STUDY OF EFFICACY AND SAFETY OF ADDITION OF

VILDAGLIPTIN(DPP-4 INHIBITOR) TO ON GOING TREATMENT

WITH TRIPLE DRUG THERAPY(METFORMIN,GLIMIPRIDE
AND PIOGLITAZONE) IN POORLY CONTROLLED TYPE 2
DIABETES MELLITUS.
Name of candidate

Dr. Vivek Rana

(Batch 2009 2012)

Name of Supervisor

Dr. Hari Krishan Madaan

Name of co-supervisor

Dr. Savita Kapila

ABSTRACT
The study will be conducted on 30 patients attending outdoor
patient department (OPD) or admitted in Department of Medicine,
Rajindra Hospital, Patiala to evaluate the efficacy and safety of
addition of Vildagliptin to ongoing triple drug therapy (Glimipride,
Metformin and Pioglitazone) in poorly controlled type-II Diabetes
Mellitus as regard control of

FBS, HbA 1c, Lipid profile and Liver

function tests. Study will be conducted over period of 12 weeks and at

the end of 12 weeks HbA1c will be repeated along with FBS, Lipid
profile and Liver function tests.

STUDY OF EFFICACY AND SAFETY OF ADDITION OF

VILDAGLIPTIN(DPP-4 INHIBITOR) TO ON GOING TREATMENT
WITH TRIPLE DRUG THERAPY(METFORMIN,GLIMIPRIDE
AND PIOGLITAZONE) IN POORLY CONTROLLED TYPE 2
DIABETES MELLITUS.

INTRODUCTION
The prevalence of diabetes mellitus is rapidly increasing all over
the world. In Asia and especially in India, the projected increase in the
incidence of diabetes mellitus by 2010 is assumed to be 40 million
persons with majority having type 2 diabetes mellitus and globally
numbers are expected to rise from 151 million in 2000 to 221 million
by 2010 and 300 million by 2025. Prevalence of diabetes was 4% in
1995 and expected to rise to 5.4% by 2015 (KING et al, 1998)
Diabetes mellitus refers to group of common metabolic disorders
that share the phenotype of hyperglycemia. Depending apon the
etiology of diabetes mellitus, factors contributing to hyperglycemia
include
ii

Reduced Insulin secretion

Decreased glucose utilization

Increased glucose production

Broadly Diabetes is divided into two types.

Type-I : Result of complete or near total Insulin deficiency which can be
(a)

Immune mediated

(b)

Idiopathic

Type-II : Chronic progressive disease characterized by

(a)

Decreased Insulin sensitivity of target cells

(b)

Compensatory hyperinsulinemia

(c)

Beta cell exhaustion

Leading to state of chronic hyperglycemia

All these metabolic factors lead to Insulin resistance syndrome
which is characterized by
(a)

Impaired glucose metabolism

(b)

Central obesity

(c)

Dyslipidemia

(d)

Hypertension

(e)

Atherosclerosis
(Granberry et al, 99)
iii

Criteria for diagnosis of Diabetes mellitus by American Diabetic

Association (ADA), 2007
(i)

Symptoms of diabetes plus RBS > 11.1 mmol /L (200 mg/dl)

(ii)

Fasting plasma glucose > 7.0 mmol/L (126 mg/dl)

(iii)

Two hour plasma glucose > 11.1 mmol/L (200 mg/dl) during an
oral glucose tolerance test (OGTT).

The test should be performed as described by W.H.O using

glucose load concentration equivalent of 75 grams of anhydrous
glucose dissolved in water.
In the absence of unequivocal hyperglycemia these criteria
should be confirmed by repeat testing on different day.
Risk factors for Type-II Diabetes Mellitus
-

Family history

Obesity (BMI > 25 Kg/m )

Race / Ethinicity

Previously identified IFG and IGT

History of GDM or delivery of baby > 4 Kg ( >9 lb)

Hypertension ( BP >140/90 mm of Hg )

HDL Cholesterol < 35 mg/dl and TGs >250 mg/dl

iv

PCOD or Acanthosis nigricans

History of vascular disease

The aim of the treatment in Diabetes mellitus is to bring the

daily blood glucose profile to as close as possible to that of a nondiabetic persons including peaks and troughs induced by diet ,
exercise, stress and emotion. Ideally treatment aim should be to
prevent diabetic coma and other long term complications.
(Alberti et al, 1998 )
Various treatment modalities
1. Diet therapy
2.

Oral hypoglycemic agents ( OHAs )

3.

Insulin therapy

ORAL HYPOGLYCEMIC AGENTS ( OHAs )

1. SECRETAGOGUES

(a) Sulphonylureas : These act by sulphonylureas receptors on

pancreatic cell membrane and increase insulin secretion.
(b) Glinides : it acts in analogue manner by binding to
sulphpnylurea receptors as well as other distinct receptors
causing Insulin release.
v

2. INSULIN SENSITISERS

(a) Biguanides: These do not cause Insulin release but suppress

hepatic gluconeogenesis and glucose output from liver and
enhance Insulin mediated glucose disposal in muscle and fat.
(b) Thiazolidinediones: These are selective agonist for nuclear
peroxisome proliferators activated receptor gamma (PPAR-)
which enhances transcription of several Insulin responsive
genes and tend to reverse insulin resistance.
(c) -

glucosidase

inhibitors:

These

are

complex

oligosaccharides which reversibly inhibit -glucosidase, final

enzymes of carbohydrate digestion in brush border of small
intestine mucosa.
(d) Incretins :
(i)

GLP-1 agonist : Exenatide, Liraglutide

(ii)

DPP-4 inhibitors : Sitagliptin, Vildagliptin, Saxagliptin

INCRETINS
Incretins based therapy addresses the progressive nature of type
2 Diabetes mellitus not only by addressing glucose control but also
with weight neutral (DPP-4 inhibitors) and weight reducing effects

vi

(GLP-1 receptor agonist). Preclinical data suggest that incretin based

therapy may also preserve -cell function holding promise of truly
disease modifying therapy.
DPP-4 inhibitors also commonly called as Gliptins are relatively
new class of drugs for treatment of type 2 Diabetes mellitus. These
agent work in a unique way to improve insulin secretion from -cells of
pancreas in response to increase in blood glucose and simultaneously
decrease glucagon output from -cells of pancreas which results in
decreased hepatic glucose output. Specifically, gliptins decrease the
breakdown of GLP-1 such that the circulating levels reach high normal
physiological

GLP-1

range.

This

results

in

more

prompt

and

appropriate secretion of Insulin and suppression of Glucagon in

response to a carbohydrate containing meal. Since these drugs
improve Insulin secretion in response to an increase in blood glucose,
it seems appropriate to pair them with drugs that have different
mechanism of action, such as Insulin sensitizers like Metformin.
Infact, improvement in fasting and post prandial blood glucose levels,
improved -cell function and improvement in HbA1c levels have been
demonsrated in numerous clinical trials using different Gliptins as
monotherapy and in combination with various type-2 DM medications
including Insulin.
REVIEW OF LITERATURE
vii

There are various studies showing comparison of Vildagliptin

with other Oral hypoglycemic agents and few combinations.
Serra et al (2008) in their study observed that co-administration
of Vildagliptin with either Glyburide or Pioglitazone in patients with
type-2 DM improves post prandial glycemic control without notable
effects on drug pharmacokinetics.
Garber et al (2008) concluded in their study that in patients with
type-2

DM

inadequately

controlled

with

prior

Sulphonylurea

monotherapy addition of Vildagliptin (50 mg or 100 mg) daily to

Glimipride (4 mg OD ) improves glycemic control and is well tolerated.
Addition of Vildagliptin 50 mg daily to Sulphonylurea monotherapy
may be a particularly attractive therapy in elderly patients.
Schweizer et al (2009) studied that Vildagliptin is an effective
and well tolerated treatment option in elderly patients with DM-2,
demonstrating

similar

improvements

in

glycemic

controls

as

Metformin with superior GI tolerability.

Ahren et al (2009) observed that DPP-4 inhibitors increases
Insulin secretion and reduces glucagons secretion by preventing the
inactivation of GLP-1, thereby lowering the levels of blood glucose.
HbA1c levels reduced by approximately 0.6% 1.1% in studies upto 52
viii

weeks. DPP-4 inhibitors are safe and tolerable with no increased risk
of adverse effects as compared to placebo and have low risk of
hypoglycemia.
Billi et al (2009) observed that when Vildagliptin is added to
Metformin , it demonsrates favourable safety and tolerability over one
year. Vildagliptin provided additional HbA 1c lowering to that achieved
with

Metformin

alone

and

comparable

to

that

achieved

with

Pioglitazone, with only Pioglitazone causing weight gain.

Foley et al (2009) reported in a multi-center, double blind,
randomized, active controlled study to compare efficacy and safety of
two years of monotherapy with Vildagliptin and Gliclazide in drug
nave patients with type-2 DM showed HbA 1c values slightly higher in
Gliclazide group. Thus showing improved glycemic control in drug
nave patients with type-2 DM. Vildagliptin had significant benefits in
terms of less weight gain and less hypoglycemia.
Mathieu et al (2009) showed that Vildagliptin treatment has also
been associated with beneficial extrapancreatic effects including
improved Insulin sensitivity, improved peripheral Insulin sensitivity
and improved post prandial triglyceride rich lipoprotein metabolism.
Blonde et al (2009) reported that Vildagliptin is as effective as
Thiazolidinediones after 3 month treatment as an add on therapy to
ix

Metformin in a primary care population that included diverse patient

subgroups.
Tahrani et al (2009) have found in active controlled trials that
Vildagliptin-Metformin combination has been shown to produce
equivalent reduction in HbA1c levels to Pioglitazone-Metformin and
Glimipride-Metformin

combination

without

significant

risk

of

hypoglycemia and without causing weight gain.

Goodman et al (2009) reported in their study of efficacy and
tolerability of Vildagliptin in patients with type-2 DM inadequately
controlled with Metformin therapy that Vildagliptin 100 mg given as
morning dose is an effective and well tolerated treatment option and is
equally efficacious when given either as morning or evening dose.
Rosenstock et al (2009) observed in their study of long term 2
year safety and efficacy of Vildagliptin compared with Rosiglitazone in
drug nave patients with type-2 DM that the overall lipid profile
significantly improved with Vildagliptin compared to Rosiglitazone and
lower incidence of peripheral edema was seen with Vildagliptin as
compared to Rosiglitazone.
Bosi et al (2009) found that in treatment nave patients,
combination of Vildagliptin and both high dose and low dose

Metformin provide superior efficacy to monotherapy

treatment with

comparable overall tolerability profile and low risk of hypoglycemia.

There is as such no study available which shows effect of
addition of Vildagliptin in ongoing triple drug therapy in poorly
controlled type-2 Diabetes Mellitus. Present study is planned to study
its effect on glycemic control and lipid profile.

AIMS AND OBJECTIVES

1. To study the addition of Vildagliptin to ongoing triple drug therapy

in poorly controlled DM-2.
2. To study HbA1c levels after addition of Vildagliptin.
3. To study the adverse effects of Vildagliptin.
4. To study the effect of Vildagliptin on lipid metabolism.

xi

MATERIAL AND METHODS

The study will be conducted on 30 patients of type-2 Diabetes

Mellitus attending OPD/admitted in Dept of Medicine, Rajindra
Hospital, Patiala.
Inclusion criteria
1. Patients with type-2 Diabetes Mellitus on triple drug therapy
but not controlled adequately.

xii

Written consent for the trial will be obtained from all patients
after examining them in detail.
Exclusion criteria
1. Patients in diabetic ketoacidosis.
2. Patients with previous history of Insulin treatment
3. Patients

with

severe

complications

such

as

Retinopathy,

Nephropathy, Neuropathy, Cardiovascular diseases and acute or

severe infections.
4. Pregnant women and nursing mothers or those who are planning
to conceive in near future.
5. Patients

taking

drugs

influencing

glucose

metabolism

like

corticosteroids, diuretics, -blockers, etc.

6. Impaired renal and liver function.
7. Patients who refuse to give informed written consent.

METHOD
Patients will be verified for fulfilling inclusion criteria and ruled out
for presence of exclusion criteria. All the patients and their relatives
will be informed about the trial in their vernacular language. Written
consent will be taken. A detailed history of each patient will be taken
xiii

as per proforma attached. Complete clinical examination will be done.

After doing routine investigation as enumerated in the proforma
including FBS, HbA1c, Liver function tests and Lipid profile will be
done.
30 patients will be started on Vildagliptin on low dose 50 mg OD .
Patients will be followed every 2 weeks for their FBS levels and if
required dose of Vildagliptin will be increased to 100 mg OD after 4
weeks.
Study will be conducted over period of 12 weeks and at the end
12 weeks HbA1c will be repeated along with FBS, Liver function tests
and Lipid profile.
Patient can be discontinued from the study if at any stage it
is found that patient has developed life threatening symptoms or it is
observed that continuation of study is not in the interest of the
patient.

BIOCHEMICAL INVESTIGATIONS
1. Fasting blood sugar
xiv

2. HbA1c
3. Liver function tests
4. Lipid profile
FASTING BLOOD GLUCOSE (FBS)
Glucose oxidase peroxidase method
Principle
Glucose oxidase converts glucose to gluconic acid. Hydrogen peroxide
is formed in this reaction, in presence of peroxidase, oxidatively
couples 4-amino antipyrine and phenol to produce red quinoneimine
dye. This dye has absorbance maximum at 505 nm (500-550 nm). The
intensity

of

the

colour

complex

is

directly

proportional

concentration of glucose in specimen.

GOD
-D Glucose + O2 +H2O

Gluconic acid + H2O2

POD
H2O2 + 4- aminoantipyrine + phenol

Red dye + H2O

Calculation
Glucose in mg% = Absorbance of sample
X 100
Absorbance of standard
Expected values
Fasting blood glucose 60 to 110 mg%
xv

to

Postprandial blood glucose - < 145 mg%

Glycosylated Hemoglobin:
It is determined by spectrophotmetric ion exchange resin method as
described by Gonen and Rubenstein (1978)
Principle: Whole blood is mixed with the lysing reagent to
prepare hemolysate. This is then mixed with a weakly binding cation
exchange resin. The non-glycosylated hemoglobin binds to the resin
leaving GHb (Glycosylated Hb) free in the supernatant. The GHb is
determined by measuring the absorbance of GHb fraction and of the
total Hb (THb) against deionized water at 415nm.
Calculations:
Absorbance of GHb
GHb% =

x l 0 x Temperature factor (Tf)

Absorbance of THb
Tf = 1.0 at temperature 23C
Tf = 0.9 at temperature 30C

Calculation of HbA1C
It is done as per the conversion chart.

xvi

Conversion chart of glycosylated hemoglobin A 1% to mean

blood glucose and glycosylated hemoglobin A1%.
A1

A1C

MBG

A1

A1C

MBG

6.0

4.30

35

9.9

7.56

178

6.1

4.38

39

10.0

7.64

182

6.2

4.46

43

10.1

7.73

186

6.3

4.54

46

10.2

7.81

189

6.4

4.63

50

10.3

7.89

193

6.5

4.71

54

10.4

7.98

197

6.6

4.79

58

10.5

8.06

200

6.7

4.88

61

10.6

8.15

205

6.8

4.96

65

10.7

8.23

207

6.9

5.05

68

10.8

8.31

211

7.0

5.13

72

10.9

8.40

215

7.1

5.21

76

11.0

8.48

219

7.2

5.30

79

11.1

8.56

222

7.3

5.38

83

11.2

8.65

226

7.4

5.46

87

11.3

8.73

230

7.5

5.55

90

11.4

8.82

233

7.6

5.63

94

11.5

8.90

237

7.7

5.72

98

11.6

8.98

241

7.8

5.80

101

11.7

9.07

244

7.9

5.88

105

11.8

9.15

248

8.0

5.97

109

11.9

9.24

252

8.1

6.05

112

12.0

9.32

255

8.2

6.14

116

12.1

9.40

259

8.3

6.22

120

12.2

9.49

263

8.4

6.30

123

12.3

9.57

266

8.5

6.39

127

12.4

9.65

270

xvii

8.6

6.47

131

12.5

9.74

274

8.7

6.55

134

12.6

9.82

277

8.8

6.64

138

12.7

9.91

281

8.9

6.72

142

12.8

9.99

285

9.0

6.81

145

12.9

10.07

288

9.1

6.89

149

13.0

10.16

292

9.2

6.97

153

13.1

10.24

295

9.3

7.06

156

13.2

10.33

299

9.4

7.14

160

13.3

10.41

304

9.5

7.22

164

13.4

10.49

309

9.6

7.31

167

13.5

10.58

314

9.7

7.39

171

13.6

10.66

320

9.8

7.48

175

13.7

10.74

326

Nathan (1984)
Liver function tests

Serum Bilirubin:
It is estimated by method of Malloy and Evelyn (1937).
Principle:
Bilirubin in diluted serum is made to react with diazo reagent in
presence of methanol and the coloured complex formed is read at 540nm.
Calculation:
Serum bilirubin (mg%)
= Reading of unknown Reading of control

S.G.O.T:

Reading of standard Reading of blank

xviii

10

mg%

It is estimated by International Federation of Clinical Chemistry

(IFCC) Method, Kinetic.
Principle:
L-Aspartate + 2-Oxoglutarate

Oxaloacetate + NADH

MDH

Sample pyruvate + NADH

AST

Oxalocetate
+ L-Glutamate

Malate + NAD
LDH

L-Lactate + NAD

AST

Asparate aminotransferase

MDH

Malate dehydrogenase

LDH

Lactate dehydrogenase

Calculation:
The general formula for converting absorbance change into
international Units (IU) of activity is:
IU/L

A / min . T .V . 10 3
S .V . Absoptivity P

Where:
T.V.

Total reaction volume (l)

S.V.

Sample volume (l)

Absorptivity

millimolar absorptivity of NADH at 340 nm

6.22

cuvette lightpath (cm)

1 cm

xix

Activity of AST

Abs/min 1768

S.G.P.T:
It is estimated by International Federation of Clinical Chemistry
(IFCC) Method, Kinetic.
Principle:
L-Alanine + 2-Oxoglutarate
Pyruvate + NADH

LDH

ALT

Pyruvate + L-Glutamate

L-Lactate + NAD

ALT

Alanine aminotransferase

LDH

Lactate dehydrogenase

Calculation:
Determine the mean absorbance change/min (A/min) for every
reading, find the mean value.
The general formula for converting absorbance change into
International Units (IU) of activity is :
IU/L

A / min . T .V . 10 3
S .V . Absoptivity P

Where:
T.V.

Total reaction volume in (l)

S.V.

Sample volume in (l)

Absorptivity

millimolar absorptivity of NADH at 340 nm

6.22
xx

cuvette lightpath = 1cm

Activity of ALT
at 370C (IU/L)

Abs/min Factor (1768)

Serum Alkaline Phosphatase:

It is estimated by PNPP Method.
Principle:
Alkaline Phosphatase cleaves p-nitrophenyl phosphate (p-NPP) into
p-nitrophenol and phosphate. p-nitrophenol is a yellow colour compound
in alkaline medium and absorbs light at 405 nm. The rate of increase in
absorbance at 405 nm. is proportional to Alkaline phosphatase activity in
specimen.
p-nitrophenyl phosphate

ALK
.PHOS
.

p-nitrophenol + phosphate

Calculation:
Average change in absorbance per minute is calculated.
Alkaline Phosphatase (IU/L) = Abs./min 2720

LIPIDOGRAM
A.

Determination of Total Serum Cholesterol

xxi

It is analysed by in vitro enzymatic colorimetric method

described by Allain et al. (1974).
Principle
Cholesterol esters are hydrolysed by cholesterol esterase to free
cholesterol and fatty acids. Free cholesterols are oxidized to cholest-4en-3one and hydrogen peroxide is liberated.
This then couples with 4 aminoantipyrine and phenol in the
presence of peroxidase to form a colored compound. The intensity of
color developed is proportional to the cholesterol concentration and is
measured at 510 nm wavelength or with green filter.
Cholesterol esters + H2O

Cholesterol + Fatty Acids

Cholesterol Esterase

Cholesterol + O2

Cholest-4-en-3-one + H2O2
Cholesterol Oxidase

H2O2 + phenol + 4Aminoantipyrine

Red Quinone + H2O

Peroxidase

Calculation
Absorbance of test
200 mg%
Serum Cholesterol (mg%) = Absorbance of s tan dard

B.

Estimation of HDL-Cholesterol

xxii

It is determined by enzymatic method after precipitation of serum by

phosphotungstate and magnesium chloride as describe by Burstein et
al (1970).
Principle
It is based on principle that LDL Cholesterol, VLDL &
Chylomicron are precipitated by polyanions in presence of metal ions
to leave HDL-Cholesterol fraction in solution. The HDL Cholesterol in
supernatant is separated by centrifugation and measured for its
cholesterol content as described by method of Allain (1974).

Serum + Precipitating Reagent

Precipitate + Supernatant
(VLDL + LDL)
(HDL)
cholesterol + Fattyacid

HDL - cholesterolesters + H2O

Cholesterol
Esterhydrolase

peroxidase
H2O2+Phenol + 4 amino Antipyrine Quinoneimine dye + H2O
(Red colored)

The red colored complex is formed, whose absorbance is proportional

to HDL-Cholesterol concentration.
CALCULATIONS
HDL Cholesterol (mg%) =

Absorbance of Test
Absorbance of standard

DETERMINATION OF TRIGYLCERIDE

xxiii

X 100

Triglyceride will be measured by invitro enzymatic colorimetric

method described by Mcgowan et al (1983).
Principle
Glycerol released from hydrolysis of Triglycerides by Lipoprotein
lipase is converted by glycerase kinase into glycerol 3 phosphatse
which is oxidized by glycerol phosphate oxidase to Dihydroxiacetone
phosphate and hydrogen peroxide. In presence of peroxidase, H 2O2
oxidises phenolic chromogen to a red colored compound.

Lipoproteinlipase
Triglyceride + H2O
Glycerolkinase
Glycerol + ATP

L- - Glycerol-3-Phosphate+O2

Glycerol + Fatty acid

L- Glycerol3 Phosphate + ADP

Dihydro-Oxyacetone phosphate+H2O2

Peroxidase
H2O2+2Chlorophenol+4Amino antipyrine
Benzoquinone-mono-

4-(Oimino) phenazone+

2H2O+HCL

The Quinonimine formed is proportional to total triglyceride

concentration.
Calculations
Total Triglyceride (mg%) =

Absorbance of sample
X 200
Absorbance of standard
xxiv

DETERMINATION OF LOW DENSITY LIPOPROTEIN CHOLESTROL

LDL
Cholesterol will be determined by formula devised by Frieldewald
et al, (1972) after determining total cholesterol, HDL Cholesterol and
Triglycerides
Formula
LDL-C (mg%)=Total Cholesterol-(Triglyceride+HDL C).

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xxix

PROFORMA

Name

Age

Sex

Cr. No.

OPD No.

Address

Chief complaints

Brief History of Present

Illness

Past History
Hypertension

Bronchial Asthma

:
xxx

Tuberculosis

CVA

MI/Angina

Personal History
Smoker/Non Smoker :
Alcoholic/Non-Alcoholic:

Family History
Diabetes Mellitus

Hypertension

Myocardial Infarction :
CVA

Examination

GPE
Anemia
Cyanosis
Jaundice
xxxi

Oedema
Pulse
Blood Pressure
-Supine
-Standing
-Respiratory Rate
-Temperature
System Examination
-Abdomen
-CVS
-CNS
-Chest
Investigation
HB
TLC
DLC
FBS
Blood Urea
Serum Creatinine
Urine C/E
xxxii

ECG
Lipidogram
LFT
HbA1c

xxxiii