The document provides an overview of diabetes treatment updates, focusing on the prevalence of diabetes in Pakistan and management strategies for type 2 diabetes. It highlights the role of Sitagliptin as a DPP-4 inhibitor, detailing its mechanism of action, benefits, and clinical findings, including its effect on glycemic control and tolerability. Additionally, it covers treatment combinations, the role of incretins, and therapeutic guidelines from the ADA.

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