Renal Data System. National Institutes of
Health, National Institute of Diabetes and Digestive and Kidney
Diseases, 2014:188–210.
13. Barbara GW, Joseph TD, Terry LS, et al., Pharmacotherapy Handbook,
Seventh edition: 210.
14. About diabetes, World Health Organization, Retrieved 4 April 2014.
15. Diabetes Fact sheet N°312, WHO, October 2013, Retrieved 25 March
2014.
16. Kitabchi AE, Umpierrez GE, Miles JM, et al., Hyperglycemic crises in
adult patients with diabetes. Diabetes care, 2009; 32: 1335–43.
17. Rother KI, Diabetes treatment—bridging the divide. The New England
Journal of Medicine, 2007; 356:1499-501.
18. Harsh Mohan, Textbook of Pathology. 2010; sixth edition: 818-25.
19. RSSDI textbook of diabetes mellitus. (Rev. 2nd ed.). New Delhi: Jaypee
Brothers Medical Publishers, 2012: 235.
91
20. Riserus U, Willett WC, Hu FB. Dietary fats and prevention of type 2
diabetes. Progress in Lipid Research, 2009; 48: 44-51.
21. Cooke DW, Plotnick L. Type 1 diabetes mellitus in pediatrics.
Pediatrics in Review, 2008; 29: 374–84.
22. John W.S., Charles R.C., Gerald JM, Joseph RE., et al., Prevalence,
Risk Factors, and Complications of Diabetes in the Kilimanjaro Region:
A Population-Based Study from Tanzania. PLOS ONE, October 6th ,
2016.
23. Yanping D, Yoshimasa T, Wen Z and Yanling Wu. Review Risk Factors
Contributing to Type 2 Diabetes and Recent Advances in the Treatment
and Prevention. International Journal of Medical Sciences 2014;
11(11): 1185-1200.
24. Prediabetes, Canadian diabetes association clinical practice guidelines,
2013, Chronic disease burden update, state of illinosis, illinosis
department of public health, volume 1, issue 2, Nov 2012.
25. Sumanth M. M., Bala S, Gautam R, Ashok Kumar D. Risk Factors of
Diabetes Mellitus in Rural Puducherry. Online Journal of Health and
Allied Sciences 2012; 11(1): 1-7.
26. Clinical Pharmacy and Therapeutics by Roger Walker, fifth edition:
691-694.
27. Manouk B and Charles A. Prevalence and complications of diabetes
mellitus in Northern Africa, a systematic review. BMC Public health
2013; 13: 387. 201313:387.
92
28. Loewen SL, Haas LB. Complications of diabetes: acute and chronic.
Nurse Practitioner Forum, 1991; 2(3):181-7.
29. Huzar JG. Diabetes now. Preventing acute complications. RN. 1989;
52(8):34-40.
30. Sun J, et al., Protection from Retinopathy and Other Complications in
Patients with Type 1 Diabetes of Extreme Duration. Diabetes Care,
2011; 34: 968.
31. Bonnefont RD. The role of antioxidant micronutrients in the prevention
of diabetic complications. Treatments in Endocrinology. 2004; 3 (1):
41–52.
32. Juster SK, Smith AG. Updates in diabetic peripheral neuropathy.
Faculty Review, 2016;5: F1000 -738.
33. Callaghan BC, Cheng HT, Stables CL, et al., Diabetic neuropathy:
clinical manifestations and current treatments. Lancet Neurology,
2012;11(6):521–34.
34. Tesfaye S, Boulton AJ, Dyck PJ, et al., Diabetic neuropathies: update on
definitions, diagnostic criteria, estimation of severity, and
treatments. Diabetes Care, 2010; 33(10):2285–93.
35. Tesfaye S, Vileikyte L, Rayman G, et al., Painful diabetic peripheral
neuropathy: consensus recommendations on diagnosis, assessment and
management. Diabetes Metabolism Research and Reviews,
2011;27(7):629–38.
93
36. Sadosky A, Mardekian J, Parsons B, et al., Healthcare utilization and
costs in diabetes relative to the clinical spectrum of painful diabetic
peripheral neuropathy. Journal of Diabetes Complications, 2015;
29(2):212–17.
37. Gordois A, Scuffham P, Shearer A, et al., The health care costs of
diabetic peripheral neuropathy in the US. Diabetes Care, 2003;
26(6):1790–5.
38. Scheen AJ. Pathophysiology of insulin secretion. Annals of
Endocrinology. 2004; 65(1):29-36.
39. Howard R, Kathleen CZ, Shridar G, Roberto C and Walter SZ.
Physiology and Pathophysiology of Insulin Secretion, Diabetes Care,
1990; 13(6): 655-666.
40. National Diabetes Information Clearing house, Diagnosis of Diabetes
and Prediabetes, 2014: 4-7.
41. Classification and Diagnosis of Diabetes, American Diabetes Association,
Diabetes Care, 2015; 38(1): S8-S16.
42. Tripathi KD, Essentials of Medical Pharmacology, Jaypee brothers
medical publishers, 6th edition: 254-274.
43. Bosenberg LH, Vanzyl DG. The mechanism of action of oral anti-
diabetic drugs. 2008: 80-88.
44. Harrigan RA, Nathan MS, Beettie P. Oral agents for the treatment of
type 2 diabetes mellitus: pharmacology, toxicology and treatment,
Annals Of Emergency Medicine. 2001: 68-78.
94
45. David MN, John BB, Davidson MB. Medical Management of
Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the
Initiation and Adjustment of Therapy. Diabetes care, 2009; 32: 193-203.
46. Guideline for the management in primary health care of diabetes: 06-17.
47. Ramachandran, A., Snehalatha, C., Vijay, V. and Vishwanathan, M.
(1996) Diabetic retinopathy at the time of diagnosis of NIDDM in South
Indian subjects. Diabetes Research and Clinical Practice, 32, 111-114.
48. Chihiro, Y.N. (1998) Aldose reductase in glucose toxicity: A potential
target for the prevention of diabetic complications. Pharmacological
Reviews, 50, 21-33.
49. Itagaki I, Shimizu K, Kamanaka Y, Ebata K, et al., The effect of an
aldose reductase inhibitor (epalrestat) on diabetic nephropathy in rats.
Diabetes Research and Clinical Practice, 1994; 25:147-154.
50. Hotta N, Kakuta H, Koh N, Fukasawa H, et al., In-vitro retinal and
erythrocyte polyol pathway regulation by hormones and an aldose
reductase inhibitor. Diabetes Research and Clinical Practice, 1991; 14 :
29-35.
51. Ramirez MA and Boria NL. Epalrestat: an aldose reductase inhibitor for
the treatment of diabetic neuropathy. Pharmacotherapy 2008; 28: 646-
55.
52. Sharma S.R. and Sharma N. Epalrestat, an aldose reductase inhibitor, in
diabetic neuropathy: An Indian perspective. Annals of Indian Academy
Neurology, 2008; 11: 231- 235.
95
53. Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on
diabetic neuropathy. Clinical Neurology and Neurosurgery. 1992;
94(2):105-11.
54. Sun Y, Lai M.S and Lu CJ. Effectiveness of vitamin B12 on diabetic
neuropathy: Systematic review of clinical controlled trials. Acta
Neurologica Taiwanica, 2005; 14: 48-54.
55. Hotta N, Akanum Y, Kawamori R, Matsuoka K, et al., Long term
clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic
peripheral neuropathy. Diabetes Care. 2006; 29: 1538-44.
56. Ito A, Nozawa RI, Ibuki C, Atarashi H, et al., Examination of
questionnaire items regarding diabetic peripheral neuropathy in
epalrestat- treated patients and their usefulness in the treatment of this
disorder – Influence on Treatment course. Yakugaku Zasshi 2009; 129:
1239-1247.
57. Karunanithi P, Mallayasamy M, Manikandan S, Rajasoundara P., et al.,
Comparative study of efficacy between pregabalin and epalrestat in
diabetic neuropathic Pain. Asian Journal of biomedical and
pharmaceutical sciences 2014; 04(35): 49-54.
58. Maladkar M, Saggu NJS, Moralwar P, Aziz A., et al., Evaluation of
efficacy and safety of epalrestat and epalrestat in combination with
methylcobalamin in patients with diabetic neuropathy in a randomized,
comparative trial. Journal of diabetes Mellitus 2013; 3(1): 22-26.
96
59. Maladkar M., Rajadhyaksha G, Vengataswamy N, Hariharan S., et al.,
Efficacy, safety, and tolerability of epalrestat compared to
methylcobalamine in patients with diabetic neuropathy. International
Journal of diabetes in developing countries 2009; 29(1); 28-34.
60. Ruan Y, Jianhua MA., Xiaojing Xie., et al., Effects of epalrestat
combined with methylcobalamin on diabetic peripheral neuropathy.
Jiangsu Medical Journal. 2012; 03.
61. Ide H, Fujiya S, Asanuma Y, Tsuji M, Sakai H, Agishi Y. Clinical
usefulness of intrathecal injection of methylcobalamin in patients with
diabetic neuropathy. Clinical Therapeutics 1987; 9(2):183-92.
62. Kuwabara S, Nakazawa R, Azuma N, et al., Intravenous
methylcobalamin treatment for uremic and diabetic neuropathy in
chronic hemodialysis patients. Internal Medicine 1999 Jun; 38(6):
472-5.
63. Bhavani J and Lian LL. Vitamin B supplementation for diabetic
peripheral neuropathy. Singapore Medical Journal, 2016; 57:55-59.
64. Mizukami H, Ogasawara S, Yamagishi S, Takahashi K, et al.,
Methylcobalamin effects on diabetic neuropathy and nerve protein
kinase C in rats. European Journal of Clinical Investigation 2011 ;
41(4):442-50.
65. Vasudevan D, Manoj M N, Qayum I M. Efficacy and safety of
methylcobalamin, alpha lipoic acid and pregabalin combination versus
pregabalin monotherapy in improving pain and nerve conduction
97
velocity in type 2 diabetes associated impaired peripheral neuropathic
condition. Annals Indian Academy of Neurology 2014;17:19-24.
66. Terashima H, Hama K. Effects of a new aldose reductase inhibitor on
various tissue in-vitro. Journal of Pharamacology and Experimental
Therapeutics, 1984; 229: 226–230.
67. Sharma SR, and Sharma N. Epalrestat, an aldose reductase inhibitor, in
diabetic neuropathy: An Indian perspective. Annals of Indian academy
of neurology, 2008; 11(4); 231-235.
68. John WS, Diana Faulds, Karen LG. A Review of its Pharmacology, and
Therapeutic Potential in Late-Onset Complications of Diabetes
Mellitus. Drugs & Aging, 1993; 3 (6): 532–555.
69. Thakkar K, Billa G. Treatment of vitamin B12 deficiency-
methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the
confusion. European Journal of Clinical Nutrition, 2015; 69: 1–2.
70. Ram P, Atul P and Rajiv R. Efficacy and Tolerability of a Fixed Dose
Combination of Methylcobalamin and Pregabalin in the Management of
Painful Neuropathy. North American Journal of Medical Sciences,
2012; 4(11): 605-607.
71. Gupta JK and Qureshi SS. Potential Benefits of Methylcobalamin: A
Review. Austin Journal of Pharmacology and Therapeutics, 2015;
3(3): 1-4.
72. Manish M, Chitra T, Urja D. Post-Marketing Surveillance of Fixed Dose
Combination of Methylcobalamin, Alpha Lipoic Acid, Folic Acid,
98
Biotin, Benfotiamine & Vitamin B6-Nutripathy for the Management of
Peripheral Neuropathy. Journal of Diabetes Mellitus, 2014; 4: 124-132.
73. Jacqueline CD, Arlene RN, Ludwig FD. A prospective, open label, 24-
week trial of methylcobalamin in the treatment of diabetic
polyneuropathy. Journal of Diabetes Mellitus, 2012, Vol.2, No.4, 408-
412.
74. Dyck PJ, Karnes J, O'Brien PC, Swanson CJ. Neuropathy Symptom
Profile in health, motor neuron disease, diabetic neuropathy, and
amyloidosis. Neurology, 1986;36:1300-8.
75. Borghini I, Ania LA, Regazzi R, et al., Alpha, beta II,delta and epsilon
protein kinase C isoforms and compound activity in the sciatic nerve of
normal and diabetic rats. Journal of Neurochemistry, 1994; 62: 686-96.
76. Hempel A, Maasch C, Heintze U, et al., High glucose concentration
increase endothelial cell permeability via activation of protein kinase C
alpha. Circulation Research, 1997;81:363-71.
77. Mara L. The Polyol Pathway as a Mechanism for Diabetic Retinopathy:
Attractive, Elusive, and Resilient. Experimental Diabetes Research,
2007, 1-31.
99
ANNEXURES
f
(Annexure I A)
INFORMATION SHEET
You are invited to participate in this study titled “Comparison of efficacy
and safety of Epalrestat with Methylcobalamin in patients with diabetic
neuropathy.”
Study Purpose:
The purpose of this study is to evaluate the comparison of efficacy and
safety of Epalrestat with Methylcobalamin in patients with diabetic neuropathy.
Study Details:
Along with you total 165 patients will be included in this study.
You will be enrolled only after giving your voluntary consent.
The study involves administration of epalrestat or methylcobalamin or
combination of epalrestat with methylcobalamin for the period of 12
weeks. For analytical purpose, 5 ml of blood sample will be colleted from
your vein by expert for routine baseline investigations like FBS, PPBS,
HbA1C, ALT, AST, serum albumin, serum total bilirubin, serum
creatinine, serum urea, urine albumin, urine sugar at first week of therapy
and at each follow-up visit like 4th, 8th and 12th weeks of therapy.
You will be asked questions to assess pain intensity by VAS scoring
method and to assess your loss of sensation, burning sensation, numbness,
muscle cramps, spontaneous pain, weakness, dizziness, loss of sensation
of heat & cold assessed by Michigan neuropathy screening instrument
score method as mentioned in the proforma.
Benefit of participating this study:
By participation in this study you will be recovered from the problem of
diabetic neuropathic related complications.
Risks involved in participation of this study:
As these epalrestat, aldose reductase inhibitor and methylcobalamin have
produce adverse effects like head ache, nausea, vomiting, skin rash, swelling, hot
flush, gastric discomfort and diarrhoea. If any unwanted side effects occur, it will
be treated free of cost and your health will be safe guarded.
Rights:
Participation in this study is purely voluntary. If you do not want to
participate you can withdraw from study at any time.
Confidentiality:
Your participation will be kept confidential. The investigators and other
authorized personnel will only have access to the data. The information will be
used for publication and further research without revealing your identity.
Annexure : I (B)
Ma;tpy; gq;F ngWgtUf;fhd jfty; gbtk;
Ma;tpd; jiyg;G:
‘ePhpopT Nehapdhy; J}z;lg;gl;l euk;Gf; NfhshW cs;sth;fspy;
Vghy;hp];Nll; kw;Wk; nkj;jpy; Nfhghyikd; kUe;Jfspdhy; Vw;gLk; gyhgyd;
kw;Wk; ghJfhg;G gw;wpa xg;gPl;L Ma;T”.
Ma;thsh; : lhf;lh;. C.g;hPj;,
(kUe;jpay; gl;l Nkw;gbg;G khztp)
fw;gf tpehafh kUj;Jtf; fy;Y}hp kw;Wk;
Muha;r;rp ikak;>
rpd;dNfhsk;ghf;fk;>fhQ;rpGuk; khtl;lk;-603 308.
Ma;T topfhl;b : lhf;lh; P. N[f;fg; th;fP];, M.D.,
Nguhrphpah;>
kUe;jpay; Jiw>
fw;gf tpehafh kUj;Jtf; fy;Y}hp kw;Wk;
Muha;r;rp ikak;>
rpd;dNfhsk;ghf;fk;>fhQ;rpGuk; khtl;lk;-603 308.
Ma;tpd; Nehf;fk; kw;Wk; ed;ikfs;:
jq;fsplk; Nkw;nfhs;stpUf;Fk; Ma;T Vghy;hp];Nll; kw;Wk;
nkj;jpy;Nfhghyikd; Mfpait ePhpopT Nehapdhy; Vw;glf;$ba euk;G
NfhshWfis rhpnra;a cjTk; kUe;JfshFk;. ,jpy; Vghy;hp];Nll;> My;Nlh];
hpnlf;Nl]; vd;w vd;irkpd; jLg;ghdhfTk; kw;Wk; nkj;jpy;Nfhghyikd;>
itl;lkpd; gp-12 MfTk; nray;gLfpwJ. Nkw;fz;l ,uz;L kUe;JfSk; ePhpopT
Neha; cs;sth;fspy; tsh;rpij khw;wj;jhy; cz;lhFk; rhh;gpl;lhy; vd;w
nghUspid fl;Lf;Fs; itf;fTk; kw;Wk; vjph;kiw tpidahf ,uj;jj;jpy; cs;s
rh;f;fiu mstpid fl;Lg;gLj;jTk; cjTfpwJ.
,e;j Ma;Tf;fhf ,uj;jj;jpy; cs;s %d;W khj rh;f;fiu kjpg;gPL> vil>
cau tpfpj FwpaPL> ,uj;j mOj;jk;> fy;yPuy; nray;ghLfs;> rpWePuf nray;ghLfs;>
rpWePhpy; cs;s rh;f;fiu msT> ghj vhpr;ry;> eikr;ry;> typ> euk;G RSf;F kw;Wk;
jirgpbg;G gw;wpa midj;J tptuq;fSk; Fwpf;fg;gLtjhy;> ,e;j Ma;T ePhpopT
Nehapdhy; cz;lhFk; midj;J euk;G rk;ge;jkhd NfhshWfis rhpnra;a
cjTk;. ,e;j Ma;tpypUe;J ngwg;gLk; jfty;fs; jq;fisg; Nghd;w gy;NtW
NehahspfSf;F kpf;f gadspf;Fk;.
-2-
Ma;T Kiw:
jhq;fs; ,t;tha;tpd; fPo; 12 thuq;fs; ,Ug;gPh;fs;> ,jpy; 4 Kiw
kUj;Jtkidf;F tuNtz;Lk;. mt;Ntisapy; kUj;Jt> ,uj;j kw;Wk; rpWePh;
ghpNrhjidf;F cl;gLj;jg;gLtPh;fs;. Ma;tpy; gq;Nfw;Fk; NghJ NtW ve;j
kUe;Jk; cl;nfhs;sf; $lhJ. mt;thW cl;nfhs;s Nehpl;lhYk;> Ma;thshplk;
njhptpf;f Ntz;Lk;.
Vw;glf;$ba gpd;tpisTfs;:
Vghy;hp];Nll; kw;Wk; nkj;jpy; Nfhghyikd; rfpj;Jf; nfhs;s $ba
kUe;JfNs Vghy;hp];Nll; cs;nfhs;Sk; NghJ Fkl;ly;> the;jp> ,iug;ig
mnrsfhpak;> tapw;Wg;Nghf;F kw;Wk; Njhy; mhpg;G NkYk; Njhy; nfhg;Gsq;fs;
Mfpait tu Nehplyhk;. nkj;jpy; Nfhghyikd; cl;nfhs;Sk; NghJ jiytyp
mhpg;G> tPf;fk; kw;Wk; fl;Lg;ghlw;w ,af;fq;fs; Mfpait tuNehplyhk;. ,it
midj;Jk; Fzg;gLj;jf; $baitNa. NkYk; ,it Nghd;w kw;Wk; NtW ve;j
vjph;ghuhj gpd; tpisTfs; Vw;gl NehpbDk;> Ma;thshplk; cldbahf njhptpf;f
Ntz;Lk;.
ek;gfj; jd;ik tptuk;:
jq;fspd; kUj;Jtg; gbtq;fs; kpFe;j ,ufrpaj;Jld; ghJfhf;fg;gLk;. gpw
kUj;Jth;fs; / Ma;thsh;fs; / ed;elj;ij FOtpdh; kw;Wk; Njitg;gl;lhy; kUe;J
xOq;F Kiw mjpfhhpaplk; kl;LNk ntspaplg;gLk;. mt;tha;tpd; KbTfs;>
jq;fspd; ngah; ntspaplhky;> Muha;r;rp ,jo;fspy; gpuRhpf;fg;gLk;.
Ma;tpy; jq;fspd; gq;Nfw;G kw;Wk; chpikfs;:
,e;j Ma;tpy; jq;fspd; gq;Nfw;G jq;fSila Ra KbthFk;. ve;Neuj;jpYk;
vt;tpj tpsf;fKkpd;wp ,jpypUe;J tpyf jq;fSf;F chpikAz;L. mt;thW
NehpbDk; jq;fspd; cly;epiyf;F Vw;w rpfpr;ir toq;fg;gLk;. jq;fs; cly;epiy
Nkhrkile;jhNyh NtW Neha; Vw;gl;lhNyh> Ma;thshplk; clNd njhptpf;f
Ntz;Lk;. jq;fSf;F ,e;j rpfpr;ir cfe;jjy;y vd Ma;thsUf;F Njhd;wpdhy;>
cldbahf jq;fspd; xg;Gjypd;wp jq;fis Ma;tpypUe;J tpyf;fyhk;. Ma;T
Fwpj;J VNjDk; GJ tpguk; fpilj;jhy;> jq;fSf;F mwptpf;fg;gLk;. mjd;gpwFk;
,t;tha;tpy; njhlh;tJ jq;fsJ Ra KbthFk;.
njhlh;G tptuk;:
Ma;tpd; NghJ NkYk; VNjDk; tptuq;fs; / Nfs;tpfs; Njhd;wpdhy;
fPo;f;fz;l egh;fis njhlh;G nfhs;syhk;.
lhf;lh;. N[f;fg; th;fP];.P : 75987-40423
lhf;lh;. g;hPj;;.C : 80568-58786
Annexure II (A)
CONSENT FORM
I, the undersigned confirmed that…
I have read and understood the information about the study titled
“Comparison of efficacy and safety of Epalrestat with Methylcobalamin
in patients with diabetic neuropathy” as provided in the information sheet.
I have been given opportunity to ask questions about the project and my
participation.
I understand that I can withdraw myself from study at any time without
giving any reason.
Procedures regarding confidentiality have been very well explained to
me.
The use of data for publication, research sharing and archiving has been
explained to me.
I voluntarily agree to participate in the study research.
I along with the researcher agree to sign and date this informed consent
form.
Signature Signature
Name of the Participant: Name of the Researcher:
Date: Date:
Annexure : II (B)
Ma;T xg;Gjy; gbtk;
Ma;tpd; jiyg;G
‘ePhpopT Nehapdhy; J}z;lg;gl;l euk;Gf; NfhshW cs;sth;fspy; Vghy;hp];Nll;
kw;Wk; nkj;jpy;Nfhgyikd; kUe;Jfspdhy; Vw;gLk; gyhgyd; kw;Wk; ghJfhg;G gw;wpa
xg;gPl;L Ma;T”.
gq;F ngWgthpd; ngah; ............................................. gq;F ngWgthpd; taJ
................... q;F ngWgthpd; vz;.................................................... Mz; / ngz; ....................
Ma;T Nkw;nfhs;sg;gLk; ,lk; : rh;f;fiu Neha; Gw kw;Wk; mf Nehahspfs; gphpT>
fw;gf tpehafh kUj;Jtf; fy;Y}hp kw;Wk;
Muha;r;rp ikak;>
rpd;dNfhsk;ghf;fk;>
fhQ;rpGuk; khtl;lk;-603 308.
gq;FngWgth; ,jid Fwpf;fTk; [ ]
1. NkNy Fwpg;gpl;Ls;s kUj;Jt Ma;tpd; tpguq;fs; vdf;F
tpsf;fg;gl;Ls;sJ. vd;Dila re;Njfq;fis Nfl;fTk; mjw;fhd
jFe;j tpsf;fq;fis ngwTk; tha;g;gspf;fg;gl;Ls;sJ vd ehd;
Ghpe;J nfhz;Ls;Nsd;.
2. ,e;j Muha;r;rpapy; vd; gq;Nfw;G jd;dpr;irahdJ kw;Wk; vd;
kUj;Jtg; ghJfhg;G kw;Wk; rl;l chpikfs; ghjpf;fg;glhky; ve;j
Neuj;jpYk; ve;j fhuzKkpd;wp ehd; ,jpypUe;J tpyfp nfhs;s
jilNaJk; ,y;iy vdTk; ehd; Ghpe;J nfhz;Ls;Nsd;.
3. ehd; Ma;tpypUe;J tpyfpdhYk; $l kUj;Jt Ma;T
Nkw;nfhs;Sk; kUj;Jtkid mth;fspd; rhh;ghf gzpahw;Wk;
kUj;Jth;fs;> ed;elj;ij newpKiwfs; FO kw;Wk; xOq;FKiw
Mizaq;fs; jw;Nghija Ma;T kw;Wk; ,jw;F njhlh;ghf elj;jg;
ngwf;$ba NkYk; VNjDk; tUq;fhy Ma;T ,uz;Lk; Fwpj;j vd;
cly;ey gjpTfis Muha vd; mDkjpg; ngw Ntz;ba
mtrpakpy;iy vdTk; ehd; Ghpe;J nfhz;Ls;Nsd;. ,itfis
mZfpg; ngw ehd; xg;Gf; nfhs;fpNwd;. MapDk; %d;whk;
egh;fSf;F jug;gLk; my;yJ gpuRhpf;fg;gLk; VNjDk; jfty;fspy;
vd; jdpg;gl;l milahsk; ntspg;gLj;jglkhl;lhJ vdTk; ehd;
Ghpe;J nfhz;Ls;Nsd;.
--2--
4. Ma;tpd; NghJ Nkw;nfhs;sg;gLk; ghpNrhjidfSf;fhf vd;
clypypUe;J ,uj;jk; kw;Wk; rpWePh; vLg;gjw;F rk;kjpf;fpNwd;.
5. ,e;j Muha;r;rpapypUe;J ntspg;gLk; VNjDk; jfty;fs; my;yJ
KbTfis gad;gLj;j mj;jifa gad;ghL mwptpay; rhh;e;j
NjitfSf;fhf kl;Lk; vDk; gl;rj;jpy; ehd; mjw;F epge;jid
VJk; tpjpf;fkhl;Nld; vd xg;Gf; nfhs;fpNwd;. NkNy Fwpg;gpl;l
Ma;tpy; gq;F nfhs;s rk;kjpf;fpNwd;.
6. vdf;F nfhLf;fg;gl;l mwpTiufspd; gb ele;J nfhs;tJld;
,e;j Ma;it Nkw;nfhs;Sk; kUj;Jt mzpf;F cz;ikAld;
,Ug;Ngd; vd;Wk; cWjpaspf;fpNwd;. vd; cly; eyk;
ghjpf;fg;gl;lhNyh> vjph;ghuhj tof;fj;jpw;F khwhd Neha;mwpFwp
njd;gl;lhNyh clNd ,ij kUj;Jt mzpaplk; njhptpg;Ngd; vd
cWjp mspf;fpNwd;.
gq;Nfw;gthpd; ifnahg;gk; ...................................... ,lk; ..........................
Njjp................. / fl;il tpuy; Nuif
gq;Nfw;gthpd; ngah; kw;Wk; tpyhrk; : ...........................................................................
........................................................................................................................................
Ma;thshpd; ifnahg;gk; ............................... ,lk; ..................... Njjp .......................
Ma;thshpd; ngah; .........................................
ANNEXURE – III
IEC APPROVAL CERTIFICATE
ANNEXURE – IV
Comparison of efficacy and safety of Epalrestat with
Methylcobalamin in patients with Diabetic neuropathy
PROFORMA
NAME:
Age : OP. No:
Sex : M / F ID No:
Marital Status: M / Single Edu. Status : L / IL
ADDRESS: Phone No :
Randomised Group : Group A [ ] Group B [ ] Group C [ ]
Whether Informed consent
Obtained : Yes [ ] No [ ]
Chief Complaints / Reason for admission:
History of Present illness:
Past Medical History:
Past Medication History:
Personal History:
Smoker : Y/N Alcoholic : Y/N
Tobacco : Y/N Known Allergies : Y/N
-1-
VISIT 1-BASELINE
General Physical Examination:
Ht: Wt: BMI:
Pallor : Edema: Icterus :
Cyanosis: Clubbing: Lymphadenopathy :
Vital Signs :
Temp. : ……. BP : …….. Pulse : ……. RR : ……..
SYSTEMIC EXAMINATION:
CVS : RS : Abdomen ;
NERVOUS SYSTEM: 1. VAS Pain Scoring Method: [�/ �]
0 1-2 3-4 5-6 7-8 8-10
No Pain Mild Pain Moderate
Pain Severe Pain
Very Severe Pain
Worst Pain
2. Michigan Neuropathy Screening Instrument : [�/ �]
Refer Page No : 5& 6
LABORATORY INVESTIGATION:
1. Hemogram: Hb : (g/dl) CBC :
2. FBS: (60-90) PPBS : (80-150)
3. HbA1C :
4. URINE EXAMINATION:
Colour: ….. Albumin: …… Sugar : …….. Deposits:
5. Liver Function Test:
AST:…… ALT: ……. Albumin: ……… Total
Bilirubin: …
6. Renal Function Test:
Urea: ……… Sr. Cr : ……. Uric acid: ……. BUN: ……..
-2-
VISIT 2 - END OF 4 WEEKS
Wt: BP : …….. ADR : ………
FBS : ……… Empty foils returned : Yes [ ] No [ ]
NERVOUS SYSTEM:
1. VAS Pain Scoring Method: [�/ �]
0 1-2 3-4 5-6 7-8 8-10
No Pain Mild Pain Moderate
Pain Severe Pain
Very
Severe Pain Worst Pain
VISIT 3 - END OF 8 WEEKS
Wt: BP : …….. ADR : ………
FBS : ……… Empty foils returned : Yes [ ] No [ ]
NERVOUS SYSTEM:
1. VAS Pain Scoring Method: [�/ �]
0 1-2 3-4 5-6 7-8 8-10
No Pain Mild Pain Moderate
Pain Severe Pain
Very
Severe Pain Worst Pain
-3-
VISIT 4 - END OF 12 WEEKS
General Physical Examination:
Ht: Wt: BMI:
Pallor : Edema: Icterus :
Cyanosis: Clubbing: Lymphadenopathy :
Vital Signs :
Temp. : ……. BP : …….. Pulse : ……. RR : ……..
SYSTEMIC EXAMINATION:
CVS : RS : Abdomen ;
NERVOUS SYSTEM: 1. VAS Pain Scoring Method: [�/ �]
0 1-2 3-4 5-6 7-8 8-10
No Pain Mild Pain Moderate
Pain Severe Pain
Very Severe Pain
Worst Pain
2. Michigan Neuropathy Screening Instrument : [�/ �]
Refer Page No : 5 & 6
LABORATORY INVESTIGATION:
1. Hemogram: Hb : (g/dl) CBC :
2. FBS: (60-90) PPBS : (80-150)
3. HbA1C :
4. URINE EXAMINATION:
Colour: ….. Albumin: …… Sugar : …….. Deposits:
5. Liver Function Test:
AST:…… ALT: ……. Albumin: ……… Total
Bilirubin: …
6. Renal Function Test:
Urea: ……… Sr. Cr : ……. Uric acid: ……. BUN: ……..
Adverse Drug Reactions : …………
-4-
MICHIGAN NEUROPATHY SCREENING INSTRUMENT
PATIENT VERSION
A. History (To be completed by the person with diabetes)
Please take a few minutes to answer the following questions about the feeling in your legs and feet. Check
yes or no based on how you usually feel. Thank you.
1. Are you legs and/or feet numb? Yes No
2. Do you ever have any burning pain in your legs and/or feet? Yes No
3. Are your feet too sensitive to touch? Yes No
4. Do you get muscle cramps in your legs and/or feet? Yes No
5. Do you ever have any prickling feelings in your legs or feet? Yes No
6. Does it hurt when the bed covers touch your skin? Yes No
7. When you get into the tub or shower, are you able to tell the
hot water from the cold water? Yes No
8. Have you ever had an open sore on your foot? Yes No
9. Has your doctor ever told you that you have diabetic neuropathy? Yes No
10. Do you feel weak all over most of the time? Yes No
11. Are your symptoms worse at night? Yes No
12. Do your legs hurt when you walk? Yes No
13. Are you able to sense your feet when you walk? Yes No
14. Is the skin on your feet so dry that it cracks open? Yes No
15. Have you ever had an amputation? Yes No
Total:
-5-
MICHIGAN NEUROPATHY SCREENING INSTRUMENT
B. Physical Assessment (To be completed by health professional)
1. Appearance of Feet
Right Left
a. Normal 0 Yes 1 No Normal 0 Yes 1 No
b. If no, check all that apply: If no, check all that apply:
Deformities Deformities
Dry skin, callus Dry skin, callus
Infection Infection
Fissure Fissure
Other Other
specify: specify:
Right Left
2. Ulceration
Absent Present Absent Present
0 1 0 1
Present/ Present/
3. Ankle Reflexes
Present Reinforcement Absent Present Reinforcement Absent
0 0.5 1 0 0.5 1
4. Vibration Present Decreased Absent Present Decreased Absent
0 0.5 1 0 0.5 1
perception at
great toe
5. Monofilament Normal Reduced Absent Normal Reduced Absent
0 0.5 1 0 0.5 1
Signature: Total Score /10 Points
-6-
MASTER CHART
Annexure V – MASTER CHART
Group- A
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2)
HbA1C
(%)
FBS
(mg/dl)
PPBS
(mg/dl)
Urine Sugar
(Nil/Trace/P/PP)
MNSI
(Physician
Version)
1 65 F 25.45 7.65 150.26 270.25 Nil 7.0
2 62 M 25.54 7.45 165.56 265.63 Nil 7.5
3 58 F 25.75 7.63 153.34 272.28 Nil 7.0
4 55 F 25.32 7.78 166.26 274.78 T 7.5
5 30 M 24.98 7.27 154.65 256.90 Nil 7.0
6 63 M 24.89 7.28 165.15 269.45 Nil 7.5
7 44 F 26.15 7.55 153.34 290.28 P 7.5
8 58 M 25.23 7.45 172.56 250.56 T 6.5
9 35 F 25.65 7.63 168.27 265.43 Nil 7.0
10 35 F 25.65 7.48 157.56 275.23 Nil 6.5
11 61 M 25.87 7.77 171.78 276.45 P 7.0
12 45 F 25.35 7.28 152.15 269.34 Nil 7.5
13 45 F 25.75 7.27 157.34 274.78 Nil 7.0
14 64 M 25.32 7.28 168.56 257.90 Nil 7.5
15 47 M 24.98 7.55 158.27 249.45 Nil 7.0
16 40 F 26.15 7.45 167.56 289.28 Nil 7.5
17 62 F 25.23 7.63 168.78 250.56 Nil 7.5
18 50 F 25.65 7.48 158.78 290.43 Nil 6.5
19 40 F 25.65 7.77 150.15 270.23 Nil 7.0
20 65 M 25.87 7.28 170.34 276.45 Nil 6.5
21 61 F 25.35 7.84 167.56 269.34 Nil 6.5
22 28 F 25.75 7.98 161.27 265.32 Nil 7.0
23 65 F 25.32 7.46 152.56 275.45 Nil 6.5
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2)
HbA1C
(%)
FBS
(mg/dl)
PPBS
(mg/dl)
Urine Sugar
(Nil/Trace/P/PP)
MNSI
(Physician
Version)
24 64 F 25.23 7.63 170.15 274.78 Nil 6.5
25 53 F 25.65 7.78 154.34 256.90 Nil 7.0
26 63 M 25.65 7.27 171.56 269.45 T 6.5
27 32 M 25.87 7.38 166.27 290.28 Nil 7.0
28 60 F 25.35 7.55 159.56 250.56 Nil 7.5
29 47 F 25.75 7.45 166.78 276.43 Nil 7.0
30 28 F 25.32 7.53 157.15 264.23 Nil 7.5
31 43 F 24.98 7.48 160.34 276.45 Nil 7.0
32 63 M 26.15 7.97 164.56 269.34 Nil 7.5
33 55 F 25.23 7.28 173.27 274.78 Nil 7.5
34 63 M 25.65 7.27 152.56 257.90 Nil 6.5
35 55 F 25.65 7.28 183.78 279.45 Nil 7.0
36 63 M 25.87 7.55 143.78 259.28 Nil 6.5
37 40 F 25.35 7.45 165.15 255.56 T 6.5
38 38 M 25.75 7.63 155.34 285.43 Nil 7.0
39 60 F 25.32 7.48 165.56 270.23 Nil 6.5
40 42 F 24.65 7.77 163.27 276.45 Nil 7.0
41 60 F 26.10 7.28 162.56 269.34 Nil 7.5
42 50 F 25.27 7.84 160.34 245.32 Nil 7.0
43 60 F 25.34 7.98 164.56 295.45 Nil 7.5
43 58 M 25.65 7.46 163.27 279.45 Nil 7.5
45 35 F 25.65 7.48 162.56 259.28 Nil 6.5
46 63 F 25.87 7.77 168.78 232.56 Nil 7.0
47 50 F 25.35 7.28 158.24 290.43 Nil 6.5
48 65 F 25.75 7.84 172.45 281.23 Nil 6.5
49 45 M 25.32 7.98 153.15 279.16 Nil 7.0
50 34 M 24.65 7.46 183.52 276.34 Nil 6.5
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2)
HbA1C
(%)
FBS
(mg/dl)
PPBS
(mg/dl)
Urine Sugar
(Nil/Trace/P/PP)
MNSI
(Physician
Version)
51 60 M 25.23 7.46 142.17 271.26 Nil 7.0
52 51 F 24.65 7.45 140.34 269.28 Nil 7.0
53 63 F 26.10 7.53 184.56 272.56 Nil 7.5
54 64 M 25.27 7.48 168.27 270.43 Nil 7.0
55 62 M 25.34 7.37 157.56 271.23 Nil 7.5
Group- B
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2) HbA1C (%) FBS (mg/dl)
PPBS
(mg/dl)
Urine
Sugar
(Nil/Trace/
P/PP)
MNSI
(Physician
Version)
1 45 M 25.27 7.84 140.15 255.28 Nil 7.5
2 42 F 25.34 7.56 180.34 292.56 Nil 8.0
3 55 M 25.65 7.56 155.56 280.43 Nil 7.0
4 62 M 25.65 7.45 173.27 261.23 Nil 7.0
5 40 F 25.87 7.45 157.56 289.16 Nil 7.5
6 62 M 25.35 7.53 165.34 256.34 T 7.5
7 40 F 25.75 7.48 144.56 271.26 Nil 7.5
8 36 M 25.32 7.97 183.27 275.67 Nil 7.0
9 60 F 24.65 7.28 142.56 278.56 Nil 7.0
10 31 M 25.23 7.27 173.78 279.16 Nil 7.5
11 39 M 24.56 7.28 168.24 275.45 T 7.5
12 43 M 25.31 7.55 167.45 280.45 Nil 7.5
13 64 M 26.01 7.45 183.15 255.15 Nil 7.5
14 62 F 25.53 7.63 143.52 295.19 Nil 7.5
15 62 M 25.01 7.48 167.17 278.56 Nil 8.0
16 42 M 25.25 7.77 160.78 279.16 Nil 7.0
17 47 F 24.78 7.28 145.34 275.45 T 7.0
18 59 F 25.75 7.84 184.34 280.45 Nil 7.5
19 38 M 25.32 7.98 144.67 285.15 Nil 7.5
20 60 F 24.65 7.46 184.98 265.19 Nil 7.5
21 59 M 25.23 7.48 154.87 294.18 Nil 7.0
22 55 M 24.56 7.77 175.27 254.39 Nil 7.0
23 57 F 25.31 7.28 155.27 295.76 Nil 7.5
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2) HbA1C (%) FBS (mg/dl)
PPBS
(mg/dl)
Urine
Sugar
(Nil/Trace/
P/PP)
MNSI
(Physician
Version)
24 51 M 25.53 7.98 167.56 255.45 Nil 7.5
25 65 M 25.01 7.46 165.34 280.45 Nil 7.0
26 38 M 25.29 7.46 144.56 274.15 T 7.5
27 60 F 25.16 7.45 183.27 278.19 Nil 7.5
28 59 M 24.85 7.53 168.56 284.18 Nil 7.5
29 60 F 25.67 7.48 157.78 264.39 Nil 7.0
30 26 F 26.02 7.97 168.24 285.76 Nil 7.0
31 34 M 25.36 7.28 157.45 265.45 Nil 7.5
32 40 F 25.45 7.27 183.15 280.45 Nil 7.5
33 60 F 25.53 7.28 143.52 279.15 Nil 7.5
34 43 M 25.01 7.38 182.17 271.19 Nil 7.5
35 63 F 25.29 7.46 155.78 272.18 Nil 7.5
36 60 F 25.16 7.46 160.34 276.31 Nil 8.0
37 43 M 24.85 7.45 159.34 277.76 T 7.0
38 58 F 25.67 7.53 184.67 273.45 Nil 7.0
39 60 F 26.02 7.48 159.98 280.45 Nil 7.5
40 43 M 25.36 7.27 160.87 255.15 Nil 7.5
41 62 F 25.45 7.28 155.27 295.19 Nil 7.5
42 60 F 26.02 7.67 160.27 294.18 T 7.0
43 43 M 25.36 7.28 168.78 254.39 Nil 7.0
43 64 F 25.45 7.45 163.34 255.76 Nil 7.5
45 60 F 25.53 7.45 166.24 294.89 Nil 8.0
46 55 F 25.01 7.73 168.67 270.56 Nil 7.0
47 62 M 25.16 7.53 160.98 281.67 Nil 7.0
48 50 F 24.85 7.39 162.85 275.67 Nil 7.5
49 50 M 25.67 7.46 167.27 270.45 Nil 7.5
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2) HbA1C (%) FBS (mg/dl)
PPBS
(mg/dl)
Urine
Sugar
(Nil/Trace/
P/PP)
MNSI
(Physician
Version)
50 55 F 26.02 7.23 185.27 274.56 Nil 7.5
51 47 F 25.36 7.45 145.32 282.53 Nil 7.0
52 63 M 25.65 7.98 185.27 275.45 Nil 7.5
53 63 M 25.65 7.46 145.27 280.45 Nil 7.0
54 53 M 25.87 7.46 168.78 276.15 Nil 7.0
55 40 F 25.35 7.45 160.34 275.19 Nil 7.5
Group- C
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2)
HbA1C
(%)
FBS
(mg/dl)
PPBS
(mg/dl)
Urine
Sugar
(Nil/Trace/
P/PP)
MNSI
(Physician
Version)
1 64 M 25.45 7.75 144.43 254.34 Nil 7.0
2 52 F 23.56 7.98 185.27 290.45 Nil 7.5
3 63 M 26.54 7.46 145.27 286.15 Nil 7.5
4 65 F 24.87 7.46 183.78 265.19 Nil 7.5
5 63 F 25.10 7.45 169.34 294.18 Nil 7.0
6 63 M 24.78 7.53 160.24 279.39 Nil 6.5
7 45 F 25.40 7.48 166.67 274.76 Nil 6.5
8 40 F 26.1 7.77 162.98 284.89 Nil 6.5
9 62 M 25.16 7.28 144.85 278.56 Nil 6.5
10 60 F 25.34 7.27 185.27 276.67 Nil 7.0
11 61 M 25.89 7.28 185.27 275.67 Nil 7.0
12 34 M 24.78 7.78 160.32 279.45 PP 7.0
13 63 M 25.40 7.46 159.27 271.56 Nil 7.0
14 44 F 26.1 7.46 154.27 276.53 Nil 6.5
15 48 M 25.16 7.45 163.78 280.45 Nil 6.5
16 62 M 25.34 7.73 165.34 276.15 Nil 6.5
17 56 F 25.89 7.48 169.24 275.19 T 6.5
18 36 M 25.45 7.27 159.67 294.18 Nil 7.0
19 63 F 23.56 7.78 166.98 254.39 Nil 7.0
20 49 F 26.54 7.27 162.85 293.76 Nil 7.0
21 50 F 24.87 7.28 160.27 254.89 Nil 7.0
22 45 M 25.10 7.45 170.27 275.56 Nil 7.0
23 35 M 24.78 7.45 165.32 276.67 T 6.5
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2)
HbA1C
(%)
FBS
(mg/dl)
PPBS
(mg/dl)
Urine
Sugar
(Nil/Trace/
P/PP)
MNSI
(Physician
Version)
24 55 F 26.1 7.53 175.27 276.45 Nil 7.0
25 64 M 24.87 7.48 155.27 274.56 Nil 7.0
26 51 F 25.10 7.77 173.78 278.53 T 7.0
27 56 F 24.78 7.28 155.34 274.45 Nil 7.0
28 38 M 25.40 7.27 166.24 274.56 Nil 6.5
29 64 F 26.1 7.28 162.67 276.53 Nil 6.5
30 40 M 25.16 7.78 167.98 280.45 Nil 6.5
31 50 F 25.34 7.46 161.85 276.15 Nil 6.5
32 63 F 25.89 7.46 168.27 275.19 Nil 7.0
33 50 F 24.78 7.45 162.27 294.18 T 7.0
34 60 F 25.40 7.73 170.32 254.39 Nil 7.0
35 50 F 26.1 7.48 160.27 283.76 Nil 7.0
36 64 F 25.16 7.27 166.27 264.89 Nil 7.0
37 63 F 25.34 7.78 162.78 285.56 Nil 6.5
38 47 F 25.89 7.27 167.34 266.67 T 6.5
39 63 M 25.45 7.28 162.24 276.45 T 7.0
40 54 M 23.56 7.45 168.67 274.56 Nil 7.0
41 42 F 25.16 7.45 160.98 276.53 Nil 7.0
42 52 F 25.34 7.46 168.85 280.45 Nil 7.0
43 40 M 25.89 7.46 161.27 276.15 Nil 6.5
43 50 F 24.78 7.45 166.27 275.19 Nil 6.5
45 50 M 25.40 7.73 164.32 284.18 Nil 6.5
46 26 F 25.89 7.48 160.45 264.39 Nil 6.5
47 58 M 25.45 7.27 168.78 273.76 Nil 7.0
48 65 M 23.56 7.78 174.26 274.89 T 7.0
49 60 F 26.54 7.56 154.65 275.56 Nil 7.0
S.No Age (Yrs) Sex (M/F) BMI
(Kg/m2)
HbA1C
(%)
FBS
(mg/dl)
PPBS
(mg/dl)
Urine Sugar
(Nil/Trace/P
/PP)
MNSI
(Physician
Version)
50 54 F 24.87 7.84 184.27 276.67 Nil 7.0
51 53 M 25.10 7.46 143.27 275.20 Nil 7.0
52 64 F 25.34 7.46 166.27 276.25 T 6.5
53 58 F 26.1 7.46 164.32 275.56 Nil 6.5
54 62 F 24.87 7.95 160.45 277.53 Nil 7.0
55 47 M 25.10 7.73 168.78 273.45 Nil 7.0