Sitagliptin 2015


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Sitagliptin 2015

  1. 1. TREATMENT OF DIABETES - WHAT IS NEW ? Sitagen 50mg,100mg / Sitagen-M 50/500mg 1
  2. 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. 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. 4 Choice of agents in current use a) Sulfonylureas b) Insulin c) Thiazolidindiones (TZDs) d) Biguanides e) α- Glucosidase inhibitors f) Meglitinides
  5. 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. 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. 7. Basic Steps in the Management of Type 2 Diabetes + + +
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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.
  13. 13. DPP-4
  14. 14. Inhibition of DPP-4 Increases ActiveGLP-1
  15. 15. 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.
  16. 16. 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
  17. 17. 18 Newer Therapies  GLP-1 analogs: Exenatide  Dipeptidyl Peptidase-4 (DPP 4) inhibitors: Sitagliptin, Saxagliptin, Vildagliptin Pharmacology & Therapeutics.2010:125;328–361
  18. 18. 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
  19. 19. 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)
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  21. 21. 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
  22. 22. 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.
  23. 23. 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
  24. 24. 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.
  25. 25. 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
  26. 26. 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
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  29. 29. 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.
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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
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