261540604tintu Chacko PDF

A COMPARATIVE STUDY OF TENELIGLIPTIN VERSUS OTHER
STANDARD GLIPTINS USED IN TYPE II DIABETES MELLITUS

PATIENTS
A Dissertation Submitted to
THE TAMIL NADU Dr. M.G.R. MEDICAL UNIVERSITY
CHENNAI-600032
In partial fulfillment of the requirement for the award of the Degree of
MASTER OF PHARMACY
in
PHARMACY PRACTICE
OCTOBER-2017
DEPARTMENT OF PHARNACY PRACTICE,

KMCH COLLEGE OF PHARMACY,
KOVAI ESTATE, KALAPATTI ROAD,
COIMBATORE-641048.
A COMPARATIVE STUDY OF TENELIGLIPTIN VERSUS OTHER
PATIENTS
A Dissertation Submitted to
THE TAMIL NADU Dr. M.G.R. MEDICAL UNIVERSITY
CHENNAI-600032
In partial fulfillment of the requirement for the award of the Degree of
MASTER OF PHARMACY
in
PHARMACY PRACTICE
OCTOBER-2017
Submitted by
Tintu Chacko
(Reg. No. 261540604)
Under the Guidance of

Mr. C .Dhandapani, M.Pharm, (Ph.D)
Asst. Professor, Department of Pharmacy Practice
DEPARTMENT OF PHARMACY PRACTICE,

KMCH COLLEGE OF PHARMACY,
KOVAI ESTATE, KALAPATTI ROAD,
COIMBATORE-641048.
Prof. Dr. A.Rajasekaran, M. Pharm., Ph.D.,
Principal,
KMCH College of Pharmacy,
Kovai Estate, Kalapatti Road,
Coimbatore - 641 048.
Tamil Nadu
CERTIFICATE
This is to certify that the dissertation work entitled “A COMPARATIVE

STUDY OF TENELIGLIPTIN VERSUS OTHER STANDARD
GLIPTINS USED IN TYPE II DIABETES MELLITUS PATIENTS”
was carried out by (Reg. No. 261540604). The work mentioned in the
dissertation was carried out at the Department of Pharmacy Practice, KMCH
College of Pharmacy, Coimbatore, Tamilnadu for the partial fulfillment for
the degree of Master of Pharmacy during the academic year 2016-2017 and
is forwarded to the Tamilnadu Dr.M.G.R.Medical University, Chennai.
Date: Signature
Place: Coimbatore Prof. Dr. A. Rajasekaran, M.Pharm., Ph.D.

Mr. C. Dhandapani, M.Pharm, (Ph.D)
Asst. Professor, Dept. of Pharmacy Practice,
KMCH College of Pharmacy,
Kovai Estate, Kalapatti Road,
Coimbatore -641 048.
Tamil Nadu
CERTIFICATE
This is to certify that the dissertation work entitled “A COMPARATIVE

STUDY OF TENELIGLIPTIN VERSUS OTHER STANDARD
GLIPTINS USED IN TYPE II DIABETES MELLITUS PATIENTS” is
a bonafide work carried out by Ms. Tintu Chacko (Reg. No. 261540604).
The work mentioned in the dissertation was carried out at the Department of
Pharmacy Practice, KMCH College of Pharmacy, Coimbatore, Tamil Nadu,
under my supervision and guidance during the academic year 2016-2017.This
research work either in part or full does not constitute any of any
thesis/dissertation.
Date: Signature
Place: Coimbatore Mr. C. Dhandapani,M.Pharm, (Ph.D)

DECLARATION
I do here by declare that to the best of my knowledge and belief ,the

dissertation work entitled “A COMPARATIVE STUDY OF
TENELIGLIPTIN VERSUS OTHER STANDARD GLIPTINS USED
IN TYPE II DIABETES MELLITUS PATIENTS” submitted to the Tamil
Nadu Dr. M.G.R. Medical university , Chennai, in the partial fulfillment for
the Degree of Master of Pharmacy in Pharmacy practice, was carried
out at Department of pharmacy practice , KMCH College of Pharmacy,
Coimbatore under the guidance of Mr. C. Dhandapani,M.Pharm, (Ph.D)
during the academic year 2016-2017.
Date: Signature
Place: Coimbatore Ms. Tintu Chacko
(Reg. No. 261540604)
EVALUATION CERTIFICATE
This is to certify that the work embodied in the thesis entitled “A

COMPARATIVE STUDY OF TENELIGLIPTIN VERSUS OTHER
PATIENTS” submitted by Ms. Tintu Chacko (Reg. No. 261540604). to the
Tamil Nadu Dr. M.G.R. Medical university, Chennai, in the partial
fulfillment for the Degree of Master of Pharmacy in Pharmacy
Practice, is a bonafide research work carried out by the candidate during the
academic year 2016-2017 at KMCH College of Pharmacy, Coimbatore,
Tamilnadu and the same was evaluated by us.
Examination Center: K.M.C.H College of Pharmacy, Coimbatore
Date:
Internal Examiner External Examiner
Convener of Examination
ACKNOWLEDGEMENT
First and foremost I pay obeisance to the Almighty for blessing me with all the
confidence, courage, inspiration and curiosity to complete this project.
I take this opportunity to express my deep sense of gratitude and faithfulness to my

esteemed teacher and guide, Mr. C .Dhandapani, M.Pharm.,(Ph.D) Assistant Professor,
Department of Pharmacy Practice, for this remarkable guidance, patience, constant
encouragement, constructive comments and painstaking efforts for the successful
completion of this work.
I put across my honest thanks and gratitude to my clinical guide, Dr. Irania S.V,
MD., D.A.A, Kovai Medical Center and Hospital, for this guidance, valuable directions
and interest shown towards the research work.
I would also like to express my sincere and heartfelt gratitude to

Dr. P. Velayutham MD., DM and Dr. T.R Sivananam MBBS. D. Diac for their
contributions and support which helped me to successfully proceed with my work.
I extend my sincere thanks and gratitude to my Principal, Dr. A. Rajasekaran,

M.Pharm., Ph.D., for providing me with co-operative and creative environment which
enabled me to work assiduously.
I extend my sincere thanks to Dr. Nalla G. Palanisamy, M.D., AB (USA),

Chairman of Kovai Medical Center and Hospital and Madam Trustee, Dr. Thavamani D.
Planiswamy, M.D., AB (USA), for providing me with outstanding infrastructure,
resources and the opportunity to work in a clinical setting.
I expressed my sincere thanks to all my teachers, Dr. Suchandra Sen, Dr. Sankar,
Dr. K. T.Manisenthil Kumar, Mrs. Sathyaprabha, Mr. A. Vijjayakumar,
Dr. K.S.G Arulkumaran, Mrs.Aparna, Ms.Sreedevi, Ms.Geethu Grace, Mrs.Vennila
and all the other teaching and non-teaching staffs of KMCH college of Pharmacy for their
encouragement and judicious help.
My special thanks to the Library Staff of KMCH college of Pharmacy, for proving
the library facilities which contribute to the successful completion of my project work.
I also take this opportunity to acknowledge the help extended to me by
Mrs. Indrani Rajendran, Staff Nurse of General Medicine Department for their
immense help and co-operation. Without her timely assistance, the data collection would
not have been possible.
I take this opportunity to thank my father Mr. K.S Chacko and my mother
Mrs. Lilamma Chacko who shower their blessings always, and also my sister Mrs. Tinu
Chacko and my brother Master Akhil Chacko who supported me through all stages. It
also gives me great pleasure to dedicate my work to such adorable and affectionate parents,
sister and brother without whom I wouldn’t have been able to reach this stage. For their
invaluable affection, concern, encouragement and for the prayers they have offered for the
successful completion of my project.
Last but not the least, I owe my thanks and gratefulness to my ever loving friends
for their memorable support, help and encouragement, and my heartfelt sincere thanks to
all those who directly and indirectly contributed to the successful completion of my work.
Above all, I bow my work in feet of Almighty who let me to the actualization of
this research work.
ABBREVIATIONS
AACE : American Association of Clinical Endocrinology
ACE : American College of Endocrinology
ADA : American Diabetes Association
DPP-4 inhibitor : Dipeptidyl Peptidase 4 inhibitor
FPG : Fasting Plasma Glucose
FBS : Fasting Blood Sugar
GIP : Gastric Inhibitory Polypeptide
GLP : Glucagon like peptide 1
HbA1C : Glycated Hemoglobin
IDF : International Diabetes Federation
PPG : Postprandial Plasma glucose
PPBS : Postprandial Blood Sugar
SrCr : Serum Creatinine
SGPT : Serum glutamic pyruvic transaminase
SUs : Sulfonyl ureas
T2DM : Type II Diabetes Mellitus
TZD : Thiazolidinediones
INDEX
SL.NO. CONTENTS PAGE NO.
1. INTRODUCTION 1
2. REVIEW OF LITERATURE 13
3. AIM AND OBJECTIVES 21
4. METHODOLOGY 22
5. TABLES AND FIGURES 26
6. RESULTS AND ANALYSIS 53
7. DISCUSSION 60
8. CONCLUSION 69
9. BIBLIOGRAPHY 71
ANNEXURES
Annexure I: Letter of Approval from Ethics

10.
Committee of the Hospital.
Annexure II: Patient Data Collection Form

Introduction
1. INTRODUCTION
Diabetes mellitus was first reported in Egyptian manuscript about 3000 years
ago. In 1936, the distinction between type 1 and type II DM was clearly made. Type II
DM was first described as a component of metabolic syndrome in 1988.1
Type II diabetes (formerly known as non-insulin dependent DM) is due to
insufficient insulin production from beta cells in the setting of insulin resistance.2
Insulin resistance, which is the inability of cells to respond adequately to normal levels
of insulin, occurs primarily within the muscles, liver, and fat tissue. In the liver, insulin
normally suppresses glucose release.3
The prevalence of Type II Diabetes Mellitus (DM) is increasing all over the
world, especially in South Asia. India has largest population of diabetic patients. The
International Diabetes Federation (IDF) estimates the number of people with diabetes
in India will reach 80 million by the year 2025.4
MANAGEMENT OF TYPE II DIABETES MELLITUS
Pharmacological agents:
There are at least seven different classes of agents used as monotherapy, or in

combinations for the treatment of diabetes mellitus. Treatment include Metformin,
Sulphonylureas,Meglitinides, Alpha-glucosidase inhibitors, Thiazolidinediones (TZD),
DPP-4 inhibitors and insulin. Many conventional agents frequently exhibit reduced
efficacy over time, leading to inadequate glycaemic control.
Metformin was recommended by most guidelines as first line therapy for

T2DM. However, due to the progressive nature of T2DM, inevitable combination
therapies are often required if glycemic targets not to be maintained by metformin
monotherapy. Insulin resistance and pancreatic cell dysfunction are the two main
pathophysiological reasons of T2DM, hence, proper treatment for such disease should
target both these defects.
Department of Pharmacy Practice 1

Introduction
Figure 1: Treatment Algorithm for Type II Diabetes Mellitus

Introduction
GLIPTIN: DPP-4 INHIBITORS

Dipeptidyl peptidase 4 (DPP-4) inhibitor is a relatively new class of
antihyperglycemic agents that are now recommended as first or second-line agents in
treatment of diabetes by guidelines like American Diabetes Association (ADA) 2016
and American Association of Clinical Endocrinologists and American College of
Endocrinology 2016.
DPP-4 inhibitors control fasting plasma glucose (FPG) and postprandial plasma
glucose (PPG) levels through selective inhibition of DPP-4, resulting in increased
plasma concentrations of active glucagon-like peptide-1.
DPP-4 inhibitors unlike Sulfonylureas, Meglitinides, or insulin are weight
neutral and no risk of hypoglycemia. DPP-4 inhibitors, selectively inhibit the DPP-4
enzyme that degrades two major incretin hormones: GIP (gastric inhibitory
polypeptide) and GLP-1(glucagon -like peptide1).
They are reported to have glucose lowering efficacy, without the risk of
hypoglycemia, when added to the treatment regimen of patients in whom metformin
monotherapy is no longer sufficient or when initial dual therapy metformin is required.
DPP-4 inhibitors are reported to be well tolerated and efficacious in diverse population
with type II DM including the elderly patient with renal impairment.5
There are 11 different compounds of DPP‑ 4Is have been made available
worldwide, of which mostly available in Japan. In India, 4 DPP‑ 4Is are already
available and marketed that includes Sitagliptin, Vildagliptin, Saxagliptin, and
Linagliptin. Recently, two newer molecule Teneligliptin and Gemigliptin have been
added to this segment.
Importantly, teneligliptin has been already approved and marketed product in
Japan since 2012 and in Korea since 2014.
However, teneligliptin is neither approved in the USA or in Europe although it
was registered in the US Food and Drug Administration (FDA) for Phase 1 clinical
development in 2007 and Phase II clinical developments in European Medicines
Agency in 2009, without any further progress.

Introduction
Although various DPP-4 inhibitors have different pharmacokinetic and

Pharmacodynamic profiles, they are remarkably similar with regards anti-
hyperglycemic properties with a very safe adverse effect profile (weight neutral without
causing hypoglycemia).
The DPP-4 inhibitors based on their structure can be divided into those that
mimic the DPP-4 molecule (peptidomimetics, vildagliptin and saxagliptin) and those
that do not (non-peptidomimetics, sitagliptin, alogliptin, linagliptin).
They are competitive reversible inhibitors of the DPP-4 substrate acting extra-
cellularly. The molecules have varying affinities toward the DPP-4 substrate 5.
A list of available gliptins are follows
 Sitagliptin (Merck Sharp and Dohme Corp, approved as Januvia by US FDA in

year 2006)
 Vildagliptin (Novartis, approved as Galvus by EU in year 2007)
 Saxagliptin (Bristol-Myers Squibb, approved as Onglyza by US FDA in 2010)
 Linagliptin (Boerhinger Ingelheim, approved as Tradjenta by US FDA in year
2011)
 Alogliptin (developed by Takeda Pharmaceutical Company Limited, approved for
use in Japan)
 Teneligliptin (approved and marketed product in Japan since 2012 and in Korea
since 2014)

Introduction
Figure 2: Mechanism action of gliptins7
EFFICACY OF DPP-4 INHIBITORS AND RECOMMENDATION FOR USE

1. As monotherapy
DPP-4 inhibitors have demonstrated a modest and comparable glycated
hemoglobin lowering effect. Current guidance from the American Diabetes Association
recommends an HbA1c goal of <7% for the most patient and stringent goal of <6.5 if
this can be attained without significant hypoglycemia and side effects.5
2. As initial dual therapy with other anti-diabetic agents
DPP-4 inhibitors along with other anti-diabetic agents, significantly improved
glycated hemoglobin when compared with monotherapy arms.
In patients with T2DM inadequately controlled with metformin, SUs, or
thiazolidinedione monotherapy, the addition of DPP-4 inhibitor was associated with
significant improvements in HbA1c outcomes, as compared to placebo control.5
Introduction
3. In triple combinations
DPP-4 inhibitors consistently provided additive glycemic benefits. As add-on
to metformin and SU or a TZD, individual DPP-4 inhibitors have each been observed
to significantly reduce HbA1c from baseline as compared to dual therapy; and
significantly increase the proportion of patients achieving A1C <7%.5
SAFETY AND TOLERABILITY OF DPP-4 INHIBITORS
1. Low risk for hypoglycemia
A low risk of hypoglycemia was consistently observed in studies in treatment-
native patient receiving DPP-4 inhibitor monotherapy during 18 to 13 week therapy.
Hypoglycemia was also low with DPP-4 inhibitor therapy administrated in dual and
triple combination with metformin, an SGLT2 or a TZA.
2. Weight gain
A neutral or mildly beneficial effect on weight was observed when DPP-4
inhibitors was used in combination regimens including metformin or an SGLT2.
EFFICACY AND SAFETY IN PATIENTS WITH RENAL INSUFFICIENCY
In patients with T2DM and moderate-to-severe chronic kidney disease, DPP-4
inhibitors effectively improved glycemic outcomes, with an A1c-lowering effect
ranging from -0.8% at 52 weeks, with two respective DPP-4 inhibitors. For patients
with mild renal impairment, no dose adjustment is needed for the currently available
DPP-4 inhibitors.5
EFFICACY AND SAFETY OF DPP-4 INHIBITORS IN ELDERLY PATIENTS
1. Efficacy profile
 Available data in older patients demonstrate that DPP-4 inhibitors
administered alone or in combination with other antidiabetic medications,
effectively improve glycemic outcome in this patient population.
2. Safety profile
 Studies including elderly population showed that the incidence of adverse
events are generally similar between the DPP-4 inhibitor group and
comparator groups, and no notable safety issues were observed.

Introduction
 There was a low risk of hypoglycemia DPP-4 inhibitor treatment groups.

 A neutral or mildly beneficial effect on weight was observed in DPP-4
inhibitor treatment groups. 5
TENELIGLIPTIN
Teneligliptin belongs to third generation DPP-4 inhibitor and it is approved for
type 2 diabetes mellitus patients. It is a novel chemo type prolylthiazolidine based DPP-
4 inhibitor, shows a unique chemical structure which is characterized by five
consecutive rings (J-shaped), thereby potentially producing unique characteristics
including its glucose lowering efficacy and half-time.
It is administered with 20- 40 mg once daily. Since the metabolites of this drug
are excreted through hepatic (approximately35%) and renal (about 65%) route, no dose
adjustment is necessary in patients with renal impairment. The efficacy and safety
profiles of teneligliptin are similar to those of other DPP-4 inhibitors. It because of its
long half-life (approximately 26 hr.), this drug is shown to stabilize the glucose
fluctuations throughout the day.
Teneligliptin is a third generation DPP-4 inhibitor approved for treatment of
type II diabetes. It is currently available in Japan, South Korea, Argentina and India.
Teneligliptin is under pre-registration in Indonesia & under Phase I trials in US & Phase
II trials in Denmark, Germany, Hungary, Lithuania, Poland, Romania & UK.5
Chemistry of teneligliptin
Teneligliptin, {(2S, 4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-

1-yl] pyrrolidin-2-yl} (1, 3-thiazolidin-3-yl) methanone hemipentahydrobromide
hydrate exhibits a unique structure that is characterized by five consecutive rings and
is peptidomimetic.
An X-ray co-crystal structure of teneligliptin with DPP-4 demonstrates that the
key interaction occurs between the phenyl ring on the pyrazole and the S2 extensive
subsite of DPP-4, which not only enhances the potency of the drug but also increases
its selectivity.1

Introduction
Figure 3: Chemical structure of Teneligliptin6
Metabolism and excretion

CYP3A4, a cytochrome P450 isozyme and flavin-containing monooxygenases
(FMO1 and FMO3) play major roles in the metabolism of teneligliptin. In vitro,
teneligliptin exhibits a weak inhibitory effect for CYP2D6, CYP3A4, and FMO;
however, it demonstrates no inhibitory effect for CYP1A2, CYP2A6, CYP2B6,
CYP2C8, CYP2C8/9, CYP2C19, and CYP2E1. In addition, teneligliptin does not
induce the expression of CYP1A2 or CYP3A4.
About 34.4% of teneligliptin is excreted unchanged via the kidney and the
remaining 65.6% teneligliptin is metabolized and eliminated via renal and hepatic
excretion; 216 hours after the administration of 14C-labeled teneligliptin (20 mg), the
cumulative excretion percentages of radioactive teneligliptin in urine and feces were
45.4% and 46.5%, respectively.5
Dosage & Administration
The recommended dosage of Teneligliptin is 20 mg once daily. Teneligliptin
can be administered irrespective of food, preferably before breakfast. It is also advisable
to up titrate the dosage to 40 mg once daily in patients who do not achieve adequate

Introduction
glycemic control as required. No dosage adjustment is required in patients with

mild/moderate/severe renal impairment & mild/moderate hepatic impairment.
No dosage adjustment is required in elderly patients. Efficacy & safety of Teneligliptin
is not studied in children. Teneligliptin should be used with caution in patients with
severe hepatic impairment &those with heart failure (NYHA Class III - IV), because of
a lack of clinical experience in these populations.5
Pharmacodynamic Advantage of Teneligliptin5
 Unique Structural Advantage
 Sustained DPP-4 Inhibition & High GLP-1 Concentration
 Insulin/Glucagon Modulator
 24 Hours Glucose Control
 β-Cell Preservation
 Reduction in Short-Term Glycemic Fluctuations
Pharmacokinetic Advantage of Teneligliptin
Teneligliptin is rapidly absorbed in healthy volunteers after a single
radiolabeled 20 mg dose, with maximum plasma concentrations attained in 1.33 hr. The
drug is 78% - 80% bound to plasma proteins. In humans, Teneligliptin is primarily
metabolized by cytochrome P450 (CYP) 3A4 & flavin monooxygenases (FMO) 1 and
3 to several metabolites of unknown biological activity.
Pleiotropic Benefits of Teneligliptin
 Improvement in Endothelial Function
 Improvement in Lipid Profile
 Natriuretic & Diuretic Effects of Teneligliptin
 Weight Neutral
SITAGLIPTIN
This is the first gliptin to be US FDA approved. The recommended dose is 100
mg once a day. Its absorption is unaffected by food. For patients with moderate renal
impairment (creatinine clearance 30 to 50 mL/min) the recommended dose is 50
mg/day and for severe renal impairment (creatinine clearance is <30 mL/min) the

Introduction
recommended dose is 25 mg/day. In a meta-analysis it was shown to be more effective

at reducing fasting blood sugar compared to vildagliptin, but overall efficacy was
similar.
Figure 4: Chemical structure of Sitagliptin
The Asian study (China India Korea study) suggested that sitagliptin was more
effective in the Indian population with greater HbA1c reductions of approximately
1.3% compared to placebo.6
VILDAGLIPTIN
This is the second gliptin to be approved for commercial use although still not
US FDA approved. The recommended dose is 50 mg twice a day. Its absorption is
unaffected by food. It is extensively metabolized by the liver and has >90%
bioavailability following a single oral dose.
Figure 5: Chemical structure of Vildagliptin

Introduction
No dosage adjustment is required for liver disease although a greater amount of

inactive metabolites (30% greater) are retained in patients with severe liver disease
(Childs grade C). In patients with renal impairment no dose adjustment is required for
mild renal insufficiency however for moderate renal insufficiency half the
recommended dose of 50 mg is suggested.7
CURRENT POSITION OF GLIPTINS IN DIABETES MANAGEMENT

GUIDELINES
The American Diabetes Association (ADA), American Association of Clinical

Endocrinologists (AACE), European Society, and NICE (UK) guidelines suggest that
gliptins should be considered over other anti-diabetic therapies especially if the patient
is experiencing an increased incidence of hypoglycemia and/or weight gain.
It is clear that even major guidelines appreciate their usefulness with the only
apprehension being that they have not withstood the test of time and therefore classified
under less well-validated therapies. As data emerges suggesting sustained anit-
hyperglycenic benefits they should replace current practices that include popular use of
SU +/– insulin as second and third line agents to metformin.8
Current indications for use of gliptins are:
1. First line in T2DM with HbA1c <7%

2. Second line as add-on therapy in T2DM patients already on 1 out of the
following {metfromin, SU, TZD, alfa-glucosidase inhibitor, miglitinide})for
uncontrolled T2DM with HbA1c >7%
3. Third line as add-on therapy in T2DM patients already on combination therapy
(2 out of the following {metfromin, SU, TZD, alfa-glucosidase inhibitor,
miglitinide)
Contraindications or indication for stopping gliptin therapy includes previous

or current adverse reaction to gliptins (hypersensitivity) or failure to achieve an HbA1c
reduction of greater than 0.5% over a 6 month period.

Introduction
Gliptins have revolutionized the concept of diabetes management and have

provided a breath of fresh air to healthcare professionals dealing with diabetes. They
provide an effective and safe alternative to the management of diabetes. Shown to
reduced HbA1c from 0.5 to up to 2% effectively and safely (weight neutral without any
if at all hypoglycemia) this new class of drugs is here to stay.
Even major diabetes management guidelines have acknowledged them for their
safe adverse effect profile and urge healthcare professionals to use gliptins should they
be struggling with regards weight or hypoglycemias with their patients. Recently,
plagued with issues such as pancreatitis and cancer, these drugs need to stand the test
of time and should they emerge victorious they will represent the only class of drugs
that help improve beta-cell health, addressing the original triumvirate pathogenetic
theory proposed for T2DM.8

Review of Literature
2. REVIEW OF LITERATURE
1. Manish Maladkar, 5 et al., conducted a study on 194 patients with type II

diabetes mellitus, were treated for 120 days with teneligliptin (20 mg/day) alone
teneligliptin add on Glimepiride. Result shows that teneligliptin offers unique
pharmacokinetic advantage with long half-life of 26.9 hours allowing convenient
once daily administration irrespective of food. It has unique dual mode of
elimination via renal & hepatic, and hence can be administered safely in patients
with renal impairment.
2. Wakaba Tsuchimoch, 9 et al., conducted study on ten patients with type 2
diabetes mellitus, were treated for 3 days with teneligliptin (20 mg/day).
Postprandial profiles for glucose, insulin, glucagon, active glucagon-like
peptide-1, active glucose-dependent insulinotropic polypeptide (GIP), and 24 h
glycemic fluctuations were measured via continuous glucose monitoring for 4
days. The result show that teneligliptin improved 24hours blood glucose levels
by increasing active incretin levels and early-phase insulin secretion, reducing
the postprandial insulin requirement, and reducing glucagon secretion. Even
short-term teneligliptin treatment may offer benefits for patients with T2DM.
3. Abhijeet Jain, 10 et al., The study was conducted as patients were randomly
allotted into two groups. 50 patients were started with teneligliptin 20 mg/day
along with metformin 1000 mg/day.Both group subjects had high FBS, PPBS
and HbA1c at the start of study. After 24 weeks of treatment with teneligliptin
and metformin, subjects had significant decrease in FBS, PPBS and HbA1c.This
study showed that teneligliptin can be an effective alternative to other drugs for
add on therapy to the patients who are inadequately controlled with metformin
alone.
4. Merlin C. Thomas, 11 et al., conducted study on 12-week, randomized, placebo-
controlled trials on DPP-4 inhibitors in C50 patients with T2DM and RI.
Outcomes assessed by change in HbA1c, overall safety, and incidence of
hypoglycemic events (HEs).The result which shows that HbA1c reductions were
similar at weeks 12 and 52. In the 12-week, placebo-controlled phase, sitagliptin
and vildagliptin reduced HbA1c levels by 0.6–0.7. So that DPP-4 inhibitors have

the potential to improve glycemic control in patients with RI without increasing

the risk of overall AEs.
5. Fuyuhiko Marubayashi, 12 et al., conducted post-hoc pooled analysis used data
from two Phase III clinical studies involving 702 Japanese patients. Evaluated
teneligliptin as monotherapy and combined with a sulfonylurea, glinide,
biguanide, or a-glucosidase inhibitor. Safety measures included adverse events
(AEs), adverse reactions and hypoglycemia. .Which shows that Hypoglycemia
was more frequent in the sulfonylurea combination therapy group than in other
groups. Teneligliptin administered once daily as monotherapy or combination
therapy resulted in a decrease in HbA1c, which was maintained for 52 weeks.
6. Hamamoto.Y, 13 et al., study conducted a 12- or 16-week, placebo-controlled
phase 2 and 3 trials, oral teneligliptin 20 or 40 mg once daily, as monotherapy or
in combination with metformin, glimepiride or pioglitazone improved glycaemic
control, including in patients with end-stage renal disease, and was generally
well tolerated. This result shows that teneligliptin is a useful treatment option for
adults with T2DM who have not responded adequately to diet and exercise
regimens, or the addition of antidiabetic drugs.
7. Takashi Kadowaki, 14 et al., conducted a teneligliptin as monotherapy and
combined with a sulfonylurea, glinide, biguanide, or a-glucosidase inhibitor.
Safety measures included adverse events (AEs), adverse reactions and
hypoglycemia. The main efficacy measure was the change in glycated
hemoglobin (HbA1c) from baseline. And this pooled analysis provides evidence
for the safety and efficacy of long-term use of teneligliptin as monotherapy or
combination therapy in Japanese T2DM patients.
8. Takehiro Hashikata, 15 et al., conducted a study on 29 patients who had
insufficiently controlled diabetes and consented to the study protocol were
enrolled. All participants were evaluated at baseline and at 3 months after the
additional treatment with teneligliptin. The study shows that the Teneligliptin
treatment was associated with improvements in LV function and endothelial
functions, and an increase in serum adiponectin levels. These results support the
cardio-protective effects of teneligliptin in T2DM patients and increase in serum
adiponectin levels.

9. Rika Ito, 16 et al., an open-label, prospective clinical study was conducted.

Thirteen patients (mean age 55.5 ± 3.9 years) with T2D underwent OGTT before
and after teneligliptin 20 mg/day monotherapy. Plasma levels of glucose (PG),
insulin, and C-peptide were measured at 0, 30, 60, 90, and 120 min after glucose
loading in the OGTT. The result shows that twelve weeks of teneligliptin
treatment improved IGI30min, AUC120min, and the SUIT index in Japanese
patients with T2D.
10. Enrique Z. Fismanet, 17 et al., the study conducted in 3 years of treatment,
approximately 50 % of diabetic patients could achieve acceptable glucose levels
with monotherapy. And monitored about the HbA1c, PPBS, FBS and also lipid
profile .Study results shows that a definite relationship between gliptins
treatment in hyperglycemia and improved cardiovascular outcomes remains
uncertain and needs yet to be proven.
11. Yuya Nakamura, 18 et al., the effects of dipeptidase-4 (DPP-4) inhibitors in
diabetic hemodialysis (HD) patients, the findings have yet to be reviewed
comprehensively. Eyesight failure caused by diabetic retinopathy and aging-
related dementia make multiple daily insulin injections difficult for HD patients.
The result shows that treating HD patients with DPP-4 inhibitors does not result
in an increased incidence of adverse events. Furthermore, DPP-4 inhibitors are
strongly anticipated to be effective in HD patients with diabetes.
12. Valentina Lukashevich, 19 et al., conducted a study compared the safety and
efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe
renal impairment (RI). This study was a parallel-arm, randomized, multicenter,
double-blind, 24 week study. In each group glycemic parameters are meauserd.
Results shows that compared with sitagliptin demonstrated similar efficacy and
both drugs were well tolerated.
13. Jun-ichiro Mera, 20 et al., conducted a study with Vildagliptin 50 mg once daily
was administered for 2 years. Various glycemic parameters are measured.The
study concluded that Vildagliptin is a promising therapeutic option for safe,
effective glycemic control in type 2 diabetic patients with ESRD
14. Hirotoshi Ohmura, 21 et al., conducted study on 3,247 subjects treated with
sitagliptin were retrospectively recruited. Glucose parameters were collected at

baseline, and 1, 3 and 6 months after initiation of sitagliptin. And also check
whether about the sitagliptin-induced reduction in HbA1c using linear mixed
effect model. The result shows that reduced HbA1c level from 7.44±1.20% at
baseline to 6.73±0.99% at 6 months. So the sitagliptin is effective for diabetic
management and generally well tolerated in Japanese patients with type 2
diabetes.
15. Yun‑ Zhao Tang, 22 et al., conducted a study on randomized study on oral
hypoglycemic agents such that vildagliptin and sitagliptin used in 535 T2DM
patients. Body mass index, HbA1c, FPG and PPG, insulin dose, and adverse
events were evaluated during the study. The result shows that the baseline
HbA1c was reduced by vildagliptin is 66.27 % and 52.73 % sitagliptin.so that
the study concluded that DPP-4 inhibitors appear to be effective and safe as add-
on therapy for T2DM patients on dual combination of insulin and a traditional
OHA. Vildagliptin was more effective in decreasing insulin requirement and
achieving glycemic control when compared to the other two.
16. Eiji Kutoh, 8 et al., newly diagnosed, drug naive Japanese subjects with type 2
diabetes (T2DM) were assigned to 20 mg/day teneligliptin monotherapy (n =
31). At 3 months, levels of glycemic and other parameters were compared with
those at baseline. Result shows that Teneligliptin might be effectively and safely
used as an initial therapy for newly diagnosed T2DM. Glycemic efficacy of
teneligliptin is obtained through activating beta-cell function as well as
decreasing insulin resistance.
17. Atef Halabi, 23 et al., teneligliptin was compared in 3 groups of 8 subjects
assigned according to their degree of hepatic impairment (mild, moderate, or
matched healthy subjects). Hepatic impairment was associated with an increase
in maximal plasma concentration and overall exposure to teneligliptin. Study
shows that teneligliptin was well tolerated by subjects with hepatic impairment.
These results may indicate that caution will be needed when administering
teneligliptin to subjects with hepatic impairment.
18. Seiichi Tanaka, 24 et al., conducted Twenty-six patients with type 2 diabetes
were admitted for glycemic control. After admission, patients continued to be
treated with optimal dietary therapy plus insulin therapy, with or without other

anti-diabetes drugs, until they achieved stable glycemic control. The result shows
that Add-on treatment with teneligliptin led to significant improvements in 24-h
mean glucose levels, the proportion of time in normo glycemia, mean amplitude
of glycemic excursions, and total area under the curve within 2 h after each meal.
19. Wakaba Tsuchimochi, 25 et al., conducted a Ten patients with T2DM were
treated for 3 days with teneligliptin (20 mg/day). Postprandial profiles for
glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active
glucose-dependent, fluctuations were measured via continuous glucose
monitoring for 4 days. Once daily teneligliptin administration for 3 days
significantly lowered postprandial and fasting glucose levels. The result shows
that Teneligliptin improved 24 h blood glucose levels by increasing active
incretin levels and early-phase insulin secretion, reducing the postprandial
insulin requirement, and reducing glucagon secretion. Even short-term
teneligliptin treatment may offer benefits for patients with T2DM.
20. Brian Green, 26 et al., conducted 70 patients with type 2 diabetes were admitted
for glycemic control. After admission, patients continued to be treated with
optimal dietary therapy plus insulin therapy, with or without other antidiabetic
drugs, until they achieved stable glycemic control .the result shows that Gliptins
increase nutrient-stimulated insulin secretion in type 2 diabetes with low-risk of
hypoglycemia and without weight gain.
21. Line P. Malha, 27 et al., conducted a study randomized open-label clinical trial
that recruited 69 patients with previously treated with a combination therapy of
metformin and sulphonylurea. Patients in the control group were maintained on
their usual metformin and sulphonylurea regimen with dose adjustment for the
fasting period. Patients in the study group were given vildagliptin 50 mg twice
daily. Result shows that calculated change in hemoglobin A1C from baseline to
last visit was similar for both groups.
22. Fatemeh Hayati, 28 et al., study conducted in 24-week, non-randomized, open-
labeled trial study, T2DM patients (n=93) who were on optimum dosage of
metformin and sulphonylurea were additionally treated with 100 mg sitagliptin
daily. The end point was assessed by investigating the changes in HbA1c and
also FPG. Safety was assessed by recording of hypoglycemia, change in body

mass index, blood pressure, lipid profiles HDL, LDL, total cholesterol (Tc) and
triglycerides, AST, ALT, ALP, urea, uric acid and creatinine level. And the result
shows that mean HbA1c was reduced by 0.41%, and overall, 18.27% of patients
achieved an HbA1c goal of <7%. After 6 months study concluded that Sitagliptin
is effective and safe to be used in combination with metformin and sulphonylurea
therapies.
23. Chun-Jun Li, 29 et al., conducted study on randomized, open-label, parallel
clinical trial, enrolled inadequately controlled [HbA1c] ≥7.5% to ≤10%) patients
with type 2 diabetes, who were treated by dual combination oral hypoglycemic
agents and patients had been randomized to add-on 5 mg saxagliptin group or
100 mg sitagliptin once daily group, or 50 mg vildagliptin twice daily group for
24 weeks. HbA1c, FBG and P2hBG, body weight, BMI, episodes of
hypoglycemia and adverse events were evaluated. And the result shows that
After 24 weeks, HbA1c, FBG, and P2hBG of each group were significantly
decreased.
24. Dongsheng Cheng, 30 et al., study conducted on randomized-controlled trials
that assessed the efficacy and safety of DDP-4 inhibitors compared with placebo,
no treatment, or active drugs were identified using PubMed, and EMBASE. The
result which shows that DPP-4 inhibitors reduced HbA1c significantly and had
no increased risk of hypoglycemia or weight gain. So that DPP-4 inhibitors are
effective at lowering HbA1c in T2DM patients with moderate to severe renal
impairment. DPP-4 inhibitors also have a potential advantage in lowering the
risk of adverse events.
25. Paul Craddy, 31 et al., study conducted on Systematic review of randomized
controlled trials, health economic evaluation studies, systematic reviews, and
meta-analyses, followed by primary Bayesian Mixed treatment comparison
meta-analyses (MTCs), and secondary frequents direct comparison a Meta-
analyses using a random effects model. And which shows that this systematic
review and MTC showed similar efficacy and safety for DPP-4 inhibitors as
treatment for type 2 diabetes, either as monotherapy or combination therapy.
26. Yoshinobu Nabikaru, 32 et al., the absorption, metabolism and excretion of
teneligliptin were investigated in healthy male subjects after a single oral dose

of 20 mg teneligliptin. This study indicates the involvement of renal excretion

and multiple metabolic pathways in the elimination of teneligliptin from the
human body. Teneligliptin is unlikely to cause conspicuous drug interactions or
changes in its pharmacokinetics patients with renal or hepatic impairment, due
to a balance in the elimination pathways.
27. Kazuoki Kondo, 33 et al., In an initial 12-week, double-blind, placebo
controlled, parallel-group study, patients (n = 204) were randomized to
teneligliptin 20 mg or placebo once daily added to their stable pioglitazone
therapy. This was followed by a 40-week, open-label period during which all
patients received teneligliptin once daily. The end point HbA1c from baseline to
week 12. Patients in the teneligliptin group showed significantly greater
reductions in HbA1c compared with the placebo group at week. The change in
fasting plasma glucose from baseline to week 12 was greater in the teneligliptin
group than in the placebo group (P < 0.001).
28. Miyako Kishimoto, 34 et al., assess blood glucose control over 24 hours and the
safety of teneligliptin at 10 and 20 mg doses, a randomized, double-blind,
placebo-controlled, parallel-group study was conducted at four locations in
Japan. Among the 99 patients who participated, 32 were treated with a placebo,
34 were treated with teneligliptin at a dose of 10 mg, and 33 were treated with
teneligliptin at a dose of 20 mg before breakfast for 4 weeks. These results
indicate that the once-daily administration of teneligliptin before breakfast
improved blood glucose control, even at dinnertime.
29. Sandhu-Minhas, 35 et al., study conducted as Retrospective population based
cohort study. The cohort included 72 738 new users of oral antidiabetic drugs
(8032 (11%) used sitagliptin; 7293 (91%) were taking it in combination with
other agents) followed for a total of 182 409 patient years. Based on this study
the result shows that Sitagliptin use was not associated with an excess risk of all
cause hospital admission or death compared with other glucose lowering agents
among newly treated patients with type 2 diabetes.

30. Masaya Sakamoto, 36 et al., conducted a study on Twenty patients with type 2
diabetes mellitus were randomly allocated to groups who received vildagliptin
then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting
each drug, and CGM was used to determine that 24-hour blood glucose level,
fasting blood glucose level, highest postprandial blood glucose level and time,
increase in blood glucose level after each meal, were measured. The study which
shows that showed that mean 24-h blood glucose, highest blood glucose level
after supper, and hyperglycemia after breakfast were significantly lower in
patients with type 2 diabetes mellitus taking vildagliptin than those taking
sitagliptin.
31. Hyun Jeong Jeon, Tae Keun Oh, 37 conducted in a randomized, open-label,
comparative study, and 106 patients with type 2 diabetes were enrolled. And
HbA1c FPG, 2h-PPG reduction from baseline are monitored. Result shows that
the comparable HbA1c reduction was observed with a mean±standard deviation
change from baseline to the 32-week endpoint of -0.94±1.15% in the vildagliptin
group and -1.00±1.32% in the glimepiride group. So that the gliptins are much
better than the other oral hypoglycemic agents.
32. Chahal. H, 38 et al., conducted 50 patients with type 2 diabetes were admitted
for glycemic control under gliptins .the result shows that gliptins cause a modest
reduction in glycated hemoglobin when used as monotherapy or combination
therapy, of around 0.7–1%. They appear to be more potent when baseline
glycated hemoglobin is higher. They appear to be well-tolerated, and are taken
orally once daily. So these are useful in treating obese patients with type 2
diabetes, in combination with metformin, or a glitazone, or both.

Aim and Objectives
3. AIM AND OBJECTIVES
AIM
To determine the therapeutic efficacy and safety of Teneligliptin when

compared with other standard gliptin molecules such as sitagliptin and vildagliptin.
OBJECTIVES
 Whether this drug used as primary, secondary or add on therapy as third

molecule.
 To find out whether it could be used as a monotherapy in special patients
with metformin side effect.
 Find out the usefulness of the teneligliptin and since it is low cost therapy to
be recommended more than the other standard gliptins since it may quite
useful in developing country like India.

Methodology
4. METHODOLOGY
STUDY SITE:
This study was performed in the Department of General medicine

(Diabetology), Kovai Medical Center and Hospital (KMCH) at Coimbatore, Tamil
Nadu India. The proposed protocol for the study was presented and approved by the
Hospital Ethical Committee (Annexure 1).
STUDY DURATION:
The study period was from 25th February 2017 – 30th July 2017 (6 months).
SOURCE OF DATA:
Patient medical record - Patient medical record is observed and the required data
such as age, op number, height, weight, FBS, PPBS, HbA1c, Serum creatinine, and
SGPT was recorded. Other data such as educational status, material status, social habits,
family history, employment status, duration of diabetes mellitus and adverse drug
reactions were collected by directly interviewing the patient.
STUDY DESIGN:
The study is a hospital based prospective and retrospective observational study

in which all the patients presented with type II diabetes mellitus to the General medicine
department were considered. The study included describing data collected in terms of
their level of measurement and summarizing them in forms of tables, graphs, and
numerical values. Mainly the Paired Students‘t’ test and One-way ANOVA test was
used to finalize the result.
STUDY POPULATION:
A total 155 patients who came to the General medicine department with type II
diabetes mellitus were included in the study.

Methodology
STUDY CRITERIA:
Inclusion criteria:
 Patients with type II diabetes with an HbA1C level ≥ 6.5%.

 FBS level ≥ 126 mg/dl.
 PPBS level ≥ 200 mg/dl.
Exclusion criteria:
 Patients with Type 1 diabetes.

 Patients with Gestational diabetes.
 Patients having more than 10% HbA1C
METHODS OF DATA COLLECTION:
 Patient case notes.
 Medication/ treatment chart.
 Laboratory data report & other relevant source.
 Communication with the patients.
STUDY PROTOCOL:
Procedure:
The study was carried out after an approval from the ethical committee of the
hospital on 25th February 2016. According to the inclusion criteria the patient who had
type II diabetes were included in the study.155 patients were studied by the time period
of 6 months. Patients were divided in to three groups namely, Group-A teneligliptin (55
patients), Group-B sitagliptin (50 patients) and Group-C vildagliptin (50 patients).

Methodology
Figure 6: Patient Recruitment and Randomization
Group-A was further divided in to 3 subgroups, 5 patients were on teneligliptin

20mg as monotherapy, 25 patients on Teneligliptin add on Metformin as dual therapy.
And 25 patients were on Teneligliptin add on Metformin plus Sulfonylurea as
combination therapy.
Group–B was further divided into two sub groups, containing each 25 patients
Sitagliptin add on metformin as dual therapy, and Sitagliptin add on metformin plus
sulfonylurea as combination therapy. Group-C was also divided into two sub groups
containing each 25 patients vildagliptin add on metformin as a dual therapy, and
vildagliptin add on metformin plus sulfonylurea as combination therapy.
The patients were followed monthly during the study registration period. At the
time of entry, complete medical history, and laboratory evaluation were obtained.
Patient demographics were also considered and recorded. The following procedures are

Methodology
were performed before and after 3 months of teneligliptin, vildagliptin, sitagliptin

treatment. HbA1C, FBS, PPBS, Serum Creatinine, SGPT were measured. These
essential data were collected using data collection form. After 3 months treatment, these
patients interviewed again to assess if there any adverse drug reactions.
Literature Review: An extensive literature survey was done on safety, efficacy of

gliptin molecule in type II diabetes mellitus patients. The literature supporting the study
was gathered from various journal like Diabetes technology and therapeutics,
International Journal of Pharma and Bio sciences, Scholar Journal of Applied Medical
Sciences (SJAMS), International Journal of Research in Medical Sciences, Informa
Health care, Journal of Diabetes Mellitus, Journal of Diabetes Ther, Endocrine Journal
and Advanced Publication, International Journal of Medical Sciences and Public
Health, Journal Of Diabetes Research and Clinical Metabolism, Indian Journal of
Endocrinology and Metabolism, Diabetes and Metabolism Journal.
STATISTICAL ANALYSIS:
Statistical analysis was performed using the IBM SPSS (statistical package for
the social services) software version 20. The baseline characteristics were studied by
percentage. Difference between the before and after treatment were examined for
statistical significance using the student′s Paired t-test. ANOVA were performed to
determine overall difference between before and after treatment groups. The result were
presented as mean ± SD or %. In all cases p-value ≤ 0.005 was considered as statistically
significant.

Tables and Figures
5. TABLES AND FIGURES
Table 1: Distribution of overall study population based on gender (n=155)
Gender Frequency Percentage (%)
Male 92 59
Female 63 41
Figure 7: Plot of overall study population based on gender (n=155)
FEMALE
41%
MALE
59%

Tables and Figures
Table 2: Distribution of study population based on gender (n=150)
Teneligliptin (n=50) Sitagliptin (n=50) Vildagliptin(n=50)

Percentage Percentage Percentage
Gender Frequency (%) Frequency (%) Frequency (%)
Male 31 21 29 19 29 19
Female 19 13 21 14 21 14
Figure 8: Plot of study population based on gender (n=150)
25
21
20 19 19
PERCENTAGE
15 14 14
13
Male
10 Female
0
TENELIGLIPTIN SITAGLIPTIN VILDAGLIPTIN
GENDER

Tables and Figures
Table 3: Distribution of overall study population based on age (n=155)
Age Frequency Percentage (%)

30-40 20 13
41-50 35 23
51-60 67 43
61-70 21 13
71-80 12 8
Figure 9: Plot of overall study population based on age (n=155)
45 43
40
35
30
PERCENTAGE
25 23
20
15 13 13
10 8
0
30-40 41-50 51-60 61-70 71-80
AGE

Tables and Figures
Table 4: Distribution of patients based on Age Group (n=150)
Teneligliptin (n=50) Sitagliptin (n=50) Vildagliptin (n=50)

Age Percentage Percentage Percentage
Frequency Frequency Frequency
(%) (%) (%)
30-40 7 5 7 5 6 4
41-50 12 8 11 8 11 8
51-60 22 14 20 13 22 14
61-70 6 4 7 4 7 5
71-80 3 2 5 3 4 3
Figure 10: Plot of patients based on Age Group (n=150)
14 14
14
13
12
10 TENELIGLIPTIN
PERCENTAGE
SITAGLIPTIN
8 8 8
8
VILDAGLIPTIN
6
5 5 5
4 4 4
4
3 3
2
2
0
30-40 41-50 51-60 61-70 71-80
AGE

Tables and Figures
Table 5: Distribution of overall study population based on family-history (n=155)
Family-history Frequency Percentage (%)

Yes 69 45
No 86 55
Figure 11: Plot of overall study population based on family-history (n=155)
60
55
50
45
PERCENTAGE
40
30
20
10
0
YES NO
FAMILY-HISTORY

Tables and Figures
Table 6: Distribution of patients based on Family History (n=150)

Family-
history Percentage Percentage Percentage
Frequency Frequency Frequency
(%) (%) (%)
Yes 23 15 23 15 21 14
No 27 18 27 18 29 20
Figure 12: Plot of patients based on Family History (n=150)
20
20
18 18
18
16 15 15
14
14
PERCENTAGE
12
10 YES
NO
8
0
FAMILY-HISTORY

Tables and Figures
Table 7: Distribution of overall study population based on duration

of diabetes mellitus (n=155)
Duration Frequency Percentage (%)
0-5 98 63
6-10 57 37
Figure 13: Plot of overall study population based on duration of diabetes mellitus
(n=155)
70
63
60
PERCENTAGE
50
40 37
30
20
10
0
0-5 0-6
DURATION

Tables and Figures
Table 8: Distribution of patients based on Duration of Diabetes (n=150)

Percentage Percentage Percentage
Duration Frequency (%) Frequency (%) Frequency (%)
0-5 33 23 31 21 31 21
6-10 17 11 19 12 19 12
Figure 14: Plot of patients based on Duration of Diabetes (n=150)
25
23
21 21
20
PERCENTAGE
15
12 12
11 0-5
10 6-10
0
DURATION

Tables and Figures
Table 9: Distribution of FBS (Dual therapy) levels in the study population (n=75)
Before Treatment After Treatment

FBS Mean ± SD Mean ± SD
Teneligliptin + Metformin 168.92±24.55 123.62±10.12
Sitagliptin + Metformin 168.68±24.13 123.64±10.45
Vildagliptin + Metformin 168.16±23.91 142.89±21.16
Figure 15: Plot FBS (Dual therapy) levels in the study population (n=75)
180 168.92 168.68 168.16

160
142.89
140
MEAN DIFFERENCE
123.62 123.64
120
100
BEFORE TREAMENT
80
AFTER TREATMENT
60
40
20
0
TENE+MET SITA+MET VILDA+MET
FASTING BLOOD SUGAR

Tables and Figures
Table 10: Distribution of PPBS (Dual therapy) levels in the study
population (n=75)
PPBS Mean ± SD Mean ± SD
Figure 16: Plot of PPBS (Dual therapy) levels in the study population (n=75)
300
274.56 273.32 275.88
250
MEAN DIFFERENCE
200 190.44
165.10 165.11
150 BEFORE TREATMENT
AFTER TREAMENT
100
50
0
POST PRANDIAL BLOOD SUGAR

Tables and Figures
Table 11: Distribution of HbA1C (Dual therapy) levels in the study
population (n=75)
Before treatment After treatment

HbA1C
Mean ± SD Mean ± SD
Figure 17: Plot of HbA1C (Dual therapy) levels in the study population (n=75)
8.77 8.81 8.73

9
7.9
8 7.1
7.1
7
MEAN DIFFERENCE
6
5
BEFORE TREATMENT
4
AFTER TREATMENT
3
2
1
0
HbA1C

Tables and Figures
Table 12: Distribution of Serum Creatinine (Dual therapy) levels in the study
population (n=75)
Serum Creatinine Mean ± SD Mean ± SD
Figure 18: Plot of Serum Creatinine (Dual therapy) levels in the study
population (n=75)
0.83
0.83
0.823
0.82
0.81
MEAN DIFFERENCE
0.8
0.79 0.791 BEFORE TRETMENT
0.79
AFTER TREATMENT
0.78 0.78
0.78
0.77
0.76
0.75
SERUM CREATININE

Tables and Figures
Table 13: Distribution of SGPT (Dual therapy) levels in the study
population (n=75)
SGPT Mean ± SD Mean ± SD
Figure 19: Plot of SGPT (Dual therapy) levels in the study population (n=75)
35 34.92
34.5
MEAN DIFFERENCE
34.01
34 33.91 33.91
33.84
33.51 BEFORE TREATMENT

33.5
AFTER TREATMENT
33
32.5
SGPT

Tables and Figures
Table 14: Distribution of FBS (Combination therapy) levels in the study
population (n=75)

FBS
Teneligliptin + Metformin + Glimepiride 193.8±34.30 121.5±22.69
Sitagliptin + Metformin + Glimepiride 195.3±34.05 121.4±19.96
Vildagliptin + Metformin + Glimepiride 193.4±28.66 132.9±25.07
Figure 20: Plot of FBS (Combination therapy) levels in the study
population (n=75)
200 193.8 193.3 193.4
180
160
MEAN DIFFERENCE
140 132.9
121.5 121.4
120
100
BEFORE TREATMENT
80 AFTER TREATMENT
60
40
20
0
TENE+MET+GLI TENE+MET+GLI TENE+MET+GLI
FASTING BLOOD SUGAR

Tables and Figures
Table 15: Distribution of PPBS (Combination therapy) levels in the study
population (n=75)

PPBS
Figure 21: Plot of PPBS (Combination therapy) levels in the study
population (n=75)
294.7 294.9 294.5

300
250
MEAN DIFFERENCE
199.4
200 183.4 183.9
150 BEFORE TREATMENT
AFTER TREATMENT
100
50
0
POSTPRANDIAL BLOOD SUGAR

Tables and Figures
Table 16: Distribution HbA1C of (Combination therapy) levels in the study
population (n=75)

HbA1C
Figure 22: Plot of HbA1C (Combination therapy) levels in the study
population (n=75)
10 9.49 9.47 9.48
9 8.6
8 7.49 7.5
7
MEAN DIFFERENCE
5 BEFORE TREATMENT
4 AFTER TREATMENT
0
HbA1C

Tables and Figures
Table 17: Distribution of SrCr (Combination therapy) levels in the study
population (n=75)

Serum Creatinine
Figure 23: Plot of SrCr (Combination therapy) levels in the study
population (n=75)
0.84
0.83 0.831
0.83
0.82 0.82
0.82
MEAN DIFFERENCE
0.81
0.8 BEFORE TREATMENT

0.79 0.792
AFTER TREATMENT
0.79
0.78
0.77
0.76
SrCr

Tables and Figures
Table 18: Distribution of SGPT (Combination therapy) levels in the study
population (n=75)

SGPT
Figure 24: Plot of SGPT (Combination therapy) levels in the study
population (n=75)
31.44
31.5
31
30.64
30.5
30.19
MEAN DIFFERENCE
30
29.5
29
28.6828.76 BEFORE TREATMENT
28.5 28.36 AFTER TREATMENT
28
27.5
27
26.5
SGPT

Tables and Figures
Table 19: Distribution of mean reduction in Glycemic parameters (Teneligliptin)
in the study population (n=75)
Mean Mean Mean

Category reduction reduction reduction
in HbA1C in FBS in PPG
Teneligliptin 0.92 41.33 65.83
Teneligliptin +Metformin 1.68 48.53 72.91
Teneligliptin + Metformin + Glimepiride 1.97 55.68 88.53
Figure 25: Plot of mean reduction in Glycemic parameters (Teneligliptin) in the
study population (n=75)
88.53
90
80
% MEAN REDUCION
72.91
70 65.83
60 55.68
48.53
50 TENE
41.33
40 TENE+MET
30 TENE+MET+GLI
20
10
0.92 1.68 1.97
0
HbA1C FBS PPBS
GLYCEMIC PARAMETERS

Tables and Figures
Table 20: Distribution of ADRs (Teneligliptin) in the study population (n=50)
ADRs Frequency Percentage (%)

GI irritation 4 8
Hypoglycemia 3 6
Diarrhea 1 2
Figure 26: Plot of ADRs (Teneligliptin) in the study population (n=50)
8
8
7
6
6
5
PERCENTAGE
3
2
2
0
GI irritation Hypoglycemia Diarrhea
ADVRESE DRUG REACTIONS

Tables and Figures
Table 21: Distribution of ADRs (Sitagliptin) in the study population (n=50)
GI irritation 6 12
Headache 1 2
Nausea 1 2
Diarrhea 2 4
Figure 27: Plot of ADRs (Sitagliptin) in the study population (n=50)
12
12
10
8
PERCENTAGE
4
4
2 2
2
0
GI irritation Headache Nausea Diarrhea
ADVERSE DRUG REACTIONS

Tables and Figures
Table 22: Distribution of ADRs (Vildagliptin) in the study population (n=50)

Hypoglycemia 7 14
GI irritation 4 8
Headache 2 4
Dizziness 1 2
Diarrhea 1 2
Figure 28: Plot of ADRs (Vildagliptin) in the study population (n=50)
14
14
12
10
PERCENTAGE
8
8
4
4
2 2
2
0
Hypoglycemia GI irritation Headache Dizziness Diarrhea
ADVERSE DRUG REACTIONS

Tables and Figures
Table 23: Distribution of cost effectiveness in Monotherapy
Price for 3
Group Drug Price of a tablet Difference
months
Teneligliptin 7.69 692.1
Monotherapy Sitagliptin 38.4 1080 30.71
Vildagliptin 25.7 2313 18.01
Table 24: Distribution of Cost effectiveness in Combination therapy
Price of a Price for 3

Group Drug Difference
tablet months
Teneligliptin + Metformin 12 1080
Combination
Sitagliptin + Metformin 23.2 2088 11.2
therapy
Vildagliptin + Metformin 26.52 2386 14.52

Tables and Figures
Table 25: Student paired t-test for Dual therapy (n=75)
Before After
t-value p- value
Treatment Treatment
Parameter Dual therapy
Teneligliptin+ Metformin 168.92±24.55 123.62±10.12 10.04 ≤0.000***
FBS Sitagliptin + Metformin 168.68±24.13 123.64±10.45 5.807 ≤0.000***
Vildagliptin + Metformin 168.16±23.91 142.89±21.16 12.03 ≤0.000***
Teneligliptin +Metformin 274.56±37.62 164.16±35.15 16.47 ≤0.000***
PPBS Sitagliptin+ Metformin 273.32±39.12 165.11±36.12 21.25 ≤0.000***
Vildagliptin+ Metformin 275.88±36.27 190.44±44.29 10.41 ≤0.000***
Teneligliptin+ Metformin 8.77±0.90 7.1±0.51 9.49 ≤0.000***
HbA1C Sitagliptin+ Metformin 8.81±0.91 7.1±0.56 11.56 ≤0.000***
Vildagliptin+ Metformin 8.73±0.91 7.9±0.75 18.2 ≤0.000***
Teneligliptin+ Metformin 0.83±0.33 0.83±0.33 1.732 0.104
SRCR Sitagliptin+ Metformin 0.79±0.28 0.79±0.28 1.693 0.103
Vildagliptin+ Metformin 0.78±0.25 0.78±0.25 1.693 0.103
Teneligliptin+ Metformin 33.84±3.72 33.91±3.50 -1.875 0.073
SGPT Sitagliptin+ Metformin 33.54±3.71 34.01±4.56 -1.82 0.081
Vildagliptin+ Metformin 33.91±3.83 39.96±5.61 -2.48 0.21
* ≤ 0.005 is considered as statistically significant.

Tables and Figures
Table 26: Student paired t-test for Combination therapy (n=75)
Before After
Treatment Treatment
Parameter Combination therapy t-value p-value
TENE+MET+GLI 193.8±34.30 121.5±22.69 10.25 ≤0.000***
FBS SITA+MET+GLI 195.3±34.05 121.4±19.96 11.44 ≤0.000***
VILA+MET+ GLI 193.4±28.66 132.9±25.07 9.27 ≤0.000***
TENE+MET+ GLI 294.7±43.80 183.44±19.84 13.01 ≤0.000***
PPBS SITA+MET+ GLI 294.9±44.12 183.9±20.65 15.37 ≤0.000***
VILA+MET+ GLI 294.5±41.89 199.4±23.25 14.89 ≤0.000***
TENE+MET+ GLI 0.93±0.94 7.49±0.48 11.29 ≤0.000***
HbA1C SITA+MET+ GLI 9.47±0.91 7.51±0.54 10.64 ≤0.000***
VILA+MET+ GLI 9.48±0.93 8.60±0.79 20.7 ≤0.000***
TENE+MET+ GLI 0.83±0.34 0.83±0.34 0 1
SRCR SITA+MET+ GLI 0.79±0.24 0.79±0.24 -450 0.657
VILA+MET+ GLI 0.82±0.31 0.82±0.31 -157 0.877
TENE+MET+ GLI 28.68±5.59 28.76±6.12 -0.097 0.927
SGPT SITA+MET+ GLI 30.64±6.31 31.44±6.92 -0.525 0.605
VILA+MET+ GLI 28.36±5.32 30.19±5.61 -5.07 0.621

Tables and Figures
Table 27:One-Way ANOVA test for Dual therapy (n=75)
Before Before After After

Parameter Dual therapy Treatment Treatment Treatment Treatment
f p-value f p-value
Sitagliptin+ Metformin 1.619 0.179 0.215 1.86

FBS
Vildagliptin+ Metformin 3.242 0.012 0.043 ≤0.000***

PPBS

HbA1c

SrCR
Vildagliptin+ Metformin 1.823 0.151 0.811 0.575

SGPT
Vildagliptin+ Metformin _ _ 13.901 0.141

Tables and Figures
Table 28: One-Way ANOVA test for Combination therapy (n=75)
Before Before After After

Combination Treatment Treatment Treatment Treatment
Parameter
therapy
f p-value f p-value
SITA+MET+GLI 1.434 0.26 0.373 0.693

FBS
VIDA+MET+ GLI 1.941 0.167 14.351 ≤0.000***
SITA+MET+ GLI 1.873 0.155 1.488 0.248

PPBS
VIDA+MET+ GLI 0.113 0.976 9.375 ≤0.000***
SITA+MET+ GLI 0.821 0.497 0.892 0.424

HbA1c
VIDA+MET+ GLI 0.594 0.626 9.24 ≤0.000***
SITA+MET+ GLI 0.846 0.551 1.24 0.333

SrCr
VIDA+MET+ GLI 0.787 0.592 1.417 0.262
SITA+MET+ GLI 0.885 0.594 1.528 0.25

SGPT
VIDA+MET+ GLI _ _ 3.366 0.03

Results and Analysis
6. RESULTS AND ANALYSIS
A total 155 patients with type II diabetes mellitus was included in this study.
They were divided into three groups namely Group A-Teneligliptin, Group B-
Sitagliptin and Group C-Vildagliptin.
They were further divided into three sub-groups, teneligliptin 20 mg as

monotherapy (5 patients), Teneligliptin and Metformin as dual therapy (25 patients)
and Teneligliptin and Metformin with Glimepiride as combination therapy (25
patients).
Group B was divided into the two sub-groups, containing each 25 patients
Sitagliptin with Metformin as dual therapy and Sitagliptin with Metformin plus
Glimepiride as combination therapy.
Group C was divided into the two sub-groups, containing each 25 patients
Vildagliptin with Metformin as a dual therapy and Vildagliptin with Metformin plus
Glimepiride as combination therapy.
GENERAL BASE LINE CHARACTERISTICS OF STUDY POPULATION:
The patients were categorized based on their gender. There were 92 males and
62 females in overall study population, 31 males and 19 females in group A and 29
males and 21 females in Group B and Group C. The results shows the higher
predominance in male for type II diabetes mellitus. (Table 1, 2 and Figure 7, 8)
Study population was categorized in to 5 groups on the basis of age. Among the
5 groups more number of patients were came under the category of 51-60 and less in
71-80 category. This indicates that incidence of type II diabetes mellitus is higher in
51-60 years and lower in 71-80 years. (Table 3, 4 and Figure 9, 10)
Among the study population, more number of patients (58%, 54% and54% in
group A, B and C respectively) were known to have no family history of type II
diabetes mellitus. (Table 5, 6and Figure 11, 12)

Study population was categorized into two groups on the basis of duration of
the disease in years. More number of patients were came under category 0-5 years and
less in 6-10 years. (Table 7, 8 and Figure 13, 14)
GLYCEMIC CONTROL:
The glycemic efficacy was assessed by analyzing the mean change in the value
of Fasting Blood Sugar (FBS), Post Prandial Blood Sugar (PPBS), and Glycated
hemoglobin (HbA1c) from the start of the therapy to the end of 3 months study period
in each group.
Clinical efficacy of teneligliptin
At the end of 3 months of dual therapy mean HbA1c, FPG, and PPG were
significantly (p value-≤0.0001) reduced by 7.1±0.5% 123.62±9.31mg/d L and
164.16±35.15mg/d L respectively. (Table 9, 10, 11 and Figure 15, 16, 17)
At the end of 3 months combination therapy the following results were noted (p
value-≤0.0001) reduction in HbA1c, FPG, PPG by 7.49±0.48% 121.5±22.69mg/d L
and 183.44±19.84mg/d L respectively. (Table 14, 15, 16 and Figure 20, 21, 22)
The mean reduction of HbA1c was found to be 0.92% in monotherapy, 1.68%

in dual therapy and 1.79% in combinational therapy. (Table 19 and Figure 25)
The mean reduction of FBS was found to be 41.33 mg/d L. in monotherapy,

48.53 mg/d L in dual therapy and 55.68 mg/d L. in combinational therapy (Table 19
and Figure 25)
The mean reduction of PPBS was found to be 61.58mg/d L. in monotherapy,

72.71mg/d L in dual therapy and 88.53 mg/d L. in combinational therapy. (Table 19
and Figure25)
Clinical efficacy of Sitagliptin:
After the 3 months treatment with sitagliptin significant reduction of HbA1c,

FPG, and PPG level were observed. Mean HbA1c, FPG, and PPG of dual therapy was

significantly (p value-≤0.0001) reduced by 7.16±0.56% 123.64±20.24mg/d L and

Combination therapy shown significant (p value-≤0.0001) reduction in HbA1c,

FPG, PPG by 7.51±0.54% 121.41±19.96mg/d L and 183.9±20.65mg/d L respectively.
(Table 14, 15, 16 and Figure 20, 21, 22)
Clinical efficacy of Vildagliptin:
After the 3 months treatment, dual therapy mean HbA1c, FPG, and PPG were
significantly (p value-≤0.0001) reduced by 7.9±0.75%, 142.89±21.10mg/d L and
Combination therapy shown significant (p value-≤0.0001) reduction in HbA1c,

FPG, PPG by 8.60±0.48% 132.9±25.07mg/d L and 199.49±21.80mg/d L respectively.
(Table 14, 15, 16 and Figure 20, 21, 22)
COMPARITIVE ANALYSIS
GROUP A ((TENELIGLIPTIN AND ITS COMBINATIONS) VERSUS GROUP C

(VILDAGLIPTIN AND ITS COMBINATIONS)
Effect on HbA1c
Post 3 months of treatment for the two groups are shown below. The mean
HbA1c of the dual therapy for group -A (teneligliptin with metformin) was 7.1±0.5%
and group C (Vildagliptin with metformin) therapy 7.9±0.75 %.( Table 11 and
Figure17)
The mean HbA1c of combination therapy was found to be (teneligliptin with

metformin plus glimepiride) 7.49±0.48%, which was significantly lower than the mean
HbA1c in 8.60±0.48% in group C (Vildagliptin with metformin plus glimepiride)
therapy. (Table 16 and Figure 22)

It is clearly evident that Group -A (dual and combination therapy) patients had
greater reduction in HbA1c level when compared to Group C (dual and combination
therapy).
Effect on FBS
In group A the mean FBS of dual therapy (teneligliptin with metformin)

was123.62±9.31mg/d L which was significantly lower than the mean FBS in
142.89±21.10mg/d L in group C (Vildagliptin with metformin) therapy. (Table 9 and
Figure 15)
In group A the mean FBS of combination therapy (teneligliptin with metformin

plus glimepiride) was 121.5±22.69mg/d L, which was significantly lower than the mean
FBS in 132.9±25.07mg/d L in group C (Vildagliptin with metformin plus glimepiride)
therapy. (Table 14 and Figure 20)
It is shows Group A (dual and combination therapy) patient had greater

reduction of FBS than compared to Group C (dual and combination therapy).
Effect on PPBS
In group A the mean PPBS of dual therapy (teneligliptin add on metformin) was
164.16±35.15mg/d L which was significantly lower than the mean PPBS in
190.44±29.29mg/d L mg/d L in group C (Vildagliptin add on metformin) therapy.
(Table 10 and Figure 16)
In group A the mean PPBS of combination therapy (teneligliptin add on

metformin plus glimepiride) was 183.44±19.84mg/d L which was significantly lower
than the mean PPBS in 199.49±21.80mg/d L in group C (Vildagliptin add on metformin
plus glimepiride) therapy. (Table 15 and Figure 21)
It is clearly evident that Group A (dual and combination therapy) patient had
greater reduction of PPBS than compared to Group C (dual and combination therapy)

Effect on SrCr (Serum creatinine) and SGPT
There was no significance difference was seen in SrCr level following 3 months
of therapy with teneligliptin and its combinations when compared to sitagliptin and its
combinations and vildagliptin and its combinations. (Table 12, 17 and Figure 18, 23)
SGPT level showed a slightly significant increase in all the three groups, but it
was in normal range. (Table 13, 18 and Figure 13, 18)
GROUP A (TENELIGLIPTIN AND ITS COMBINATIONS) VERSUS GROUP B

(SITAGLIPTIN AND ITS COMBINATIONS)
Effect on HbA1c
A mean reduction in HbA1c of 7.1±0.5%, was seen with teneligliptin add on
metformin therapy, while a same mean reduction in HbA1c of 7.1±0.5% was found
with sitagliptin add on metformin therapy. Comparison both the groups demonstrated
that there was no significant difference. (Table 11 and Figure17)
Mean reduction in HbA1c of 7.49±0.48% was seen with teneligliptin with

metformin plus sulfonyl urea therapy, while a slight increase of HbA1c of 7.51±0.54%
was found with sitagliptin add on metformin plus glimepiride therapy. (Table 16 and
Figure 22)
Effect on FBS
A mean reduction in FBS of 123.6±9.31mg/d L was seen with teneligliptin with

metformin therapy, while a same mean reduction in FBS of 123.64±20.24mg/d L was
found with sitagliptin with metformin therapy. Comparison both the groups
demonstrated that there was no significant difference. (Table 9 and Figure 15)
A mean reduction in FBS of 121.5±22.69mg/d L was seen with teneligliptin add

on metformin plus glimepiride, while a slight decrease of FBS of 121.41±19.96mg/d L
was found with sitagliptin add on metformin plus sulfonyl urea therapy. (Table 14 and
Figure 20)

Effect on PPBS
Mean reduction in PPBS of 164.1±35.15mg/d L, was seen with teneligliptin add

on metformin therapy, while a same mean reduction in PPBS of 164.1±30.16mg/d L
was found with sitagliptin add on metformin therapy. (Table 10 and Figure 16). On the
comparison both the group demonstrated no difference statistically.
A mean reduction in PPBS of 183.44±19.84mg/d L, was seen with teneligliptin

add on metformin plus glimepiride, while a same mean reduction in PPBS of
183.9±20.65mg/d L was found with sitagliptin add on metformin plus glimepiride
therapy. On the comparison both the group demonstrated no difference statistically.
(Table 15 and Figure 21)
It shows that both the regimens on comparison reveled similar efficacy there by
failing to prove the superiority over each other.
Effect on SrCr and SGPT
There was no significance difference between SrCr following 3 months of

therapy with teneligliptin and its combinations when compared with sitagliptin and its
combinations and vildagliptin and its combinations. (Table 12, 17 and Figure 18, 23)
SGPT level showed a slightly significant increase in three groups, but which
was still in normal range. (Table 13, 18 and Figure 19, 24)
SAFETY ANALYSYS:
Group-A
Treatment with Teneligliptin and its combination was well tolerated over the 3
months treatment period. . In monotherapy there were no ADR reported. 8 patients
experienced ADRs .Mild hypoglycemia reported in (6%) the cases, was mostly reported
ADR followed by GI irritation (8%) and less in headache (2%). (Table 20 and Figure 26)

Group-B
There were no severe ADR is reported in Sitagliptin and its combination therapy
.Mild GI irritation (12%) was occurred in the group. Other ADR including nausea (2%)
and headache (2%) and diarrhea (4%) were happened among the group. No other
frequently observed or serious ADR were observed in this study. And no hypoglycemia
occurred in any of the patient taking vildagliptin and their combination. (Table 21 and
Figure 27)
Group-C
The frequent ADR in the vildagliptin and their combination therapy were
hypoglycemia (14%) GI irritation (8%), headache (4%), dizziness (2%) and diarrhea
(2%). No severe ADR were reported in the 3 groups. All the ADR reported during the
study were mild. (Table 22 and Figure 28)
There were no incidence of renal and hepatic toxicity. There was no

significance difference between groups in terms of reported ADR.
COST EFFECTIVE ANALYSIS (CEA)
The cost effectiveness of teneligliptin, sitagliptin, and vildagliptin monotherapy

and their combination with metformin was studied. It shows that teneligliptin and its
combination with metformin was found to be more cost effective. (Table 22 and 23)

Discussion
7. DISCUSSION
The study was designed to compare safety, efficacy and cost effectiveness of
teneligliptin, sitagliptin and vildagliptin in type II diabetes mellitus patients. The study
was started with 155 patients. Each gliptin were compared with metformin and add on
therapy of metformin plus glimepiride.
In this study the patients were categorized based on their gender. There were 31
males and 19 females in teneligliptin group, 29 males and 21 females in sitagliptin
group and vildagliptin group. The results shows the higher predominance in male for
type II diabetes mellitus. This was similar to the previous studies conducted by Bennett
et al., and Howteerakul et al., which showed higher prevalence of type II DM in men
than women.
In this study population was categorized in to 5 groups on the basis of age.

Among the 5 groups more number of patients were came under the category of 51-60
and less in 71-80 category. Type II DM is commonly seen in middle-aged individuals,
especially after 50 years of age. The mean age in this study was 51-60 years, this fact
is supported by the study conducted by Miyako Kishimoto et al., .
Among the study population, more number of patients (58%, 54% and54% in
group A, B and C respectively) were known to have no family history of type II diabetes
mellitus. In this study, 40% patients had a positive family history indicating either one
or both the parents had type II DM, which was at one stage or the other transferred from
one generation to another. Also this was accordance with larger prospective study
conducted by Bennett et al., .
Study population was categorized into two groups on the basis of duration of
the disease in years. More number of patients were came under category 0-5 years and
less in 6-10 years. The average duration of DM in this study was found to be 0- 5 years,
which was in line with a previous study conducted by Jeon et al., where the mean
duration was 5.89 years.

Discussion
The glycemic efficacy was assessed by analyzing the mean change in the value
of Fasting Blood Sugar (FBS), Post Prandial Blood Sugar (PPBS), and Glycated
hemoglobin (HbA1C) from the start of the therapy to the end of 3 months study period
in each group.
Teneligliptin has been demonstrated to improve glycemic control when

monotherapy and added to glimepiride, metformin, in patients with type II diabetes. It
is confirmed that the combination of Teneligliptin, metformin and glimepiride
significantly improved glycemic control. However, in this study, the reduction in
HbA1C with teneligliptin monotherapy was greater than those in teneligliptin
metformin group and teneligliptin with metformin and glimepiride group.
In this study shows at the end of 3 months of dual therapy mean HbA1C, FPB,
and PPBS were significantly (p value-≤0.0001) reduced by 7.1±0.5% 123.62±9.31mg/d
L and 164.16±35.15mg/d L respectively. At the end of 3 months combination therapy
the following results were noted (p value ≤ 0.0001) reduction in HbA1C, FPG, PPG by
7.49±0.48% 121.5±22.69mg/d L and 183.44±19.84mg/d L respectively. The result of
this study perfectly complies with the former study conducted by, Kim et al., studied
in combination of teneligliptin with metformin in known type II diabetic Korean
patients whose glycemic status were not under controlled with metformin monotherapy,
this shows teneligliptin add on metformin plus glimepiride therapy shows the
significant reduction of glycemic parameter.
Another study conducted by in Ghosh et al., (TREAT-INDIA), there was

statistically significant improvement in mean HbA1c, FPG, and PPG with teneligliptin
therapy. Means changes in HbA1c, FPG, and PPG were 1.37%±1.15%, 51.29±35.41
mg/dL, and 80.89±54.27 mg/dL, respectively.
Subgroup analysis revealed that HbA1c (%) reduction with teneligliptin when
used as monotherapy, add-on to metformin or add-on to metformin plus combination,
was 0.98±0.53, 1.07±0.83, 1.46±1.33, respectively.

Discussion
In this study the mean reduction of HbA1C was found to be 0.92% in

monotherapy, 1.68% in dual therapy and 1.79% in combinational therapy and the mean
reduction of FBS was found to be 41.33 mg/d L. in monotherapy, 48.53 mg/d L in dual
therapy and 55.68 mg/d L. in combinational therapy. The mean reduction of PPBS was
found to be 61.58mg/d L. in monotherapy72.71mg/d L in dual therapy and 88.53 mg/d
L. in combinational therapy. The similar result were observed by, Kutoh et al., in a
3‑ month study of 31 drug naive Japanese T2DM patients, evaluated teneligliptin daily
20 mg as a monotherapy. This study found a significant reduction in HbA1C and fasting
blood glucose from the baseline.
Scott et al., in his study suggested that Teneligliptin, a DPP-4 inhibitor was
added to the armamentarium for use in patients with type II diabetes in India. In
different clinical trials conducted in Japan, Korea, and India, it has been shown to be
safe and effective in T2DM patients when used either as monotherapy and combination
antidiabetic therapy.
Recently an Indian study by Suryawanshi et al., reported the results of a 16-

week, multi centric, double-blind, placebo-controlled, Phase 3 studies of teneligliptin
20 mg daily in drug naive T2DM patients. This study (N =237) reported a significant
−0.55% glycated hemoglobin (HbA1C) reduction (placebo-subtracted) in teneligliptin
arm (P = 0.0043) compared to control. While a significant reduction in 2 hrs
postprandial glucose (PPG) (−25.8 mg/dl, P = 0.0070) versus placebo was observed, an
insignificant reduction in fasting plasma glucose (FPG) was seen (−8.8 mg/dl, P =0.18)
in teneligliptin 20 mg arm. Similarly, higher percentage of patient achieved the target
HbA1c of <7% in teneligliptin arm (43.4% vs. 27.3%, P = 0.026) compared to the
control and “overall” the drug was well tolerated.
The similar results shows that Kadowaki et al., and Kondo et al., conducted a
double-blind placebo-controlled parallel-group study in 324 Japanese patients with type
2 diabetes randomized to receive different doses of teneligliptin or placebo once daily
before breakfast for 12 weeks. These results indicate that treatment with teneligliptin

Discussion
for 12 weeks provided significant and clinically meaningful reduction in the levels of
HbA1c and FPG across the dose range studied.
Wakaba et al., study was to evaluate the effects of teneligliptin on 24 hour

blood glucose control and gastrointestinal hormone responses to a meal tolerance test,
and to investigate the glucose-lowering mechanisms of teneligliptin. Teneligliptin was
given once a day for 3 days significantly lowered fasting and postprandial glucose
levels. Significant elevations of fasting and postprandial active GLP-1 and postprandial
active GIP levels were observed.
In this study after the 3 months treatment with sitagliptin and its combination
significant reduction of HbA1c, FPG, and PPG level were observed. Mean HbA1c,
FPG, and PPG of dual therapy was significantly (p value≤0.0001) reduced by
7.16±0.56% 123.64±20.24mg/d L and 165.11±30.16mg/d L respectively. Combination
therapy shown significant (p value≤ 0.0001) reduction in HbA1c, FPG, PPG by
7.51±0.54% 121.41±19.96mg/d L and 183.9±20.65mg/d L respectively.
This was in accordance with previous studies conducted by Goldstein et al.,

and Hermansen et al., where the effects of combination of sitagliptin + metformin with
other oral hypoglycemics have been well documented. The improvement in HbA1c was
highly significant in both the study groups (p < 0.001) at the end of 24 weeks.
Previous studies by Hermansen et al., Raz et al., and Bennettet al., have
proven the improvement in HbA1c by combination of metformin and sitagliptin and
metformin and glimepiride. At the end of the study period, the intergroup comparison
between groups I and II was done for FPG, PPG, and HbA1c. It was insignificant for
FPG and HbA1C (p > 0.05) and significant for PPG (p < 0.05) indicating that the group
where combination of sitagliptin and metformin was given had a better glycemic
control in terms of PPG.
Previous studies conducted by Reasner et al., Perez-Monteverde et al., and

Wainstein et al., have proven that combination of sitagliptin and metformin produces
significant improvement in glycemic parameters such as FPG, PPG, and HbA1c.

Discussion
In this study after the 3 months treatment, dual therapy mean HbA1C, FPG, and
PPG were significantly (p value ≤0.0001) reduced by 7.9±0.75%, 142.89±21.10mg/d L
and 190.44±29.29mg/d L respectively. Combination therapy shown significant (p value
≤ 0.0001) reduction in HbA1C, FPG, PPG by 8.60±0.48% 132.9±25.07mg/d L and
199.49±21.80mg/d L respectively.
Recent studies have shown that, Matthews et al., and Filozof et al., as add-on
therapy in patients with inadequately controlled T2DM treated with vildagliptin,
metformin dual therapy and vildagliptin metformin and Sulphonylurea as combination
therapy.
Masato Odawara et al., 12-week, randomized, double-blind study evaluated

the efficacy and safety of vildagliptin 50 mg bid in Japanese patients with T2DM
inadequately controlled on metformin monotherapy.
Vildagliptin produced a statistically significant and clinically meaningful

change in HbA1c compared with placebo (-1.1% vs. -0.1%; P\0.001) as add-on to
metformin (250 mg bid or 500 mg bid) after 12 weeks of treatment in Japanese patients
with T2DM.
A similar result was obtained from Pan et al., adding vildagliptin to metformin
resulted in 1.05% reduction of HbA1C after 24 weeks treatment. In a recent Indian
retrospective study Chatterjee et al., the reduction in HbA1C was 1.9% which is
compatible with another study Bosi et al., where vildagliptin combined with metformin
was given in treating T2DM naïve patients.
The similar results shows that Ahren et al., combination of vildagliptin therapy
with metformin have also been evaluated in three double-blind controlled studies and
showed statistically meaningful reduction in Hba1c of 0.7 and 0.9%. A meta-analysis
Cail et al., of 30 randomized controlled trials showed that treatment with vildagliptin,
metformin and sulfonylurea are decreased Hba1c by 0.77%.
Post 3 months of treatment for the two groups are shown below. The mean
HbA1c of the dual therapy for group -A (teneligliptin with metformin) was 7.1±0.5%

Discussion
and group C (Vildagliptin with metformin) therapy 7.9±0.75% .The mean HbA1c of
combination therapy was found to be (teneligliptin with metformin plus sulfonylurea)
7.49±0.48%, which was significantly lower than the mean HbA1c in 8.60±0.48% in
group C (Vildagliptin with metformin plus sulfonylurea) therapy. In this study it is
clearly evident that Group -A (dual and combination therapy) patients had greater
reduction in HbA1c level when compared to Group C (dual and combination therapy).
This fact is supported by the study conducted by Tushar et al.in which finally
concluded that teneligliptin therapy is more effective than vildagliptin therapy.
In group A the mean FBS of dual therapy (teneligliptin with metformin)

was123.62±9.31mg/d L which was significantly lower than the mean FBS in
142.89±21.10mg/d L in group C (Vildagliptin with metformin) therapy.In group A the
mean FBS of combination therapy (teneligliptin with metformin plus sulfonylurea) was
121.5±22.69mg/d L, which was significantly lower than the mean FBS in
132.9±25.07mg/d L in group C (Vildagliptin with metformin plus sulfonylurea)
therapy.
It is shows Group A (dual and combination therapy) patient had greater

reduction of FBS than compared to Group C (dual and combination therapy). The
similar result shows that the study conducted Tushar et al., in which finally concluded
that teneligliptin therapy is more effective than vildagliptin therapy.
In group A the mean PPBS of dual therapy (teneligliptin add on metformin) was
164.16±35.15mg/d L which was significantly lower than the mean PPBS in
190.44±29.29mg/d L mg/d L in group C (Vildagliptin add on metformin) therapy.
In group A the mean PPBS of combination therapy (teneligliptin add on

metformin plus sulfonylurea) was 183.44±19.84mg/d L which was significantly lower
than the mean PPBS in 199.49±21.80mg/d L in group C (Vildagliptin add on metformin
plus sulfonylurea) therapy.
It is clearly evident that Group A (dual and combination therapy) patient had
greater reduction of PPBS than compared to Group C (dual and combination therapy).
Discussion
The similar result shows that the study conducted Tushar et al., finally concluded that
teneligliptin therapy is more effective than vildagliptin therapy.
A mean reduction in HbA1C of 7.1±0.5%, was seen with teneligliptin add on

metformin therapy, while a same mean reduction in HbA1c of 7.1±0.5% was found
with sitagliptin add on metformin therapy. Comparison both the groups demonstrated
that there was no significant difference.
Mean reduction in HbA1C of 7.49±0.48% was seen with teneligliptin with

metformin plus glimepiride therapy, while a slight increase of HbA1c of 7.51±0.54%
was found with sitagliptin add on metformin plus glimepiride therapy. Comparison both
the groups demonstrated that there was no significant difference.
Which was similar to the study conducted Eto et al., Mean reduction of HbAIC
in teneligliptin therapy, and was same to the mean reduction of sitagliptin therapy. But
Wakaba Tsuchimochi et al., study shows that teneligliptin is more effective than
sitagliptin therapy because of the structural advantages of teneligliptin.
A mean reduction in FBS of 123.6±9.31mg/d L was seen with teneligliptin with

metformin therapy, while a same mean reduction in FBS of 123.64±20.24mg/d L was
found with sitagliptin with metformin therapy. Comparison both the groups
demonstrated that there was no significant difference.
A mean reduction in FBS of 121.5±22.69mg/d L was seen with teneligliptin add

on metformin plus glimepiride therapy, while a slight decrease of FBS of
therapy.
Which was similar to the study conducted Eto et al., mean reduction of FBS in
teneligliptin therapy, was equaling to the mean reduction of sitagliptin therapy. But
Wakaba Tsuchimochi et al., study shows that teneligliptin is more effective than

Discussion
Mean reduction in PPBS of 164.1±35.15mg/d L, was seen with teneligliptin add

on metformin therapy, while a same mean reduction in PPBS of 164.1±30.16mg/d L
was found with sitagliptin add on metformin therapy. On the comparison both the group
demonstrated no difference statistically.
A mean reduction in PPBS of 183.44±19.84mg/d L, was seen with teneligliptin

add on metformin plus glimepiride therapy, while a same mean reduction in PPBS of
therapy.
Which was similar to the study conducted Eto et al., mean reduction of PPBS
in teneligliptin therapy, was equality to the mean reduction of sitagliptin therapy. But
Wakaba Tsuchimochi et al study shows that teneligliptin is more effective than
On the comparison both the group demonstrated no difference statistically. It

shows that both the regimens on comparison reveled similar efficacy there by failing to
prove the superiority over each other.
In this study there was no significance difference between SrCr following 3

months of therapy with teneligliptin and its combinations when compared with
sitagliptin and its combinations and vildagliptin and its combinations. SGPT level
showed a slightly significant increase in three groups, but which was still in normal
range. The result of this study perfectly complies with the former study conducted by,
Manish Maladkar et al., his study shows that gliptins do not causes any reanal and
hepatic impairment.
Treatment with Teneligliptin and its combination was well tolerated over the 3
months treatment period. In monotherapy there were no ADR reported. In combination
therapy 8 patients experienced ADRs. Mild hypoglycemia reported in (6%) the cases,
was mostly reported ADR followed by GI irritation (8%) and less in headache (2%).

Discussion
Awadhesh Kumar Singh et al., observed that in monotherapy only <1% of

ADRs were occurred. In combination therapy hypoglycemia, GI irritation, head ache,
peripheral edema and nasopharangytis were occurred.
There were no severe ADR was found in Sitagliptin and its combination therapy
.Mild GI irritation (12%) was occurred in the group. Other ADR including nausea (2%)
and headache (2%) and diarrhea (4%) were happened among the group. Supporting to
this study Jennifer Green et al., in her study didn’t shown any hypoglycemic events
in sitagliptin therapy and GI irritation, nausea and headache were found.
The frequent ADR in the vildagliptin and their combination therapy were
hypoglycemia (14%) GI irritation (8%), headache (4%), dizziness (2%) and diarrhea
(2%).
Which was similar to the study conducted by Yun‑ Zhao Tang et al., in his the
ADR of vildagliptin therapy shows more in hypoglycemia (18.9%) and GI irritation
(16.6%).
The cost effectiveness of teneligliptin, sitagliptin, and vildagliptin monotherapy

and their combination with metformin was studied. It shows that teneligliptin and its
combination with metformin was found to be more cost effective. This fact is supported
by the study conducted by Ghosh et al., his study shows that teneligliptin is
economically effective compared with other gliptins.

Conclusion
8. CONCLUSION
Out of 150 patients, the prevalence of type 2 diabetes mellitus was higher in
males than females in age group of 51-60 years and most of the patients were observed
in the duration was 0-5 years. From this study it was observed that only female patients
having the comorbid conditions were thyroid and rheumatoid arthritis.
This study provides an evidence of safety and efficacy of teneligliptin as a

monotherapy or in combination therapies with a Metformin and Glimepiride in patients
with type II Diabetes mellitus.
The results pointed out that all the group of patients showed an improvement
in their glycemic parameters such as FBS, PPBS, and HbA1c during the study period
and from the group comparison study it was observed that the patients receiving
combination therapy of teneligliptin have better glycemic control than combination
therapy of vildagliptin.
The study demonstrated the effectiveness of teneligliptin combination and

sitagliptin combination therapy in type II diabetes mellitus patients. Both the
combinations on comparison reveled similar efficacy in glycemic parameter, there by
failing to prove the superiority in over each other.
There was no significance difference was found in SrCr and SGPT level for the
follow-up of 3 months therapy with teneligliptin combinations, sitagliptin
combinations and vildagliptin combinations.
No severe ADR were reported in the 3 groups. All the ADR reported during the
study were mild. However the incidence of ADR were numerically more in vildagliptin
combination therapy and the incidence of hypoglycemia is more in sitagliptin
combination therapy. The teneligliptin combination shows lesser side effects than the
other two combinations. Vildagliptin group shows ADR like GI irritation,
Hypoglycemia, Headache and Dizziness. In that occurrence of hypoglycemia were high
and other ADRs were mild. Sitagliptin groups shows ADRs like GI irritation, head
ache, nausea and diarrhea, in that the major ADR was GI irritation. Compare to the
Conclusion
other two groups of combination drugs, teneligliptin has less ADRs like GI irritation,
Hypoglycemia and Diarrhea. There was no incidence of renal and hepatic toxicity with
all the three combination drugs.
The cost effective analysis of teneligliptin, sitagliptin, and vildagliptin

monotherapy and their combination with metformin was done , the results shows that
teneligliptin alone and its combination with metformin was found to be more cost
effective than the other groups of drugs.
The teneligplin has more advantages than the other two gliptins in type II
diabetes mellitus patients. Teneligliptin with metformin and sulfonyl urea treatment
was effective and well tolerated in patients with type II diabetes and it has long half-
life of 26.9 hours with unique pharmacokinetic advantage which allows convenient
once daily administration irrespective of food. It has dual mode of elimination via renal
and hepatic, hence it can be administered safely in renal impairment patients. No dosage
adjustment is required in mild to moderate hepatic impairment. The appropriate
approach towards managing diabetes should be not only glycemic control but also
preservation of islet cell function early and to delay the progression of a disease.
In conclusion teneligliptin significantly improves glycemic parameters in Indian

T2DM patients with mild ADRs when prescribed as monotherapy or as add-on to
Metformin and Sulfonyl ureas and it also cost effective than the other gliptins.

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KOVAI MEDICAL CENTER AND HOSPITAL - COIMBATORE
DATA COLLECTION FORM
Date: IP No:
Name: Age: Sex: M/F
Height: Weight: BMI:
Marital status: Married Single
Social habits: Smoker Alcoholic
Past history: Jaundice Pancreatitis Rhinitis Others
Family history: Diabetes Mellitus: Yes No
Co-exiting illness: Thyroid Rheumatoid Arthritis Others
Duration of type II Diabetes Mellitus: 0-5 years 6-10 years >10 years
LAB INVESTIGATIONS
Teneligliptin Sitagliptin Vildagliptin

Parameter
Before After Before After Before After
treatment treatment treatment treatment treatment treatment
FBS( mg/dl)
PPBS (mg/dl)
HbA1C (gm %)
SrCr (mg/dl)
SGPT( IU/L)
TREATMENT CHART:
Sl.no Drug name Price/tablet Dose Freequency

20 mg Once a day
1. Teneligliptin Rs. 7
25mg/ 50mg/ Twice a day

2. Sitagliptin Rs. 42
100mg
3. Vildagliptin Rs.19.28 50mg/ 100mg Twice a day
TENELIGLPITIN USED AS
First line: Yes No
e
Second line: Yes No
s
Third line: Yes No
N
o
ADVERSE DRUG REACTIONS OF TENELIGLIPTIN
Hypoglycemia Yes No
e e
s s
Constipation Yes No
e e
N N
s
s
Nasopharyngitis Yes oe No oe
N N
s
s
Proteinuria Yes oe No oe
N N
s
s
Ketonuria Yes oe No oe
N N
s
s
Glucosouria Yes oe No oe
ECG abnormality N N
s
s
Yes o No o
(QT prolongation) e e
N N
s s
Others Yes o No o
e e
N N
s s
o o
N N
o o
ADVERSE DRUG REACTIONS OF SITAGLIPIN
Nasopharyngitis Yes No
e e
s s
Hypoglycemia Yes No
e e
N N
s
s
Constipation Yes oe No oe
N N
s
s
Diarrhea Yes oe No oe
N N
s
s
UTI Yes oe No oe
N N
s
s
Upper respiratory tract infection Yes oe No oe
N N
s
s
Peripheral edema Yes oe No oe
N N
s
s
Others Yes oe No oe
N N
s
s
o o
ADVERSE DRUG REACTIONS OF VILDAGLIPIN
N N
o o
Dizziness Yes No
e e
s s
Pancreatitis Yes No
e e
N N
s
s
Constipation Yes oe No oe
N N
s
s
Head ache Yes oe No oe
N N
s
s
UTI Yes oe No oe
N N
s
s
Hypoglycaemia Yes oe No oe
N N
s
s
Osthers Yes oe No oe
N N
s
s
o o
N N
o o
OTHER ANTIDIABETIC DRUGS:
Category Name of drug Price Dose Freequency
Oral anti diabetic

drugs
Sulfonylurea
Glitazones
Biguanide
∝-glucosidase inhibitor
ADVERSE DRUG REACTIONS OF OTHER ANTIDIABETIC DRUGS:
Hypoglycaemia Yes No
e e
Nausea Yes No
es es
Hyponatremia Yes No
se se
Lactic acidosis Yes N No N
eso seo
Renal insufficiency Yes N No N
eso eso
Liver disease Yes N No N
eso eso
Metallic taste Yes N No N
seo so
Diarrhea Yes N No N
eso eo
Weight gain Yes N No N
eso eso
Fluid retention Yes N No
seo s
Y
Heart failure Yes N No N
eso eo
N N
so so
N
oN N
o o

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A COMPARATIVE STUDY OF TENELIGLIPTIN VERSUS OTHER

STANDARD GLIPTINS USED IN TYPE II DIABETES MELLITUS

DEPARTMENT OF PHARNACY PRACTICE,

Under the Guidance of

DEPARTMENT OF PHARMACY PRACTICE,

This is to certify that the dissertation work entitled “A COMPARATIVE

Place: Coimbatore Prof. Dr. A. Rajasekaran, M.Pharm., Ph.D.

This is to certify that the dissertation work entitled “A COMPARATIVE

Place: Coimbatore Mr. C. Dhandapani,M.Pharm, (Ph.D)

I do here by declare that to the best of my knowledge and belief ,the

This is to certify that the work embodied in the thesis entitled “A

Examination Center: K.M.C.H College of Pharmacy, Coimbatore

Internal Examiner External Examiner

I take this opportunity to express my deep sense of gratitude and faithfulness to my

I would also like to express my sincere and heartfelt gratitude to

I extend my sincere thanks and gratitude to my Principal, Dr. A. Rajasekaran,

I extend my sincere thanks to Dr. Nalla G. Palanisamy, M.D., AB (USA),

AACE : American Association of Clinical Endocrinology

ACE : American College of Endocrinology

ADA : American Diabetes Association

DPP-4 inhibitor : Dipeptidyl Peptidase 4 inhibitor

FPG : Fasting Plasma Glucose

FBS : Fasting Blood Sugar

GIP : Gastric Inhibitory Polypeptide

GLP : Glucagon like peptide 1

HbA1C : Glycated Hemoglobin

IDF : International Diabetes Federation

PPG : Postprandial Plasma glucose

PPBS : Postprandial Blood Sugar

SrCr : Serum Creatinine

SGPT : Serum glutamic pyruvic transaminase

SUs : Sulfonyl ureas

T2DM : Type II Diabetes Mellitus

SL.NO. CONTENTS PAGE NO.

3. AIM AND OBJECTIVES 21

5. TABLES AND FIGURES 26

6. RESULTS AND ANALYSIS 53

Annexure I: Letter of Approval from Ethics

Annexure II: Patient Data Collection Form

MANAGEMENT OF TYPE II DIABETES MELLITUS

There are at least seven different classes of agents used as monotherapy, or in

Metformin was recommended by most guidelines as first line therapy for

Department of Pharmacy Practice 1

Figure 1: Treatment Algorithm for Type II Diabetes Mellitus

Department of Pharmacy Practice 2

GLIPTIN: DPP-4 INHIBITORS

Department of Pharmacy Practice 3

Although various DPP-4 inhibitors have different pharmacokinetic and

A list of available gliptins are follows

 Sitagliptin (Merck Sharp and Dohme Corp, approved as Januvia by US FDA in

Department of Pharmacy Practice 4

Figure 2: Mechanism action of gliptins7

EFFICACY OF DPP-4 INHIBITORS AND RECOMMENDATION FOR USE

EFFICACY AND SAFETY OF DPP-4 INHIBITORS IN ELDERLY PATIENTS

Department of Pharmacy Practice 6

 There was a low risk of hypoglycemia DPP-4 inhibitor treatment groups.

Teneligliptin, {(2S, 4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazin-

Department of Pharmacy Practice 7

Figure 3: Chemical structure of Teneligliptin6