This document discusses the treatment of diabetes with a focus on the drug Sitagliptin. It provides details on Sitagliptin's mechanism of action as an inhibitor of DPP-4, pharmacokinetics, clinical efficacy in reducing HbA1c and glucose levels, safety profile, recommended dosage, drug interactions, and regulatory approval history. Sitagliptin represents an effective newer treatment option for type 2 diabetes with a good tolerability profile.

1. TREATMENT OF DIABETES
- WHAT IS NEW ?
Jitendra Patil
M.Pharm (Pharmacology)
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2. Prevalence
• As per WHO total number of people with diabetes is projected to
rise from 171 million in 2000 to 366 million in 2030.
• India is considered to be the diabetes capital of world, with
largest population of diabetic patients, approximately 50.8 million
as per International Diabetes Federation (IDF) in year 2010.
Diabetes Care.2004;27(5):1047-1053
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Drug Review.2008;10(2):97-98

3. Choice of agents in current use
a) Sulfonylureas
b) Insulin
c) Thiazolidindiones (TZDs)
d) Biguanides
e) α- Glucosidase inhibitors
f) Meglitinides
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4. All Current Treatments for Type 2 Diabetes
Have Limitations
Sulfonyl- Insulin Meglitinides Metformin Acarbose Thiazolidi-
ureas 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;328–361 4

5. Incretins – What are they?
• Peptides produced by the intestine
• Released in response to meals
• Two major Incretins
 Glucagon like peptides (GLP-1)
 Glucose dependant insulinotropic peptide (GIP)
Pharmacology & Therapeutics.2010:125;328–361
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6. 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
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7. Dipeptidyl Peptidase 4 (DPP-4)
Inactivates GLP-1
Mixed meal
GLP-1
Intestinal Inactive
GLP-1
release
DPP-4
GLP-1 Rapid inactivation
Active
GLP-1 Actions Excreted by kidneys
Diabetes.1995;44:1126
Clinical Therapeutics.2006;28(1):55
Pharmacology & Therapeutics.2010:125;328–361

8. Newer Therapies
 GLP-1 analogs:
Exenatide
 Dipeptidyl Peptidase-4 (DPP 4) inhibitors:
Sitagliptin, Saxagliptin, Vildagliptin
Pharmacology & Therapeutics.2010:125;328–361
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9. SITAGLIPTIN
Mechanism of action (MOA)
• Sitagliptin is selective inhibitor of the enzyme DPP-4.
• Reduces hemoglobin A1c (HbA1c), fasting and postprandial
glucose by glucose dependant stimulation of insulin secretion
and inhibition of glucagon secretion.
• Delays gastric emptying and reduce appetite.
Drug Review.2008;10(2):97-98
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10. 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):97-98
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11. CLINICAL EVIDENCE
• In very well controlled randomized clinical trials Sitagliptin
(100 mg) treatment significantly improved glycemic control
by
• reducing both fasting and postprandial glucose
concentration,
• clinically meaningful reductions in glycosylated
hemoglobin (HbA1c) levels in type 2 diabetic patients.
• Improved Homeostasis model assessment of β cell and
Proinsulin-to-insulin ratio.
• Monotherapy with Sitagliptin 100 mg daily decreases mean
HbA1c by 0.6-0.98%.
Drug Review.2008;10(2):97-98
Consultant.2009:S5-11
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Pharmacology & Therapeutics.2010;25:328-361

12. Efficacy & Safety of Sitagliptin in Indian T2D patients
• 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 .
• Sitagliptin was well tolerated and no hypoglycemia
reported.
Diabetes Research and Clinical Practice.2009;83:106-116
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13. Sitagliptin and Blood Pressure
• Sitagliptin treatment significantly reduced blood pressure and
was well tolerated in type 2 diabetic and non-diabetic
hypertensive patients.
J Clin Pharmacol. 2008 May;48(5):592
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Tohoku.J.Exp.Med.2011;223:133-135

14. 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
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15. Sitagliptin Vs Voglibose
• In comparative, randomized clinical trial, once daily
Sitagliptin monotherapy showed greater efficacy and
better tolerability than thrice daily Voglibose over 12 week in
type 2 diabetes patients.
 Significantly reduced HbA1c
 Significantly reduced fasting and postprandial plasma glucose
 Significant lowered side effects
Diabetes Obese Metab.2010;12(7):613-22
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16. Side Effects
• In clinical trials, Sitagliptin demonstrated an overall incidence
of side effects comparable to placebo.
• Upper respiratory tract infection, stuffy or running nose, sore
throat, headache and diarrhea was reported with Sitagliptin.
• No significant change in body weight was reported.
• The incidence of Hypoglycemia with Sitagliptin monotherapy
was not Significantly different than placebo.
Drug Review.2008;10(2):97-98
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17. Recommended Dosage
• The recommended dose of Sitagliptin is 100 mg once
daily. It may be taken with or without food.
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18. 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):97-98
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19. Contraindications
• Sitagliptin is a pregnancy category B drug.
• Dosage adjustments are needed in patients with moderate
or severe renal function impairment.
 In moderate renal function impairment (Ccr 30 to less
than 50mL/min) dose should be reduced to 50mg once
daily. severe renal function impairment (Ccr less than 30
 In
mL/min) dose should be reduced to 25 mg once daily.
• Sitagliptin is contraindicated in diabetic ketoacidosis.
Drug Review.2008;10(2):97-98
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20. Regulatory Affairs
• 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 March, 2007 it was approved in European Union.
• In April, 2007 FDA approved the combination product of
Sitagliptin and Metformin for type 2 diabetes.
• Sitagliptin is currently approved in 70 Countries.
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21. Marketed Brands
 Januvia (Sitagliptin)
 Janumet (Sitagliptin and Metformin)
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22. Summary of Sitagliptin
 DPP-4 Inhibitor  No clinically meaningful hypoglycemia
 Reduces HbA1c  Weight neutral
 Stimulate insulin secretion  Good tolerability
 Inhibit glucagon secretion
 Slows gastric emptying
 Reduces food intake
 Improves Blood pressure
 Improves inflammatory markers
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23. THANK YOU
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