2. Oral Hypoglycemic Agents H.Rezvanian.MD

3. Objectives 1.List oral hypoglycemic agents currently on the market 2.Classify oral hypoglycemic agents based on their mechanism, onset, duration, and place in therapy 3.Describe pros and cons of the different oral hypoglycemic agents available 4.Summarize limitations and contraindications of oral hypoglycemic agents

4. Classification and Diagnosis

5. Diagnostic Criteria Fasting Glucose mg/dL 2-h OGTT mg/dL Random Glucose mg/dL A1c Normal<100<140<200<5.7% Prediabetes100-125 (IFG) 140-199 (IGT) 5.7-6.4% Diabetes ≥ 126 ≥ 200 ≥ 6.5% ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2. Note: In the absence of unequivocal hyperglycemia, result(s) should be confirmed by repeat testing.

6. Prevention, Prevention, Prevention!  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 ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16

7. Prevention, Prevention, Prevention!  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/m 2, age <60 years, and women with prior GDM  None are FDA approved for Diabetes Prevention ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16

8. A1c Monitoring  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 ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18.

9. A1C Correlation Mean plasma glucose A1C (%)mg/dLmmol/L 61267.0 71548.6 818310.2 921211.8 1024013.4 1126914.9 1229816.5 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 ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S20. Table 9. *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 Target Treatment Goal AACE/ACE 2011ADA 2012 A1c ≤6.5%<7% Fasting Glucose FPG <110 mg/dlPreprandial PG 70- 130mg/dl Postprandial Glucose 2-hr postprandial <140mg/dl Peak <180mg/dl

13. Goals: A1c  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. ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S18-19.

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 ClassBiguanides CompoundMetformin MechanismActivates AMP-kinase Action(s) Hepatic glucose production  Intestinal glucose absorption  Insulin action  Glucose Lowering Effect Fasting Post Prandial Advantages No weight gain No hypoglycemia Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages Gastrointestinal side effects (diarrhea, abdominal cramping) Lactic acidosis (rare) Vitamin B 12 deficiency Contraindications: reduced kidney function CostLow – free at Marsh

17. Pharmacology - Sulfonylureas ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassSulfonylureas (2 nd generation) Compound Glibenclamide/Glyburide Glipizide Gliclazide Glimepiride Mechanism Closes K ATP channels on β -cell plasma membranes Action(s)  Insulin secretion Advantages Generally well tolerated Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages Relatively glucose-independent stimulation of insulin secretion: Hypoglycemia, including episodes necessitating hospital admission and causing death Weight gain Primary and secondary failure CostLow – free at Marsh

18. Pharmacology – Meglitinides ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassMeglitinides Compound Repaglinide (Prandin®) Nateglinide (Starlix®) Mechanism Closes K ATP channels on β -cell plasma membranes Action(s) Insulin secretion  AdvantagesAccentuated effects around meal ingestion Disadvantages Hypoglycemia, weight gain Dosing frequency CostMedium

19. Pharmacology – Thiazolidinediones (TZD) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassThiazolidinediones (Glitazones) CompoundPioglitazone (Actos®) Mechanism Activates the nuclear transcription factor PPAR-  Action(s) Peripheral insulin sensitivity  Advantages No hypoglycemia HDL cholesterol  Triglycerides  Disadvantages Weight gain Edema Heart failure (CI with stage III and IV) Bone fractures CostHigh

20. Pharmacology – Thiazolidinediones (TZD) ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. ClassThiazolidinediones (Glitazones) CompoundRosiglitazone (Avandia®) Mechanism Activates the nuclear transcription factor PPAR-  Action(s) Peripheral insulin sensitivity  AdvantagesNo hypoglycemia Disadvantages LDL cholesterol  Weight gain Edema Heart failure (CI with stages III and IV) Bone fractures Increased cardiovascular events (mixed evidence) FDA warnings on cardiovascular safety CostHigh

21. TZDs and the FDA  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) Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1].

22. Pharmacology – Alpha-Glucosidase Inhibitors ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University. Class α -Glucosidase inhibitors Compound Acarbose Miglitol Mechanism Inhibits intestinal α -glucosidase Action(s)Intestinal carbohydrate digestion and absorption slowed Advantages Nonsystemic medication Postprandial glucose  Disadvantages Gastrointestinal side effects (gas, flatulence, diarrhea) Dosing frequency CostMedium

24. Pharmacology – Incretin Mimetics ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. ClassGLP-1 receptor agonists (incretin mimetics) Compound Exenatide (Byetta®) Liraglutide (Victoza®) Mechanism Activates GLP-1 receptors ( β -cells/endocrine pancreas; brain/autonomous nervous system Action(s) Insulin secretion  (glucose-dependent) Glucagon secretion  (glucose-dependent) Slows gastric emptying Satiety  Advantages Weight reduction Potential for improved β -cell mass/function Disadvantages Gastrointestinal side effects (nausea, vomiting, diarrhea) Cases of acute pancreatitis observed C-cell hyperplasia/medullary thyroid tumors in animals (liraglutide) Injectable Long-term safety unknown CostHigh

25. Pharmacology – Incretin Enhancers ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University. ClassDPP-4 inhibitors (incretin enhancers) Compound Sitagliptin (Januvia®) Vildagliptin (available in Europe) Saxagliptin (Onglza®) Linagliptin (Tradjenta®) MechanismInhibits DPP-4 activity, prolongs survival of endogenously released incretin hormones Action(s) Active GLP-1 concentration  Insulin secretion  Glucagon secretion  Advantages No hypoglycemia Weight “neutrality” Disadvantages Occasional reports of urticaria/angioedema Cases of pancreatitis observed Long-term safety unknown (cancer ?) CostHigh

26. Pharmacology – Amylin Analog Class Antihyperglycemic Synthetic Analog Compound Pramlintide (Symilin®) Mechanism Amylinomimetic Action(s) Glucagon secretion  (glucose-dependent) Slows gastric emptying Satiety  Advantages Potential weight loss Disadvantages Meal time injections Nausea Hypoglycemia in combination with insulin CostHigh 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. ClassBile acid sequestrants CompoundColesevelam (Welchol®) MechanismBinds bile acids/cholesterol Action(s)Bile acids stimulate receptor on liver to produce glucose Results Lowers fasting and post prandial glucose Advantages No hypoglycemia LDL cholesterol  Disadvantages Constipation Triglycerides  May interfere with absorption of other medications CostHigh

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

29. 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 The Kidneys Play an Important Role in Glucose Control Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

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

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

32. Sodium- Glucose Cotransporters SGLT1SGLT2 SiteMostly intestine with some kidney Almost exclusively kidney Sugar SpecificityGlucose or galactoseGlucose Affinity for glucoseHigh Km= 0.4 Mm Low Km = 2 Mm Capacity for glucose transport LowHigh RoleDietary glucose absorption Renal glucose reabsorption 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 Presentation Glucosuria: 1-170 g/dayGlucosuria: 1-170 g/day AsymptomaticAsymptomatic Blood Normal glucose concentration No hypoglycemia or hypovolemiaNo hypoglycemia or hypovolemia Kidney / bladder No tubular dysfunction Normal histology and function Complications No increased incidence of –Chronic kidney disease –Diabetes –Urinary tract infection 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  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 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.

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

37. Typical A1c Reductions MonotherapyRoute of AdministrationA1c (%) Reduction SulfonylureaPO1.5-2.0 MetforminPO1.5 GlitazonesPO1.0-1.5 MeglitinidesPO0.5-2.0 α -glucosidase inhibitors PO0.5-1.0 DPP-4PO0.5-0.7 GLP-1 agonistsInjectable0.8-1.5 Amylin analogsInjectable0.6 InsulinInjectableOpen to target Unger J et al. Postgrad Med 2010; 122: 145-57

38. Drug Pearls MedicationPROCON MetforminLow cost, A1c lowering, + CV effects, weight loss, PCOS Renal or hepatic impairment SulfonylureaLow cost, A1c loweringHypoglycemia, treatment failure MeglitinidesErratic meals, renal insufficiencyHypoglycemia, treatment failure PioglitazoneInsulin resistance, decrease in adipose tissue, TG reduction Edema, wt gain, CI with HF class III and IV α -glucosidase inhibitors Patients with constipationLong duration of T2DM, patients with GI problems DPP-4Well tolerated? long term safety GLP-1 agonistsObese patientsGI side effects Amylin analogsPoor PPG control despite insulin therapy GI side effects InsulinFlexible treatment (basal, basal bolus, etc) Hypoglycemia, weight gain

39. Fasting vs. Postprandial Effect Mostly targets FASTING hyperglycemia Mostly targets POSPRANDIAL hyperglycemia Insulin (long and intermediate action)Insulin (regular, rapid-action) Colesevelam α -glucosidase inhibitors SulfonylureasMeglitinides TZDPramlinitide MetforminDPP-4 inhibitors GLP-1 agonist

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)?

44. QUESTIONS