Sitagliptin 2014

TREATMENT OF DIABETES

- WHAT IS NEW ?

TREATMENT OF DIABETES

- WHAT IS NEW ?

Sitagen 50mg,100mg / Sitagen-M 50/500mg

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What is New in This Presentation

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•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 Master Decision Path For Type 2 Diabetes Glycemic ControlControl•Incretins – What are they?•What Is DPP-4?•Newer Therapies•Sitagliptin MOA•Clinical Evidence•Summary of Sitagliptin

Prevalence

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•In Pakistan 12.9 Million people with diabetes( 10% of total population)•Diagnosed: 9.4 million•Undiagnosed: 3.5milliion•Pre diabetes: 38 million people

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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;328–3615

No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies

Alpha-Alpha-Glucosidase Glucosidase InhibitorsInhibitors1,21,2

MeglitinideMeglitinidess33 SUsSUs4,54,5 TZDsTZDs6,76,7

MetformiMetforminn88

DPP-4 DPP-4 InhibitorsInhibitors

Insulin deficiency

Insulin resistance Excess hepatic glucose outputM

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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

Basic Steps in the Management of Type 2 DiabetesBasic Steps in the Management of Type 2 Diabetes

+ +

diet &exercise

Oral monotherapy

insulin

+

Oralcombination

Oral plus

Insulin/Triple Therapy

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

MetforminDPP-4 Inhibitors

GlinidesTZDs

Sulfonylureas

-Glucosidase-Inhibitors

Metformin + DPP-4-Inhibitors

Sulfonylureas + DPP-4-Inhibitors

Metformin + SulfonylureasSulfonylureas + TZDsMetformin + TZDs

Exenatide, Liraglutide

Master Decision Path Master Decision Path Type 2 Diabetes Glycemic ControlType 2 Diabetes Glycemic Control

Medical Nutrition TherapyMedical Nutrition Therapy&& Activity Plan Activity Plan start monotherapystart monotherapy

Medical Nutrition TherapyMedical Nutrition Therapy&& Activity Plan Activity Plan start monotherapystart monotherapy

Oral combination treatment 2 drugsOral combination treatment 2 drugsIf target not reached after maximumIf target not reached after maximum

dose for 4 - 8 weeks - - start oral agentdose for 4 - 8 weeks - - start oral agent

Oral combination treatment 2 drugsOral combination treatment 2 drugsIf target not reached after maximumIf target not reached after maximum

dose for 4 - 8 weeks - - start oral agentdose for 4 - 8 weeks - - start oral agent

Insulin TherapyInsulin TherapyInsulin TherapyInsulin Therapy Oral Agent(s) + InsulinOral Agent(s) + InsulinOral Agent(s) + InsulinOral Agent(s) + Insulin

Oral Combination Rx 3 drugsOral Combination Rx 3 drugsIf target not reached after maximum If target not reached after maximum doses for 4 - 8 weeks -- start insulindoses for 4 - 8 weeks -- start insulin

Oral Combination Rx 3 drugsOral Combination Rx 3 drugsIf target not reached after maximum If target not reached after maximum doses for 4 - 8 weeks -- start insulindoses for 4 - 8 weeks -- start insulin

FPG < 200FPG < 200Casual < 250Casual < 250

FPG < 200FPG < 200Casual < 250Casual < 250

FPG 200-300FPG 200-300Casual 250-350Casual 250-350

FPG 200-300FPG 200-300Casual 250-350Casual 250-350

FPG > 350FPG > 350Casual > 400Casual > 400

FPG > 350FPG > 350Casual > 400Casual > 400

At Diagnosis(mg/dl)

Targets for Targets for Glycemic ControlGlycemic Control

HbA1c <7%HbA1c <7%

Targets for Targets for Glycemic ControlGlycemic Control

HbA1c <7%HbA1c <7%

FPG > 300-350FPG > 300-350Casual > 350-400Casual > 350-400

with severe symptomwith severe symptom

FPG > 300-350FPG > 300-350Casual > 350-400Casual > 350-400

with severe symptomwith severe symptom

KK/ESSENTIAL DRUG/3.4.11/tAUNGGHU

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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

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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

What Is DPP-4?• A serine protease widely distributed throughout the body

• Cleaves N-terminal amino acids of a number of biologicallyactive 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.

DPP-4

Inhibition of DPP-4 Increases Active GLP-1

GLP-1 and GIP Are Degraded by the DPP-4 EnzymeGLP-1 and GIP Are Degraded by the DPP-4 Enzyme

MealMeal

Intestinal Intestinal GIP and GIP and GLP-1 GLP-1 releaserelease

GIP and GLP-1 GIP and GLP-1 ActionsActions

DPP-4DPP-4EnzymeEnzyme

GIP-(1–42)GIP-(1–42)GLP-1(7–36)GLP-1(7–36)

IntactIntact

GIP-(3–42)GIP-(3–42)GLP-1(9–36)GLP-1(9–36)MetabolitesMetabolites

Rapid InactivationRapid Inactivation

Half-life*Half-life*GLP-1 ~ 2 minutesGLP-1 ~ 2 minutes

GIP ~ 5 minutesGIP ~ 5 minutes

Deacon CF et al. Deacon CF et al. DiabetesDiabetes. 1995;44:1126–1131.. 1995;44:1126–1131.*Meier JJ et al. *Meier JJ et al. DiabetesDiabetes. 2004;53:654–662.. 2004;53:654–662.

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;368:1696-705Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65

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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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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

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):97-9822

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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 (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

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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 are rare.

Drug Review.2008;10(2):97-9830

• 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.

•Maximum Dose 200mg/day

•If administered with sulfonylurea: a reduced dose of sulfonylurea may be required.

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):97-9832

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

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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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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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