sitagliptin
TRANSCRIPT
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TREATMENT OF DIABETES
- WHAT IS NEW ?
TREATMENT OF DIABETES
- WHAT IS NEW ?
Jitendra PatilM.Pharm (Pharmacology)
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Prevalence
Diabetes Care.2004;27(5):1047-1053Drug Review.2008;10(2):97-982
• 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.
• As per WHO total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030.
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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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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 editionNature Reviews.2007;6:109-110
Pharmacology & Therapeutics.2010:125;328–3614
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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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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):55Pharmacology & Therapeutics.2010:125;328–361
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Dipeptidyl Peptidase 4 (DPP-4) Inactivates GLP-1
Mixed meal
Intestinal GLP-1release
Rapid inactivation
Excreted by kidneys
GLP-1 Active
DPP-4
GLP-1 Actions
GLP-1 Inactive
Diabetes.1995;44:1126Clinical Therapeutics.2006;28(1):55
Pharmacology & Therapeutics.2010:125;328–361
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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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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.
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SITAGLIPTIN
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Mechanism of action (MOA)
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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):97-9810
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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):97-98Consultant.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.
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• 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
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Sitagliptin and Blood Pressure
J Clin Pharmacol. 2008 May;48(5):592Tohoku.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.
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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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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 over 12 week in type 2 diabetes patients.
Significantly reduced HbA1c
Significant lowered side effects
Significantly reduced fasting and postprandial plasma glucose
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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.
Drug Review.2008;10(2):97-9816
• No significant change in body weight was reported.
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• The recommended dose of Sitagliptin is 100 mg once daily. It may be taken with or without food.
Recommended Dosage
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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):97-9818
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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.
19Drug Review.2008;10(2):97-98
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• 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
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Marketed Brands
Januvia (Sitagliptin)
Janumet (Sitagliptin and Metformin)
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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
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THANK YOUTHANK YOU