Sitagliptin

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Sitagliptin

  1. 1. TREATMENT OF DIABETES - WHAT IS NEW ? Jitendra Patil M.Pharm (Pharmacology) 1
  2. 2. Prevalence• As per WHO total number of people with diabetes is projected torise from 171 million in 2000 to 366 million in 2030.• India is considered to be the diabetes capital of world, withlargest population of diabetic patients, approximately 50.8 millionas per International Diabetes Federation (IDF) in year 2010. Diabetes Care.2004;27(5):1047-1053 2 Drug Review.2008;10(2):97-98
  3. 3. Choice of agents in current usea) Sulfonylureasb) Insulinc) Thiazolidindiones (TZDs)d) Biguanidese) α- Glucosidase inhibitorsf) Meglitinides 3
  4. 4. All Current Treatments for Type 2 Diabetes Have Limitations Sulfonyl- Insulin Meglitinides Metformin Acarbose Thiazolidi- ureas nedionesHypoglycemia √ √ √ Weigh gain √ √ √ √GI side effects √ √Lactic acidosis √Homocystein √ Edema √ Inability to √ √ √ achievenormoglycemiaFluid Retention √ Tripathi.2005 5th edition Nature Reviews.2007;6:109-110 Pharmacology & Therapeutics.2010:125;328–361 4
  5. 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 5
  6. 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 6
  7. 7. Dipeptidyl Peptidase 4 (DPP-4) Inactivates GLP-1 Mixed meal GLP-1Intestinal 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. 8. Newer Therapies GLP-1 analogs: Exenatide Dipeptidyl Peptidase-4 (DPP 4) inhibitors: Sitagliptin, Saxagliptin, Vildagliptin Pharmacology & Therapeutics.2010:125;328–361 8
  9. 9. SITAGLIPTINMechanism of action (MOA)• Sitagliptin is selective inhibitor of the enzyme DPP-4.• Reduces hemoglobin A1c (HbA1c), fasting and postprandialglucose by glucose dependant stimulation of insulin secretionand inhibition of glucagon secretion.• Delays gastric emptying and reduce appetite. Drug Review.2008;10(2):97-98 9 9
  10. 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 10
  11. 11. CLINICAL EVIDENCE• In very well controlled randomized clinical trials Sitagliptin(100 mg) treatment significantly improved glycemic controlby • 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 andProinsulin-to-insulin ratio.• Monotherapy with Sitagliptin 100 mg daily decreases meanHbA1c by 0.6-0.98%. Drug Review.2008;10(2):97-98 Consultant.2009:S5-11 11 Pharmacology & Therapeutics.2010;25:328-361
  12. 12. Efficacy & Safety of Sitagliptin in Indian T2D patients• Sitagliptin (100 mg) monotherapy for 18 weeks significantlyimproved glycemic control by reducing HbA1c, fasting andpostprandial glucose in Indian type 2 diabetic (T2D) patients .• Sitagliptin was well tolerated and no hypoglycemiareported. Diabetes Research and Clinical Practice.2009;83:106-116 12
  13. 13. Sitagliptin and Blood Pressure• Sitagliptin treatment significantly reduced blood pressure andwas well tolerated in type 2 diabetic and non-diabetichypertensive patients. J Clin Pharmacol. 2008 May;48(5):592 13 Tohoku.J.Exp.Med.2011;223:133-135
  14. 14. Sitagliptin and Inflammatory Markers• Sitagliptin (100 mg) treatment for 3 months decreasedinflammatory markers C-reactive protein (CRP), Interleukin-6(IL-6), Myeloperoxidase (MPO), Monocyte chemotacticprotein-1 (MCP-1) in type 2 diabetic patients withatherosclerosis.• Changes in markers levels correlated with the improvementof glycemic control as shown by Hb A1c. Journal of Clinical Lipidology.2008;2(5S):S137-138 14
  15. 15. Sitagliptin Vs Voglibose• In comparative, randomized clinical trial, once dailySitagliptin monotherapy showed greater efficacy andbetter tolerability than thrice daily Voglibose over 12 week intype 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 15
  16. 16. Side Effects• In clinical trials, Sitagliptin demonstrated an overall incidenceof side effects comparable to placebo.• Upper respiratory tract infection, stuffy or running nose, sorethroat, headache and diarrhea was reported with Sitagliptin.• No significant change in body weight was reported.• The incidence of Hypoglycemia with Sitagliptin monotherapywas not Significantly different than placebo. Drug Review.2008;10(2):97-98 16
  17. 17. Recommended Dosage• The recommended dose of Sitagliptin is 100 mg oncedaily. It may be taken with or without food. 17
  18. 18. Drug Interaction• Sitagliptin plasma concentration may be increased modest(approximately 68%) with Cyclosporine which is notexpected 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 lowerblood sugar, such as: Probencid, NSAIDs, Aspirin, Sulfadrugs, MAO inhibitors or Beta blockers. Drug Review.2008;10(2):97-98 18
  19. 19. Contraindications• Sitagliptin is a pregnancy category B drug.• Dosage adjustments are needed in patients with moderateor 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 19
  20. 20. Regulatory Affairs• In October 2006, the U.S. Food and Drug Administration(FDA) approved Sitagliptin as monotherapy and as add-ontherapy to either of two other types of oral diabetesmedications.• In March, 2007 it was approved in European Union.• In April, 2007 FDA approved the combination product ofSitagliptin and Metformin for type 2 diabetes.• Sitagliptin is currently approved in 70 Countries. 20
  21. 21. Marketed Brands Januvia (Sitagliptin) Janumet (Sitagliptin and Metformin) 21
  22. 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 22
  23. 23. THANK YOU 23

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