1. Managing Type 2 Diabetes: Review of Recent Guidelines Gina Ryan, Pharm.D., BCPS, CDE Clinical Associate Professor Mercer University College of Pharmacy and Health Sciences

2. Program Disclosures This program has not been supported by any commercial interest. Gina Ryan has received a continuing educational grant from Ortho McNeil.

3. Educational Objecives At the completion of this activity, the participant should be able to: Describe the agents that are recommended by the American Diabetes Association (ADA); Describe the mechanism of action of the most commonly used diabetes drugs; List the most common side effects observed with diabetes drugs; Describe the appropriate rationale for using second- tier diabetes drugs; and Provide quality patient counseling on commonly used diabetes drugs.

4. Poll Question Your primary practice setting is a.Retail/community pharmacy b.Hospital pharmacy c.Long-term pharmacy d.Other

5. Two Problems = Two Targets Type 2 Diabetes Insulin Resistance  DEMAND Impaired Insulin Secretion  SUPPLY IGT Increases insulin supply Sulfonylureas Incretin Mimetics Insulin Glinides Decreases insulin demand Metformin Glitazone Incretin Mimetics α-glucosidase inhibitor Lifestyle modification

6. Antihyperglycemic Therapy Insulin demand Diet and Exercise Metformin Pioglitazone (TZD) Incretin Mimetics GLP-1 agonists DPP4 inhibitors Pramlintide Alpha glucosidase inhibitors Insulin supply Sulfonylureas Insulins Incretin mimetics GLP-1 agonists DPP4 inhibitors Glinides In ADA Algorithm

7. ADA Glycemic Goals A1C<7.0% Preprandial BG– 70-130 mg/dL 1-2 hr post prandial BG<180 mg/dL

8. Management of Type 2 Diabetes ADA Consensus Statement Nathan et al. Diabetes Care 2009: 32;1-11 FBG 250 use insulin

9. Metformin BrandGenericDosing Glucophage ® metformin500 - 1000 mg BID (max 2550 mg/day) Glucophage XR ® metformin1000-2000 mg QAM

10. Metformin Decreases Insulin Demand Decreases the hepatic production of glucose Increases insulin sensitivity Reduces glucose absorption in GI tract

11. Metformin Advantages Well established Weight loss No hypoglycemia (as monotherapy) Decreases lipid levels (LDL & TG) QD dosing with ER Inexpensive Disadvantages GI upset (often transient) Lactic acidosis Long list of contraindications

12. Metformin Efficacy Lowers FBG by 60 to 70 mg/dL Lowers A1c by 1.5 % Benefits seen after first 2 - 3 weeks

13. Metformin Patient Counseling Take with food May cause GI upset Might cause weight loss May take 2-3 weeks for full effect to be observed Report extreme fatigue to prescriber

14. Management of Type 2 Diabetes ADA Consensus Statement Nathan et al. Diabetes Care 2009: 32;1-11 FBG 250 use insulin

15. Sulfonylureas BrandGenericDosing First generation Diabinese ® chlorpropamide 100 - 500 mg QD Orinase ® tolbutamide250 - 3000 mg BID Tolinase ® tolazamide100 - 750 mg QD - BID Second generation Glucotrol ® glipizide2.5 - 20 mg QD - BID Glucotrol XL ® glipizide5 - 20 mg QD DiaBeta ® glyburide1.25 - 20 mg QD Micronase ® glyburide1.25 - 12 mg QD Third generation Amaryl ® glimepiride 1 - 8 mg QD

16. Sulfonylureas Increases Insulin Supply ▫basal and glucose-stimulated pancreatic insulin secretion “pancreas”

17. Advantages Disadvantages Well established Improves fasting and postprandial glucose Once-daily dosing Inexpensive ▫Hypoglycemia ▫Weight gain ▫Beta-cell burn out Sulfonylureas

18. Poll Question How much weight gain is typically observed with sulfonylurea therapy? a.2-3 lbs b.5-15 lbs c.16-25 lbs d.>25 lbs

19. Sulfonylureas Efficacy Lowers fasting blood glucose (FBG) by 60-70 mg/dL Lowers A1c by 1.5 - 2.0 % Benefit seen after first 2 weeks

20. Sulfonlyureas Patient Education Don’t skip meals Review signs and symptoms of hypoglycemia Warn of importance of weight management Review treatment of hypoglycemia

21. Poll Question Which of the following is a sign or symptom of hypoglycemia? a. Tremor b. Thirst c. Polyuria d. Decreased heart rate

22. Management of Type 2 Diabetes ADA Consensus Statement Nathan et al. Diabetes Care 2009: 32;1-11 FBG 250 use insulin

23. Poll Question Which of the following agents can be used for basal insulin? a.NPH b.Regular c.Lispro d.Aspart

24. Basal Insulins NPH, determir, & glargine

25. Intensive Insulin TID & HS Conventional Insulin BID

26. Insulin Advantages Disadvantages Maximum effect on BG Relatively inexpensive Preserves beta-cell function?? Well studied Weight gain Hypoglycemia Poor patient acceptance

27. Management of Type 2 Diabetes ADA Consensus Statement Nathan et al. Diabetes Care 2009: 32;1-11 FBG 250 use insulin

28. Thiazolidinediones (TZD or Glitazones) BrandGenericDosing Actos ® pioglitazone15 - 45 mg QD Avandia ® rosiglitazone2 - 8 mg QD - BID

29. Poll Question Rosiglitazone is not in the ADA algorithm because it a.Increases the risk of liver failure b.Increases blood pressure c.Increases the risk of heart attacks d.It’s not effective

30. Thiazolidinediones (TZD or Glitazones) Decreases Insulin Demand ▫Improves peripheral insulin sensitivity Instestine:glucose abs Blood glucose Pancreas:insulin secretion TZD

31. Thiazolidinediones (TZD or Glitazones) Advantages Disadvantages No hypoglycemia as monotherapy Improves insulin resistance Decreases TG levels Possibly preserves beta cell function QD to BID dosing Weight gain Edema Slow onset of action Expensive

32. Thiazolidinediones (TZD or Glitazones) Efficacy: ▫Lowers FBG by 30 to 60 mg/dL ▫Lowers A1c by 1.5 % ▫3-4 month onset

33. Thiazolidinediones (TZD or Glitazones) Patient Education ▫May cause edema ▫May cause weight gain ▫Takes 3-4 months for full

34. Management of Type 2 Diabetes ADA Consensus Statement Nathan et al. Diabetes Care 2009: 32;1-11 FBG 250 use insulin

35. Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498. The Incretin Effect 0 50 100 150 200 -300306090120150180210 Time (min) Glucose (mg/dL) Insulin (pmol/L) 0 100 200 300 400 -300306090120150180210 Time (min) Oral IV Incretin Effect Insulin Secretion Is Greater in Response to Oral vs IV Glucose

36. α Cells: ↓ Postprandial glucagon secretion GLP-1 Effects Promotes satiety and reduces appetite β Cells: Enhances glucose- dependent insulin secretion Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520. Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422. Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553. Adapted from Drucker DJ. Diabetes. 1998;47:159-169. Liver: ↓ Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying ↑ β-cell response ↓ β-cell workload

37. GLP-1 Agonists Agents Exenatide (Byetta ® ) 10 mcg sq bid Liraglutide (Victoza ® ) 0.6-1.8 mcg sq qday Decreases Insulin Demand and Increases Supply Glucagon-like peptide-1 analog Decreases postprandial glucagon release Slows GI emptying Increases satiety Increase first-phase insulin secretion

38. GLP-1 Agonists Advantages Disadvantages Weight loss Decreases postprandial BG Preserves beta-cell function?? Nausea Not for monotherapy $$$ Subcutaneous Requires temperature controlled storage

39. GLP-1 Agonists Clinical Utility FBG – ↓ 63 mg/dl 2h Post prandial – ↓ 71 mg/dl Exenatide - HbA1c ↓ 0.4- 0.8% Liraglutide - HbA1c ↓ 1-1.5%

40. GLP-1 Agonists Patient Education Warn of nausea Review sq administration technique Must be kept in temperature controlled environment ▫Exenatide <36- 77ºF ▫Liraglutide <36- 86ºF

41. Agents not included in ADA Consensus Statement

42. Dipeptidyl Peptidase (DPP) IV Inhibitor Agents:  Sitagliptin (Januvia ® ) 50-100 mg po qday  Saxaglipitn (Onglyza ® ) 2.5-5 mg po qday Decreases Insulin Demand and Increases Supply ▫DPP IV breaks down GLP-1  Decreases postprandial glucagon release  Slows GI emptying  Increases satiety  Increase first-phase insulin secretion

43. Dipeptidyl Peptidase (DPP) IV Inhibitor Advantages Disadvantages No weight gain Oral agent Minimal adverse effects A1c ↓ 0.5-0.8% Saxaglipitin – has more drug interactions than sitagliptin

44. Glinides Agents ▫nateglinide (Starlix ® ) 60-120 mg po tid ac ▫repaglinide (Prandin ® ) 0.4-4 mg po tid ac Increases insulin supply ▫Requires gluocose ▫Works 1-4 hours ▫Used for postprandial glucose control “pancreas”

45. Glinides Advantages Disadvantages Targets postprandial glycemia Less hypoglycemia/ weight gain than sulfonylureas Lowers A1c 1-1.5% TID dosing Hypoglycemia Weight gain Ineffective in patients previously not controlled on sulfonylurea

46. Alpha-Glucosidase Inhibitors Agents ▫acarbose (Precose ® ) ▫miglitol (Glyset ® ) Decreases insulin demand ▫Delays breakdown of complex carbohydrates into glucose. ▫Slower and smaller increase in BG after meal

47. Alpha-Glucosidase Inhibitors Advantages Disadvantages Targets postprandial glycemia No hypoglycemia Nonsystemic TID dosing Adverse GI side effects Lowers A1C 0.5%

48. Multihormonal Regulation of Glucose Brain Plasma Glucose GLP-1 Tissues: Muscle, Fat Glucose Disposal Rate of Glucose Appearance Rate of Glucose Disappearance ↓ Food Intake Gut + Satiety Glucagon Liver Glucose Production Insulin Pancreas Amylin Gastric Emptying Brain + Satiety Inhibits Stimulates Insulin Resistance Visceral Fat Increases Stomach

49. Pramlintide (Symlin ® ) Indications – adjunctive treatment with mealtime insulin diabetes Dose ▫Type 1 initial 15 mcg sq tid ac ▫Type 2 initial 60 mcg sq tid ac Decreases insulin demand ▫a synthetic amylin analog ▫ ↓ postprandial glucagon ▫ ↑ satiety ▫slows gastric emptying

50. Pramlintide (Symlin ® ) Advantages Disadvantages Lowers A1c by 0.5-1% Targets postprandial glucose Sq administration may limit utility Transient nausea Physically incompatible with insulin Requires refrigeration ▫36°F to 46°F

51. Questions