Oral Hypoglycemic Agents

2. Oral Hypoglycemic Agents H.Rezvanian.MD

3. Objectives List oral hypoglycemic agents currently on the market Classify oral hypoglycemic agents based on their mechanism, onset, duration, and place in therapy Describe pros and cons of the different oral hypoglycemic agents available Summarize limitations and contraindications of oral hypoglycemic agents

4. Classification and Diagnosis

5. Diagnostic Criteria Note: In the absence of unequivocal hyperglycemia, result(s) should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.

6. Prevention, Prevention, Prevention! ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16 • Refer patients with IGT, IFG, or A1C 5.7–6.4% to ongoing support program • Target weight loss = 7% of total body weight • Minimum of 150 min/week of moderate physical activity • Follow-up counseling important for success • Based on cost-effectiveness of diabetes prevention, third-party payers should cover such programs • In those with pre-diabetes, monitor for development of diabetes annually

7. Prevention, Prevention, Prevention! ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16 • Medications shown to delay progression of IGT/IFG to T2DM • Metformin (US DPP, NEJM 2002) • Acarbose (STOP-NIDDM, Lancet 2002) • Pioglitazone (ACT NOW, presentation 2008) • Consider metformin for prevention of type 2 diabetes if IGT, IFG, or A1C 5.7–6.4% • Especially for those with BMI >35 kg/m2, age <60 years, and women with prior GDM • None are FDA approved for Diabetes Prevention

8. A1c Monitoring ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18. Twice Yearly in those who have stable glycemic control and no therapy changes Quarterly in patients whose therapy has changed or who are not meeting glycemic goals

9. A1C Correlation ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18. Table 8.

10. Easy A1c Correlation • NOTE: This is an estimate only • (A1C -2) x 30 • i.e. A1C= 7%; (7-2) x30 = 150mg/dL

11. Goals

12. Glycemic Recommendations *Individualize goals based on these values. †Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S20. Table 9.

13. Goals: A1c ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18-19. • Goal: <7% • Lowering A1c <7% has been shown to reduce microvascular complications and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease • More stringent goals (i.e. 6.5%)are reasonable in patients if it can be achieved without significant hypoglycemia or side effect • New diagnosis of diabetes, long life expectancy and no significant CVD • Less stringent goals (i.e. 8%) may be reasonable for those who have experienced severe hypoglycemia, limited life expectancy, advanced complications, or extensive comorbidities.

14. Oral Hypoglycemic Treatment

15. Non-Insulin Hypoglycemic Agents Oral Biguanides Sulfonylureas Meglitinides Thiazolidinediones Alpha Glucosidase inhibitors Incretin Enhancers (DPP-IV inhibitors) Resin binder. SGLT2 inhibitors Parenteral Amylin analogs Incretin mimetics

16. Pharmacology - Biguanides ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University

17. Pharmacology - Sulfonylureas ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

18. Pharmacology – Meglitinides ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

19. Pharmacology – Thiazolidinediones (TZD) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

20. Pharmacology – Thiazolidinediones (TZD) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

21. TZDs and the FDA Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1]. • Rosiglitazone • Restricted by FDA – can only be used by patients currently benefiting from therapy or do not get adequate DM treatment from other agents and not willing to use pioglitazone • 1-800-AVANDIA • Pioglitazone • FDA alert – ongoing analysis of risk of bladder cancer (with prolonged use >12 months)

22. Pharmacology – Alpha-Glucosidase Inhibitors ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.

24. Pharmacology – IncretinMimetics ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University.

25. Pharmacology – Incretin Enhancers ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University.

26. Pharmacology – Amylin Analog Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1].

27. Pharmacology – Bile Acid Sequestrants ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University.

28. The Role of SGLT-2 Inhibitors in the Management of Patients with Type 2 Diabetes

29. The Kidneys Play an Important Role in Glucose Control • Normal Renal Glucose Physiology • 180 g of glucose is filtered each day • Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation • SGLT2 reabsorbs about 90% of the glucose • SGLT1 reabsorbs about 10% of the glucose • Virtually no glucose excreted in urine Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

30. Targeting the Kidney Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

31. Renal Glucose Transport Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.

32. Sodium- Glucose Cotransporters Lee YJ, at al. Kidney Int Suppl. 2007;72:S27-S35.

33. Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition

34. Familial Renal Glucosuria Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882; Wright EM, et al. J Intern Med. 2007;261:32-43.

35. Altered Renal Glucose Control in Diabetes Marsenic O. Am J Kidney Dis. 2009;53:875-883. Bakris GL, et al. Kidney Int. 2009;75(12):1272-1277. Rahmoune H, et al. Diabetes. 2005;54(12):3427-3434. • Gluconeogenesis is increased in postprandial and postabsorptive states in patients with Type 2 DM • Renal contribution to hyperglycemia • 3-fold increase relative to patients without diabetes • Glucose reabsorption • Increased SGLT-2 expression and activity in renal epithelial cells from patients with diabetes vs. normoglycemic individuals

36. SGLT2 Inhibitors in Phase 3 Development • Empagliflozin • Canagliflozin • Dapagliflozin • Ipragliflozin

37. Typical A1c Reductions Unger J et al. Postgrad Med 2010; 122: 145-57

38. Drug Pearls

39. Fasting vs. Postprandial Effect

40. Considerations When Selecting Therapy How long has the patient had diabetes (duration of disease – preservation of β-cell function)? Which blood glucose level is not at target (fasting, postprandial, or both)? Patient preference for route of administration (oral, injection)? The degree of A1c lowering effect required to achieve goal? Side effect profile and the patients tolerability? Co – existing conditions ( CVD, osteoporosis, obesity, etc)?

41. Glycemic Control Algorithm

42. Algorithm for Adding/Intensifying Insulin

44. QUESTIONS