1. GO! Diabetes Residency Train the Trainer Program

2. Glycemic Control Oral Agents and GLP 1 Based Therapies

3. Metabolism 101 Fed State –Insulin –Glucagon –Incretins GLP-1 GIP Amylin Fasting State –Insulin –Glucagon –Incretins GLP-1 GIP Amylin

4. How The Body Handles Glucose (Fed State) MUSCLE FAT LIVER PANCREAS INSULININSULIN BRAIN Blood Glucose 60-90 mg/dL Glucose 90-140 mg/dL GLUCAGON INSULIN GLUCAGON AMYLIN GI TRACT

5. INSULININSULIN Pathophysiology of Type 2 Diabetes MUSCLE FAT LIVER PANCREAS INSULIN Hyperglycemia BRAIN INSULIN GLUCAGON INSULIN GLUCAGON INSULININSULIN AMYLIN GI TRACT A1C < 7% Premeal ~ 100mg/dL PPG < 180 mg/dL PramlintideDietary Composition Portion Control  -Glucosidase Inhibitors Weight Loss Exercise TZDs (Metformin) Insulin Sulfonylureas Insulin Analogs Glinides Incretin Rxs Metformin (TZDs)

6. Do you currently feel comfortable managing diabetic patient medications – oral agents? 1.Yes 2.No 0

7. General Rules Hypoglycemic Therapy Don’t forget lifestyle changes Target the pathophysiology –Catabolic – increase insulin –Obese –attack insulin resistance –Multifactorial (most cases) –do both Realize the need to add eventually add therapies Predict what will be needed to reach glycemic goals

8. General Rules Hypoglycemic Therapy Normalize fasting glucose levels first –Many patients will achieve glycemic targets When to target postprandial glucose levels? –Preprandial values are at goal –A1C levels are not met GOALADAVERBAL Premeal90-130~100 2 hr post prandial<180<200 HbA1C<7%

9. FPG and PPG: Contribution to A1C Monnier. Diabetes Care. 2003;26:881. 70% 60% 55% 50% 30% 40% 45% 50% 70% FastingPostprandial >10.2 9.3–10.2 8.5–9.2 7.3–8.4 <7.3 A1C (%) % Contribution to A1C

10. Biguanides: Metformin Mechanism of action –Reduces hepatic glucose production –Depends upon presence of insulin Safety and efficacy –Decreases A1C 1-2% –Adverse effects: diarrhea and nausea; main risk: lactic acidosis –Discontinuation rate 5% –Contraindications: renal, cardiac, hepatic insufficiency; IV contrast –No direct effect on kidney Dosing –Initial dose: 500 mg once a day; dosing: usually BID –Maximum effective dose: 2,000 mg per day –Titration frequency: week(s) to months –Alternate formulations: “XR” and combinations

11. Cochrane Review July 2005 “Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycemia control, and moderates weight, lipids, insulinemia and diastolic blood pressure. Sulfonylureas (SFUs), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZDs), meglitinides (glinides), insulin, and diet fail to show more benefit for glycemic control, body weight, or lipids, than metformin.”

12. Metformin Outperformed Other Meds in Obese Patients (UKPDS) Lancet 1998 Sep 12;352(9131):854-65.

13. Insulin Secretagogues: Sulfonylureas (SFU) and “Glinides” Mechanism of action –Stimulate basal and postprandial insulin secretion –Require functioning beta cells (N/A for IDDM) –Work quickly Safety and efficacy –Decrease A1C approximately 1-2% –Lower fasting glucose 20% –Adverse events: weight gain, allergy (rare); main risk, hypoglycemia –May be used as monoRx OR in combo with Metformin, TZDs. Dosing –Initial dose: 1/8 to 1/4 maximum dose; dosing: 1-2 times/day (SFU), 3 times/day (glinides) –Maximum effective dose: 1/2 maximum (full dose with glinides: repaglinide/ nateglinide) –Titration frequency: day(s) to weeks

14. Recommended Sulfonylureas Glipizide ER 5-20 mg once per day Once daily, flat profile, low plasma levels resulting in a lower risk of weight gain and hypoglycemia Glipizide 2.5 to 20 mg twice a day Twice daily. Half-life 2-4 hours, peaks in 2-3 hours. By taking it once a day at low dose it stimulates insulin secretion for 6- 12 hours Glimepiride (Amaryl) 1-8 mg daily Once daily dosing Melander A. Diabetes 2004;53 Suppl 3:S151

15. Value of Adding Instead of Switching Continue SFU (glyburide) Switch To Metformin Add Metformin -2.5 -2.0 -1.5 -0.5 0.0 0.5 09131721 25 29 Mean Change From Baseline A1C (%) Week DeFronzo RA et al. NEJM 1995;333:541 n=632 *P<0.01 † P<0.001 * * * * † † † † † †

16. Thiazolidinediones (TZD’s or Glitazones): Pioglitazone and Rosiglitazone Mechanism of action –Enhance insulin sensitivity in muscle, adipose tissue –Inhibit hepatic gluconeogenesis –Reduced rate of beta cell dysfunction Safety and efficacy –Decrease A1C 1-2% –Adverse events: edema, weight gain, anemia; rare serious risk: liver failure Dosing –Initial dose (monotherapy): 1/2 to 2/3 maximum; dosing,1-2 x/day –Maximum effective dose: maximum dose –Titration frequency: weeks to month(s)

17. TZDs: Weight Gain and Edema Derived from an increase in body fat and possibly increased fluid retention Severity appears to be proportional to level of glycemic control achieved Not inevitable and diet helps Accentuated by combination with secretagogues or insulin Usually mild to moderate and well tolerated Lebovitz H. Diabetes Metab Rev 2002;18:S23 Fonseca V. Am J of Med 2003;115:42S Patients should be instructed to inform their doctors of rapid or excessive weight gain

18. Oral Hypoglycemics TZD Lipid Effects Rosiglitazone (Avandia) –+LDL –+HDL –+Triglycerides Rosiglitazone – Black box warning for CHF and ischemic heart disease; warnings about increased fracture risk in women Pioglitzaone – Black box warning for CHF and warning about increase fracture risk. No evidence to suggest increased ischemic heart disease. Pioglitazone (Actos) –+LDL –+HDL –-Triglycerides

19. TZD Lipid Effects RCT = 735 patients 1 A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005 Jul;28(7):1547-54. PioglitazoneRosiglitazone Triglycerides -52 mg/dl-13 mg/dl HDL +5.2 mg/dl+2.4 mg/dl LDL +12.3 mg/dl+21.3 mg/dl

20. AHA/ADA Consensus Statement for TZDs Not recommended for patients with NY Heart Association class III or IV heart failure TZDs alone, or particularly in combination with insulin, may cause fluid retention which can lead to heart failure –Incidence of CHF <1% with TZD monotherapy –Increased to 2%-3% in combination with insulin Patients should be observed for signs and symptoms of heart failure 2009 Consensus Algorithm doesn’t recommend rosiglitazone Nesto RW et al. Diabetes Care 2004;27:256

21. Alpha-Glucosidase Inhibitors: Acarbose And Miglitol Mechanism of action –Delay absorption of carbohydrates –Depend upon postprandial hyperglycemia Safety and efficacy –Decrease A1C 0.5-1% –Adverse events: flatulence; main risk: rare liver enzyme elevation Dosing –Initial dose: 1/4 maximum once daily; dosing: 3 times daily –Maximum effective dose: 1/2 maximum dose –Titration frequency: week(s) to months

22. Incretin Based Therapies

23. Definition of Incretins “Gut-derived factors that increase glucose-stimulated insulin secretion” In ● cre ● tin Intestine Secretion Insulin Creutzfeldt. Diabetologia. 1985;28:565.

24. Incretins Play an Important Role in Glucose Homeostasis 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.  Insulin from beta cells (GLP-1 and GIP)  Glucagon from alpha cells (GLP-1) Release of gut hormones— Incretins 1,2 Pancreas 2,3 Glucose Dependent Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 Glucose Dependent ↓ Blood glucose GI tract ↓ Glucose production by liver Food ingestion ↑ Glucose uptake by peripheral tissue 2,4 Beta cells Alpha cells

25. INCRETIN MIMETICS GLP-1 analogs “Incretin Mimetics” Exenatide (Byetta) 5- 10 mcg SQ bid AC Liraglutide (Victoza) 0.6, 1.2 or 1.8mg SQ daily without regard to meal  Indicated for T2DM failing oral agents  “Lead in dosing” reduces side effects  Nausea most common AE. Weight loss common.  Reduce SFUs to lowest dose to reduce hypoglycemia

26. Multiple Sites of Action of GLP-1 Analogs Flint A et al. J Clin Invest 1998;101:515 Larsson H et al. Acta Physiol Scand 1997;160:413 Nauck MA et al. Diabetologia 1996;1546 Drucker DJ. Diabetes 1998;47:159 CNS Promotes satiety and reduction of appetite Stomach Slows gastric emptying Beta Cell Stimulates glucose- dependent insulin secretion Alpha Cell Inhibits glucagon secretion Liver Reduces hepatic glucose output by inhibiting glucagon release

27. Exenatide: A1C And Body Weight Reductions- Preliminary Analysis For Subjects Treated For 2 Years 2 year data for 82 week cohort (n=146) Mean ± SE 0.00.51.01.52.0 -1.5 -0.5 0.0 Duration Of Treatment (Years) Placebo Controlled Open-Label Extensions Baseline A1C=8.2% Δ A1C (%) 0.0 0.51.01.52.0 -6 -4 -2 0 Placebo Controlled Open-Label Extensions Baseline Weight=100 kg Duration Of Treatment (Years) Δ Body Weight (kg) 1.2±0.1% 5.5±0.5 kg Diabetes Metab Res Rev. 2006 Nov-Dec;22(6):483-91.

28. Glargine Vs Exenatide in Patients Failing Oral Therapies ITT patient sample Mean ± SE shown * p<0.0001, exenatide vs insulin glargine at same time point  Body Weight (lbs) * * * * * *  A1C (%) Heine RJ et al. Ann Intern Med 2005;143(8):559

29. Initiation  1 Mo 5 mcg BID Stable Dose 10 mcg BID Stable Dose Indicated for use in patients failing metformin or sulfonylurea Generally reduce SFU dose to smallest tablet to minimize risk of hypoglycemia No dosage adjustments based on meal size or physical activity No additional glucose monitoring required Exenatide Prescribing Information. 2005 General Prescribing Considerations Dosing

30. GLP-1 Based Therapy DPP-4 enzyme inhibitors prevent degradation allowing prolonged action of native GLP-1. Sitagliptin (Januvia) 100mg PO daily Saxagliptin (Onglyza) 2.5-5 mg PO daily  Advantages: well tolerated and administered orally  Disadvantages: cost, modest glycemic reduction, no long term studies

31. INCRETIN-BASED THERAPIES PROS Preserve beta cell function No weight gain Weight loss (GLP1 analogs) Weight neutral (DPP4 Inhibitors) Less hypoglycemia risk vs insulin and secretagogues Enhanced postprandial glucose control CONS Expensive Nausea (GLP1 analogs) Concern for pancreatitis and thyroid tumors Long term studies lacking

32. Key Points to Consider for Therapy Maximal benefits of metformin are observed at the recommended daily dose of 2000 mg (1 g BID) 1 Thiazolidinediones (TZDs) should be started at low doses and slowly increased to minimize side effects 2 Glucose-lowering effects of a sulfonylurea plateau at half the maximum recommended dose 3 1.Garber AJ et al. Am J Med 1997;103:491 2.Nesto RW et al. Diabetes Care 2004;27:256 3.Stenman S et al. Ann Intern Med 1993;118:169

33. Current Treatment Paradigm Pathophysiology-Oriented Approach Combination therapy from the outset Treatment designed to address the underlying pathophysiology Vigorous effort to meet glycemic targets Simultaneous rather than sequential therapy Early stepwise titrations to meet glycemic targets Harris MI et al. Diabetes Care 1998;21:518 Lifestyle Changes Monotherapy Early Combinations Of Oral Agents Intensify Combinations Of Oral Agents Add Insulin/GLP1 Analog

34. At a routine health maintenance visit, a 42-year-old obese male is found to have a fasting plasma glucose level of 118 mg/dL. Which one of the following is the most appropriate initial intervention for preventing or delaying the development of diabetes in this patient? 1.Lifestyle modification 2.Metformin (Glucophage) 3.A thiazolidinedione 4.An oral sulfonylurea agent 5.An ACE inhibitor 0

35. Which options below that are true regarding the use of thiazolidinediones (TZDs). A) The full hypoglycemic effect is seen 2 weeks after the initiation of a given dose B) The hypoglycemic effect is comparable to that of metformin (Glucophage) or a sulfonylurea C) Monitoring of liver enzymes is recommended D) Weight gain and edema are commonly associated with their use E) Their mechanism of action is enhancement of insulin sensitivity

36. A 62-year-old female is diagnosed with type 2 diabetes on the basis of consecutive fasting plasma glucose levels of 138 mg/dL and 143 mg/dL. Which of the following should be prescribed as part of her initial management? 1.Lifestyle intervention & Metformin (Glucophage) 2.An oral sulfonyurea 3.A thiazolidinedione 4.Pramlintide 0

37. How many of the following diabetes agents causes the possible side effect of Hypoglycemia? Insulin Pioglitazone (Actos) Metformin (Glucophage) Sulfonylureas Repaglinide (Prandin) Acarbose (Precose) 1.One agent 2.Two agents 3.Three agents 4.Four agents 5.Five agents 6.All six agents 0

38. A 29-year-old female with polycystic ovary syndrome asks if you can correct her oligomenorrhea and infertility. Her fasting glucose level is 100 mg/dL and she has a normal glycosylated hemoglobin level. Which of the following diabetes medications have been found to address these problems? (Mark all that are true.) A) Glyburide (Micronase, DiaBeta) B) Metformin (Glucophage) C) Pioglitazone (Actos) D) Miglitol (Glyset) E) Repaglinide (Prandin)

39. Mark all options below that are true regarding the use of metformin (Glucophage). A) Its efficacy as a hypoglycemic agent is comparable to that of sulfonylureas B) It has a lower secondary failure rate than sulfonylureas C) Its hypoglycemic effect is additive to the action of sulfonylureas D) Gastrointestinal side effects cause 20%-30% of patients to discontinue its use E) It is contraindicated in patients with a serum creatinine exceeding 1.5 mg/dL for males or 1.4 mg/dL for females

40. Which of the following oral agents should be used with caution in patients with advanced heart failure? A. Thiazolidinediones B. Metformin (Glucophage) C. Sulfonylureas D. Meglitinides E. Alpha-glucosidase inhibitors A.C&E B.A&B C.B&C D.A&D E.All of the above 0

41. Which one of the following oral agents is most likely to produce weight loss in the diabetic patient? A.Thiazolidinediones B.Metformin (Glucophage) C.Sulfonylureas D.Meglitinides E.Alpha-glucosidase inhibitors 0