Teneligliptin

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 = IN testine se CRET ion IN sulin

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. 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 NH 2 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 t ½ =1–2 min DPP-4 inhibitor 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 TZDs Metformin Insulin Resistance (Impaired insulin action) DPP – 4 INHIBITOR

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

24. LIMITATIONS OF EXISTING GLIPTINS DPP – 4 INHIBITORS t 1/2 (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 LONGER DURATION OF ACTION DPP – 4 INHIBITORS t 1/2 (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 RENAL HEPATIC

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 IG I30min , AUC 120min ,SUIT index INFERENCE PARAMETER HbA1C, PPG, POST PRANDIAL INSULIN RELEASE CLINICAL TRIAL 2

36. IGI 30 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

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