Sitagliptin

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

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)


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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

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


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Newer Therapies

GLP-1 analogs: Exenatide

Dipeptidyl Peptidase-4 (DPP 4) inhibitors: Sitagliptin, Saxagliptin, Vildagliptin


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)

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

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

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

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

Health & Medicine

Sitagliptin