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1. TREATMENT OF
DIABETES
- WHAT IS NEW ?
Sitagen 50mg,100mg / Sitagen-M 50/500mg
1

2. What is New in This Presentation
2
•Prevalence
•Oral Anti Diabetics Agent
•Management of Type 2 Diabetes
•ADA Guidelines 2014
•Strategies for Antidiabetic Treatment
•Master Decision Path For Type 2 Diabetes Glycemic Control
•Incretins – What are they?
•What Is DPP-4?
•Newer Therapies
•Sitagliptin MOA
•Clinical Evidence
•Summary of Sitagliptin

3. Prevalence
3
•In Pakistan 12.9 Million people with diabetes( 10% of total
population)
•Diagnosed: 9.4 million
•Undiagnosed: 3.5milliion
•Pre diabetes: 38 million people
10%
90%
Type 1 diabetes
Type 2 diabetes

4. 4
Choice of agents in current use
a) Sulfonylureas
b) Insulin
c) Thiazolidindiones (TZDs)
d) Biguanides
e) α- Glucosidase inhibitors
f) Meglitinides

5. All Current Treatments for Type 2 Diabetes
Have Limitations
Sulfonyl-
ureas
Insulin Meglitinides Metformin Acarbose Thiazolidi-
nediones
Hypoglycemia √ √ √
Weigh gain √ √ √ √
GI side effects √ √
Lactic acidosis √
Homocystein √
Edema √
Inability to
achieve
normoglycemia
√ √ √
Fluid Retention √
Tripathi.2005 5th edition
Nature Reviews.2007;6:109-110
Pharmacology & Therapeutics.2010:125;328–3615

6. No Single Class of Oral Antihyperglycemic
Monotherapy Targets All Key Pathophysiologies
Alpha-
Glucosidase
Inhibitors1,2
Meglitinide
s3 SUs4,5 TZDs6,7
Metformi
n8
DPP-4
Inhibitors
Insulin
deficiency
Insulin
resistance
Excess
hepatic
glucose
output
MajorPathophysiology's
1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.
3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.
5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.
7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
  
 
  
Intestinal
glucose
absorption


7. Basic Steps in the Management of Type 2 Diabetes
+ +
+

9. Strategies for Antidiabetic Treatment
Oral Triple Combination
Therapy plus Basal Insulin or
plus GLP-1-Mimeticum
Oral Monotherapy
Oral Dual Combination
Therapy
Oral Triple Combination
Therapy
NPG, Glargine, Levemir
Metformin + Sulfonylureas+DPP-4-
Inhib.
Metformin + Sulfonylureas + TZDs
Metformin
DPP-4 Inhibitors
Glinides
TZDs
Sulfonylureas
-Glucosidase-Inhibitors
Metformin + DPP-4-Inhibitors
Sulfonylureas + DPP-4-Inhibitors
Metformin + Sulfonylureas
Sulfonylureas + TZDs
Metformin + TZDs
Exenatide, Liraglutide

10. Master Decision Path
Type 2 Diabetes Glycemic Control
Medical Nutrition Therapy
& Activity Plan
start monotherapy
Oral combination treatment 2 drugs
If target not reached after maximum
dose for 4 - 8 weeks - - start oral agent
Insulin Therapy Oral Agent(s) + Insulin
Oral Combination Rx 3 drugs
If target not reached after maximum
doses for 4 - 8 weeks -- start insulin
FPG < 200
Casual < 250
FPG 200-300
Casual 250-350
FPG > 350
Casual > 400
At Diagnosis
(mg/dl)
Targets for
Glycemic Control
HbA1c <7%
FPG > 300-350
Casual > 350-400
with severe symptom
KK/ESSENTIAL
DRUG/3.4.11/tAUNGGHU

11. 11
Incretins – What are they?
Hormones produced by the gastrointestinal tract in response
to incoming nutrients, and have important actions
that contribute to glucose homeostasis.
Two hormones:
Gastric inhibitory polypeptide (GIP)
Glucagon-like peptide-1 (GLP-1).
INCRETIN= INtestinal+seCRETion of INsulin

12. 12
GLP-1: Effects in Humans
• Stimulate glucose dependant insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
• Reduces food intake
• Improves insulin sensitivity
Clinical Therapeutics.2006;28(1):55
Pharmacology & Therapeutics.2010:125;328–361

13. What Is DPP-4?
• A serine protease widely distributed throughout the
body
• Cleaves N-terminal amino acids of a number of
biologically
active peptides, including the incretins GLP-1 and
gastric inhibitory peptide (GIP), resulting in
inactivation
• Its effects on GLP-1 and GIP have been shown to affect
Incretins activity
• Inactivates GLP-1 >50% in ~1 to 2 minutes
Ahrën B. Curr Enzyme Inhib. 2005;1:65-73.

14. DPP-4

15. Inhibition of DPP-4 Increases ActiveGLP-1

16. GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal
GIP and
GLP-1
release
GIP and GLP-1
Actions
DPP-4
Enzyme
GIP-(1–42)
GLP-1(7–36)
Intact
GIP-(3–42)
GLP-1(9–36)
Metabolites
Rapid Inactivation
Half-life*
GLP-1 ~ 2 minutes
GIP ~ 5 minutes
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.

17. Food intake
Stomach
GI tract
Intestine
Increases and prolongs
GLP-1 effect on alpha-cells:
Alpha-cells
Pancreas
Insulin release
Net effect:
Blood glucose
Beta-cells
Increases and prolongs GLP-1
and GIP effects on beta-cells:
DPP-4 inhibitor
Glucagon secretion
Incretins
DPP-4
DPP-4 Inhibitors Enhance Incretin and
Insulin Secretion
Adapted from: Barnett A. Int J Clin Pract 2006;60:1454-70
Drucker DJ, Nauck MA. Nature 2006;368:1696-705
Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65

18. 18
Newer Therapies
 GLP-1 analogs:
Exenatide
 Dipeptidyl Peptidase-4 (DPP 4) inhibitors:
Sitagliptin, Saxagliptin, Vildagliptin
Pharmacology & Therapeutics.2010:125;328–361

19. 19
DPP4 inhibitors such as Sitagliptin Inhibit
the degradation of incretins and thus
Prolong the half life of Endogenous Incretins
Action of Sitagliptin is Glucose-Dependent
And Hence Hypoglycemia is Less Common

20. Drug Review.2008;10(2):97-98
• Reduces hemoglobin A1c (HbA1c), fasting and postprandial
glucose by glucose dependant stimulation of insulin secretion
and inhibition of glucagon secretion.
• Sitagliptin is selective inhibitor of the enzyme DPP-4.
• Delays gastric emptying and reduce appetite.
20
SITAGLIPTIN
20
Mechanism of action (MOA)

21. 21

22. Pharmacokinetics
 Bioavailability of Sitagliptin is approximately 87% .
 Half life is between 8-14 hours.
 It is 38% bound to plasma proteins.
 Elimination is mainly through urine.
Drug Review.2008;10(2):97-9822

23. 23
a) reducing both fasting and postprandial glucose
concentration,
b) clinically meaningful reductions in glycosylated
hemoglobin (HbA1c) levels in type 2 diabetic patients.
• Monotherapy with Sitagliptin 100 mg daily decreases mean
HbA1c by 0.6-0.98%.
CLINICAL EVIDENCE
Drug Review.2008;10(2):97-98
Consultant.2009:S5-11
Pharmacology & Therapeutics.2010;25:328-361
• In very well controlled randomized clinical trials Sitagliptin
(100 mg) treatment significantly improved glycemic control
by
• Improved Homeostasis model assessment of β cell and
Proinsulin-to-insulin ratio.

24. 24
• Sitagliptin (100 mg) monotherapy for 18 weeks significantly
improved glycemic control by reducing HbA1c, fasting and
postprandial glucose in Indian type 2 diabetic (T2D) patients .
Efficacy & Safety of Sitagliptin in Indian T2D patients
• Sitagliptin was well tolerated and no hypoglycemia
reported.
Diabetes Research and Clinical Practice.2009;83:106-116

25. 25
Sitagliptin and Blood Pressure
J Clin Pharmacol. 2008 May;48(5):592
Tohoku.J.Exp.Med.2011;223:133-135
• Sitagliptin treatment significantly reduced blood pressure
and was well tolerated in type 2 diabetic and non-diabetic
hypertensive patients.

26. 26
Sitagliptin and Inflammatory Markers
• Sitagliptin (100 mg) treatment for 3 months decreased
inflammatory markers C-reactive protein (CRP), Interleukin-6
(IL-6), Myeloperoxidase (MPO), Monocyte chemotactic
protein-1 (MCP-1) in type 2 diabetic patients with
atherosclerosis.
• Changes in markers levels correlated with the improvement
of glycemic control as shown by Hb A1c.
Journal of Clinical Lipidology.2008;2(5S):S137-138

27. 27
Sitagliptin Vs Voglibose
Diabetes Obese Metab.2010;12(7):613-22
• In comparative, randomized clinical trial, once daily
Sitagliptin monotherapy showed greater efficacy and
better tolerability than thrice daily Voglibose (alpha-
glucosidase inhibitor) over 12 week in type 2 diabetes patients.
 Significantly reduced HbA1c
 Significant lowered side effects
 Significantly reduced fasting and postprandial plasma glucose

28. 28

29. 29

30. Side Effects
• In clinical trials, Sitagliptin demonstrated an overall incidence
of side effects comparable to placebo.
• The incidence of Hypoglycemia with Sitagliptin monotherapy
was not Significantly different than placebo.
• Upper respiratory tract infection, stuffy or running nose, sore
throat, headache and diarrhea was reported with Sitagliptin
are rare.
Drug Review.2008;10(2):97-9830
• No significant change in body weight was reported.

31. 31
• The recommended dose of Sitagliptin is 100 mg once
daily. It may be taken with or without food.
•Maximum Dose 200mg/day
•If administered with sulfonylurea: a reduced dose of
sulfonylurea may be required.
Recommended Dosage

32. Drug Interaction
• Sitagliptin plasma concentration may be increased modest
(approximately 68%) with Cyclosporine which is not
expected to be clinically important.
• Digoxin plasma levels may be increased slightly
(approximately18%), no dosage adjustment is recommended.
• Care should be taken with drugs that can potentially lower
blood sugar, such as: Probencid, NSAIDs, Aspirin, Sulfa
drugs, MAO inhibitors or Beta blockers.
Drug Review.2008;10(2):97-9832

33. Contraindications
• Sitagliptin is a pregnancy category B drug.
• Sitagliptin is contraindicated in diabetic ketoacidosis.
 In severe renal function impairment (Ccr less than 30
mL/min) dose should be reduced to 25 mg once daily.
 In moderate renal function impairment (Ccr 30 to less
than 50mL/min) dose should be reduced to 50mg once daily.
• Dosage adjustments are needed in patients with moderate
or severe renal function impairment.
33Drug Review.2008;10(2):97-98

34. 34
• In October 2006, the U.S. Food and Drug Administration
(FDA) approved Sitagliptin as monotherapy and as add-on
therapy to either of two other types of oral diabetes
medications.
• In April, 2007 FDA approved the combination product of
Sitagliptin and Metformin for type 2 diabetes.
• In March, 2007 it was approved in European Union.
• Sitagliptin is currently approved in 70 Countries.
Regulatory Affairs

35. 35
Summary of Sitagliptin
 No clinically meaningful hypoglycemia
 Weight neutral
 DPP-4 Inhibitor
 Good tolerability
 Improves Blood pressure
 Stimulate insulin secretion
 Slows gastric emptying
 Reduces food intake
 Inhibit glucagon secretion
 Reduces HbA1c
 Improves inflammatory markers

36. 36