Teneligliptin, class apart gliptin

1. DIABETES Definition
Diabetes mellitus is a group of METABOLIC disorder
characterized by hyperglycemia (high blood glucose) resulting
from defects in INSULIN secretion, INSULIN action, or both –
(As per ADA).

2. DIABETES
is directly related to 2 terms
(1) METABOLISM
(2) INSULIN

3. METABOLISM

4. METABOLISM = ENERGY

5. MOST IMPORTANT MOLECULE ON WHICH
WE ARE DEPENDENT FOR THE
ENERGY
GLUCOSE

6. GLUCOSE IS UNIVERSAL STIMULATOR FOR INSULIN
SECRETION
When we eat CARBOHYDRATE (converted to GLUCOSE & enters in
blood); Increased Glucose Level in plasma stimulate pancreatic beta
cell to release INSULIN…

7. DOES GLUCOSE ALONE STIMULATE INSULIN
SECRETION?
ALONG WITH THE GLUCOSE,
• AMINO ACID,
• KETONES,
• VARIOUS NUTRIENTS &
• NEUROTRANSMITTERS
ALSO INFLUENCE INSULIN SECRETION
NO

8. MOST IMPORTANT ARE INCRETINS!!!
• INCRETIN
(hypothesized in
1902) are the gut
derived hormones
stimulating insulin
secretion on nutrient
ingestion.
INCRETIN =
INtestine
seCRETion
INsulin

9. DISCOVERY OF INCRETIN EFFECT
In 1932 by La Barre, Glucose was
given Orally shows higher
insulin release compared to the
Glucose given IV
Thus, it shows there is some gut
secreting hormone (incretin)
effect which works on glucose
lowering by enhancing the
insulin release

10. INCRETIN
(Peptide Hormone)
GIP
(Glucose dependent Insulinotropic
Polypeptide)
Secreted from K Cells in intestine
(Duodenum)
42 Amino acid Structure : GIP (1-42)
GLP – 1
(Glucagon Like Peptide – 1)
Secreted from L Cells of intestine
(ileum, jejunam & colon)
31 Amino acid Two Isoforms : GLP -1
(7-36) amide & GLP-1 (7-37)
INCRETINS RESPONSIBLE FOR INCRETIN EFFECT
Incretin effect is shown due to 2 hormones:
GIP : Glucose-dependent Insulinotropic Polypeptide &
GLP-1 : Glucagon Like Peptide - 1
ROLE IN
TYPE 2
DIABETES
MELITUS

11. RELEASE OF INCRETINS
GLP-1 is secreted more
upon stimulation from
Meal (higher
secretion on glucose
increasing diet)
INCRETINS shows insulinotropic
action which is dependent upon
glucose concentration in plasma.

12. GLP -1 offers pleiotropic effects
With this pancreatic & extra – pancreatic action,
GLP – 1 Works on the all level of Organs and Thus Provide
the Best Treatment Option for Management of T2DM

13. GLP – 1 Degradation by DPP- 4 Enzyme
GLP -1 after secretion from the gut get degraded just within 1-2
minutes by DPP-4 Enzyme which cleaves at NH2 Terminal of these
peptide hormone.

14. DPP- 4 (Dipeptidyl Peptidase - 4)
• Located on surface
anchored on brush
border of
– Intestine
– Renal membrane
– Hepatocytes
– Capillary endothelial
cells
– Also Available in
soluble form in
plasma

15. GLP-1
inactive
(>80% of pool)
Active
GLP-1
Meal
DPP-4
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
Inhibition of DPP-4 Enzyme Increase Active GLP-1 Level
which can be used to treat TYPE 2 DIABETES MELLITUS

16. CURRENT THERAPY FOR DIABETES
MANAGEMENT
THERAPEUTIC CATEGORY DRAWBACK
SULFONYLUREA HYPOGLYCEMIA
THIAZOLIDINE DIONE WEIGHT GAIN
INSULIN WEIGHT GAIN, HYPOGLYCEMIA
ALPHA GLUCOSIDASE INHIBITOR GAS, BLOATING AND DIARRHEA
DPP – 4 INHIBITORS APPARENTLY NO SUCH SIDE EFFECTS

17. DPP-4 INHIBITORS
• The first agent in DPP 4 inhibitor class - Sitagliptin - approved by FDA in
2006.
• Then followed by various molecules like Vildagliptin, Saxagliptin,
linagliptin, Alogliptin, Anagliptin & Gemigliptin.

18. Absence of first phase Insulin release in Type 2
Diabetes Mellitus Patient

19. DPP – 4 Inhibitor Increase GLP-1 level that
Increases First Phase Insulin Release
INCREASE IN GLP-1 LEVEL INCREASES THE
FIRST PHASE INSULIN SECRETION
HELP TO MAINTAIN ROUND THE CLOCK
GLYCEMIC CONTROL

20. DPP – 4 Inhibitor Improves Adiponectin Level
• DPP – 4 inhibitor
increases serum
Adiponectin level
• Adiponectin is peptide,
produced by Adipose
tissue
• Reduce insulin resistance,
improve endothelial
function & Left
Ventricular (LV) Function

21. β Cell Proliferation and Reduction in
Apoptosis
DPP – 4 inhibitors are believed to have the effect in prolongation
of lifespan of beta cell by reducing Apoptosis and increasing
proliferation

22. Traditional Oral Therapies
Pancreatic Islet Dysfunction
Inadequate
glucagon
suppression
(-cell
dysfunction)
Progressive
decline of β-cell
function
Insufficient Insulin
secretion
(β-cell
dysfunction)
Sulfonylureas
Glinides
TZDsMetformin
Insulin Resistance
(Impaired insulin action)
DPP – 4 INHIBITOR

23. Mode of Action of DPP – 4 Inhibitors
Agent Liver
Pancreas GI
Tract
Muscle
Adipose
Tissueα β
METFORMIN + - - ± + ±
Sulfonylurea - - + - - -
TZD - - ± + +
AGI - - - + - -
DPP4-
inhibitors
+ + + + + +

24. LIMITATIONS OF EXISTING GLIPTINS
DPP – 4 INHIBITORS t1/2 (hr)
Sitagliptin 8-14
Vildagliptin 2-3
Saxagliptin 2.5
? 24 hour?

25. Teneligliptin is a novel DPP-4
inhibitor acting on DPP-4 enzyme
- Firstly approved in Japan
-Approved by DCGI, INDIA

26. Mode of Action
inhibits

27. TENELIGLIPTIN ADVANTAGES
1. LONGER DURATION OF ACTION
DPP – 4 INHIBITORS t1/2 (hr)
Sitagliptin 8-14
Vildagliptin 2-3
Saxagliptin 2.5
TENELIGLIPTIN 24
TENELIGLIPTIN : 24 hr Duration of Action,
ROUND THE CLOCK GLYCEMIC CONTROL

28. TENELIGLIPTIN ADVANTAGES
2. Lowest IC50
DPP – 4 INHIBITOR
DPP-4 inhibition,
IC50 (nmol/L)
VILDAGLIPTIN 29.2
SAXAGLIPTIN 6.3
ALOGLIPTIN 4.9
SITAGLIPTIN 10.3
TENELIGLIPTIN 0.37
TENELIGLIPTIN: LOWEST IC50: HIGH POTENCY

29. TENELIGLIPTIN ADVANTAGES
3. ANCHOR LOCK STRUCTURE
UNIQUE ANCHOR LOCK STRUCTURE PROVIDES SPECIFIC BINDING TO
THE DPP – 4 ENZYME

30. TENELIGLIPTIN ADVANTAGES
4. EXCRETION
DPP – 4 INHIBITOR EXCRETION IN URINE EXCRETION IN FECES
TENELIGLIPTIN 45.4 % 46.5%
LINAGLIPTIN 5% 85%
SAXAGLIPTIN 65% 22%
SITAGLIPTIN,
VILDAGLIPTIN,
ALOGLIPTIN
76-87% 13-15%
Balanced excretion from kidney and liver
HIGHEST RENAL AND HEPATIC SAFETY AMONG THE GROUP

31. TENELIGLIPTIN ADVANTAGES
5. NO DOSAGE ADJUSTMENT IN RENAL & HEPATIC
IMPAIRMENT
RENALHEPATIC

32. PHARMACOKINETICS
PARAMETER TENELIGLIPTIN
ABSORPTION 74% absorption*
METABOLISM Hepatic metabolism via CYP3A4, CYP2D6
EXCRETION 45 % renal , 46% feces
T max 1 - 1.33 hour
HALF-LIFE 24.2 hour
DOSAGE RANGE 20 mg – 40 mg

33. Kadowaki T. et
al.
Diabetes, Obesity and Metabolism15: 810 – 818, 2013
AIM To assess the efficacy, safety and dose–response relationship of once-daily teneligliptin, a
novel dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus
(T2DM) inadequately controlled with diet and exercise
Patients 324
STUDY RESULT Treatment with teneligliptin for 12weeks provided significant and clinically meaningful
reductions in HbA1c and FPG across the dose range studied and was generally well
tolerated in Japanese patients with T2DM
INFERENCE
PARAMETER
HbA1C, FPG
CLINICAL
TRIAL 1

34. Teneligliptin Administration with different dosage
administration provide decrease in HbA1C & FPG level over
12 weeks of therapy.

35. R. Ito et al. Drugs R D
AIM Teneligliptin, a Dipeptidyl Peptidase-4 Inhibitor, Improves Early-Phase Insulin Secretion in
Drug-Naive Patients with Type 2 Diabetes
Patients 13
STUDY RESULT Twelve weeks of teneligliptin treatment improved IGI30min, AUC120min,SUIT index
INFERENCE
PARAMETER
HbA1C, PPG, POST PRANDIAL INSULIN RELEASE
CLINICAL
TRIAL 2

36.  IGI30 min Index (Insulinogenic Index)
It is determined by following formula [30-min
Insulin – 0 min Insulin] / [30-min Glucose – 0
min Glucose]
Secretion of Insulin upon Glucose ingestion
 AUC 120 min
It is the Area Under the Curve for insulin
secretion.
 SUIT index
Secretory Units of Islets in Transplantation
index
SUIT Index = [C – peptide (ng/mL) x 1500/{PG
(mg/dL) – 61.7}]
Parameters BASELINE
POST –
Treatment
IGI 30 min 0.16 0.28
AUC 120min 2692 3537

37. Teneligliptin Administration provide better postprandial
glucose control and help in postprandial insulin requirement

38. Eto T. et al. Diabetes, Obesity and Metabolism14: 1040 – 1046, 2012
AIM To assess blood glucose control over 24h and the safety of teneligliptin 10 and 20mg, a
novel dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus
inadequately controlled with diet and exercise
Patients 99
STUDY
RESULT
Once-daily teneligliptin improved blood glucose levels over 24h without hypoglycaemia
INFERENCE
PARAMETER
24 – Hr Glycemic Control
CLINICAL
TRIAL 3

39. Teneligliptin Administration Help To Achieve 24-h Glycemic
Control

40. Tsuchimochi W.
et al.
Endocrine Journal2015, 62 (1), 13-20
AIM The aim of this study was to evaluate the effects of teneligliptin on 24 h blood glucose
control and gastrointestinal hormone responses to a meal tolerance test, and to
investigate the glucose-lowering mechanisms of teneligliptin.
Patients 10
STUDY RESULT 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
INFERENCE
PARAMETER
POST PRANDIAL GLUCAGON , GLP – 1 RELEASE
CLINICAL
TRIAL 4

41. Teneligliptin Administration provides better postprandial
Glucagon reduction and also increase Active GLP – 1 level.

42. Kadowaki T. et
al.
Diabetes, Obesity and Metabolism16: 418 – 425, 2014.
AIM To assess the efficacy and safety of teneligliptin in combination with glimepiride in
Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with
glimepiride monotherapy
Patients 194
STUDY RESULT The addition of teneligliptin was effective and generally well tolerated in Japanese patients
with T2DM inadequately controlled with glimepiride monotherapy. The improvements in
glycaemic control were maintained for up to 52weeks
INFERENCE
PARAMETER
HbA1C IMPROVEMENT IN COMBINATION WITH GLIMEPIRIDE
CLINICAL
TRIAL 5

43. Glimepiride + Teneligliptin combination therapy provide
better reduction in HbA1C level then Glimepiride
monotherapy alone

44. Cha B. Y. et. al. Diabetes, Obesity andMetabolism17: 309–312, 2015
AIM To assess the efficacy and safety of teneligliptin in combination with metformin in Korean
patients with type 2 diabetes mellitus who were inadequately controlled with metformin
monotherapy.
Patients 204
STUDY RESULT Addition of teneligliptin once daily to metformin was effective and generally well
tolerated in Korean patients with type 2 diabetes
INFERENCE
PARAMETER
HbA1C IMPROVEMENT IN COMBINATION WITH METFORMIN
CLINICAL
TRIAL 6

45. Metformin + Teneligliptin combination therapy provide
better reduction in HbA1C level & FPG level then Metformin
monotherapy alone

46. “Teneligliptin 20 mg Once daily was considered to be
more potent than Voglibose 0.2 mg t.i.d. or
Vildagliptin 50 mg qd.”
“No case with
Hypoglycemia was
identified.”
CLINICAL
TRIAL 7

47. CLINICAL STUDIES
SR. NO. SUMMARY OF CLINICAL STUDIES
1
Teneligliptin administration with different dosage administration provide DECREASE IN
HbA1C & FPG LEVEL over 12 weeks of therapy
2
Teneligliptin administration provide better POSTPRANDIAL GLUCOSE CONTROL and help
in POSTPRANDIAL INSULIN REQUIREMENT
3 Teneligliptin administration help to achieve 24-h GLYCEMIC CONTROL
4
Teneligliptin administration provides better POSTPRANDIAL GLUCAGON REDUCTION and
also INCREASE ACTIVE GLP – 1 AND GIP LEVEL
5
GLIMEPIRIDE + TENELIGLIPTIN COMBINATION therapy provide better reduction in HbA1C
level then Glimepiride monotherapy alone
6
METFORMIN + TENELIGLIPTIN COMBINATION therapy provide better reduction in HbA1C
level & FPG level then Metformin monotherapy alone
7
TENELIGLIPTIN 20 mg Once daily was considered to be more potent than VOGLIBOSE 0.2
mg t.i.d. or Vildagliptin 50 mg qd.

48. Safety and Adverse Event
• LEAST CHANCE OF HYPOGLYCEMIA (NO ADVERSE EVENT OF
HYPOGLYCEMIA OBSERVED)
• There is no significant adverse event reported for the Teneligliptin except
of some cases of Nausea, eczema and constipation.
SPECIAL POPULATION
• PREGNANCY & LACTATION : It is not recommended to be used in
Pregnancy and Lactation unless the risk to benefit ratio is in favor.
• ELDERLY : Safe to be taken (with Hepatic and Renal impairment cases)
• CHILDREN : Not recommended below 12 years children

49. Indications
Patient with TYPE 2
Diabetes Mellitus
Combination
Therapy with
Biguanide
Combination
Therapy with
Sulfonylurea
Combination with
Thiazolidine dione &
Insulin
Early Diagnosis
Diet & Exercise As
therapy alone
When uncontrolled
combined with other
agents as below

50. DOSAGE CHART
DOSAGE TENELIGLIPTIN
CONTENT 20 mg Teneligliptin
RECOMMENDED DOSE 20 mg per day
MAXIMUM DOSE 40 mg
DIRECTION FOR USE
Preferably before breakfast
(Independent of FOOD intake)
DOSE ADJUSTMENT ON RENAL
IMPAIRMENT
Not needed

51. ADA – American Diabetes Association ; EASD - European Association for the Study of Diabetes;
T2DM – Type 2 diabetes mellitus; HbA1c – Glycosylated hemoglobin
Algorithmic summary of 2014 ADA-EASD policy statement recommendations for the
management of hyperglycaemia in T2DM