1. Diabetic Medication Update Gil C. Grimes, MD April 2007

2. Disclaimer

3. Goals and Objectives Targets for therapy Medication Options New choices Best initial choices Best add on therapy Contraindications for select meds

4. Treatment Goals American Diabetes Association Recommendations Control of glycemia is important Goal is HgA1c less than7%Grade B Pre-meal glucose 90-130mg/dL Post-meal glucose <180mg/dL Blood pressure <130/80 Lipid control LDL <100 mg/dL Triglycerides <150 mg/dL HDL >40 mg/dL men or >50 mg/dL women Diabetes Care 2006 Jan;29(suppl 1):S4-S42

5. Cost-effectiveness CDC cost-analysis Hypothetical cohort patients >25 yo new diabetes Antihypertensive Therapy Improved quality of life and cost savings age 25-84 Very cost-effective 85-94 Intensive Glycemic Control Increase cost and improved outcome Decreasing effect on quality of life Decreasing cost effectiveness with increasing age Lipid management improved quality of life at increased cost JAMA 2002;287(19):2542-51 [Level 2b]

6. Lifestyle Changes Dietary changes and exercise works 20-50% of patients can control their diabetes with diet, exercise and weight reduction Current trial lookAHEAD is recruiting patients for lifestyle management study

7. Exercise Exercise training reduces the HgA1c Metanalysis of 14 trials duration 8 weeks HgA1 c 7.65% vs. 8.31% 1 Increased activity reduces risk of MI, Stroke Walking 2 hours/week lower mortality NNT 61 for one year 2 1- JAMA 2001;286:1218 [Level 1a] 2- Circ 2003;163:1440 [Level 1c]

8. Dietary Advice Systematic review of 18 RCT lasting 6 months where dietary advice main intervention Diets examined: low-fat/high –carb, high- fat/low-card, low-cal (1,000 kcal/day), very-low-calorie (500 kcal/day) Data did no provide robust conclusions on effectiveness of dietary advice Exercise improves glycemic control Cochrane Library 2004 Issue2:CD004097 [Level 1a]

9. High Fiber Diet 13 patients with DM-2 randomized in crossover fashion 6 week each arm ADA diet 8gm soluble fiber 16 gm insoluble fiber High-fiber 25 gm soluble fiber and 25 gm insoluble fiber Mean pre-prandial glucose 142 vs. 130 (p=0.04) Mean HbA1c 7.2% vs. 6.9% (p=0.09) Mean LDL 142 mg/dL vs. 133 mg/dL (p=0.11) May not be generalizable due to meals etc. NEJM 2000;342(19):1392-8 [Level 1b]

10. Glycemic Index 8 men with DM-2 at VA facility randomized in crossover trial Low-biologically-available-glucose diet HbA1c 9.8% vs. 7.6% Took place in research center 1 Low glycemic meals may reduce hyperinsulinism Evidence limited Small studies with methodological problems 1- Diabetes 2004;53(9):2375-82 [Level 1b] 2- JAMA 2002;287(18):2414-23 [Level 3a]

11. Protein Restriction ADA recommendation for patients with any chronic kidney disease Limit protein intake 0.8g/kg/day Grade B Diabetes Care 2006;29(suppl 1):S4-S42

12. Medications Initial Monotherapy Sulfonylureas inexpensive Metformin inexpensive Rosiglitazone and pioglitazone are expensive and lacking long-term data Nateglinide less effective than repaglinide Acarobose and miglitol less effective poorly tolerated Medical Letter 2002;1:1

13. Monotherapy Glycemic control is more difficult over time Monotherapy vs. diet over 10 years Medication 2-3 associated with better control (HbA1c <7%) Insulin 28% vs. 9 % (NNT 6) Sulfonylurea 24% vs. 8% (NNT 7) Metformin in obese patients 13% vs. 11% (NNT 50) Only 50% attained at 3yrs Only 25% maintained at 9 years JAMA 1999 Jun 2;281(21):2005

14. Medications When monotherapy fails Add second drug with different mechanism of action Metformin (vs. pioglitazone) probably better choice for 2 nd agent 1 Dual therapy fails add insulin with metformin Less expensive than triple oral therapy No difference in diabetic control compared 2 1- Diab Care 2004;27:141 [Level 1b] 2- Diab Care 2003;26:2238 [Level 1c]

15. Medications Systematic Review of 63 RCTs duration 3 months reporting HbA1c Studied sulfonylureas, metformin, alpha- glucosidase inhibitors, thiazolidinediones, non- sulfonylurea secreatagogues Medications at maximal doses were equally effective (except nateglinide and alpha- glucosidase inhibitors) Only Sulfonylureas and metformin demonstrate long term vascular risk reduction Metformin has advantage of lack of weight gain and lack of hypoglycemia JAMA 2002;287(3):360-72 Level 1a)

16. Sulfonylureas Increase insulin secretion by pancreas Take before meals Contraindicated in sulfa allergic patients Second generation safer in renal disease Multiple drug interactions

17. Sulfonylureas First generation have more interactions Acetoheaxmide Chlorpropamide Disulfram reaction more likely May aggravate CHF or fluid retention May Cause SIADH Tolazamide Caution in renal dysfunction Tolbutamide BID dosing decreases GI side effects

18. Sulfonylureas Second-generation agents have fewer interactions Glipizide and Glyburide are less likely to have disulfram reaction Gluburide is renally eliminated watch in renal disease Glipizide little benefit to doses >20mg/day

19. Sulfonylureas and hypoglycemia 52 sulfonylurea-treated subjects with DM mean age 65 RCT glyburide or glipizide 1 Participated in 23 hour fasting study 1 week placebo vs. 10mg/day or 20 mg/day of active drug No hypoglycemia observed in 156 fasting studies Second study glipizide similar results 2 1- JAMA 1998;279(2):1442-3 [Level 1b] 2- JAMA 1999;281(12):1084- [Level 1b]

20. Metformin Mechanism Decreased endogenous glucose production Decreased hepatic gluconeogenesis 1 Improves response to insulin Enhanced insulin-mediated glucose uptake Increased use of glucose in intestine and adipose Reduced GI glucose absorption Does not stimulate insulin secretion Requires insulin to be effective 1- NEJM 1998;338(13):867-72 Level 1c

21. Metformin Side effects Gastrointestinal upset Nausea, anorexia, diarrhea, abdominal discomfort, metallic taste Dose-related Minimized by taking with meals and gradually increasing the dose 0.003% lactic acidosis

22. Metformin Risk factors for lactic acidosis Renal impairment (Creat> 1.5 mg/dL men >1.4 mg/dL women) CHF on medications Hepatic insufficiency Hypoxia Perioperative from major surgery Binge drinking Iodinated contrast agents

23. Metformin Preventive measures Hold prior to procedure Restart after 48 hours if renal function is normal Dissent on contraindications exists 1-3 Use in pt with CHF associated with decreased mortality 1,883 patients with DM and CHF HR 0.66 for metformin vs. sulfonylurea and metformin 0.54 1- CMAJ 2005 30:173(5):502-05 Level 5 2- BMJ 2003;326(7379):4 Level 5 3- Diabetes Care 2005;28(10):2345 Level 2b

24. Metformin Systematic review 29 RCT 5,259 patients mean follow-up 3 years Reduction of mortality from MI in obese or overweight patients Improves glycemic control, weight, lipids, insulinemia, and diastolic pressure Cochrane Library 2005 Issue 3:CD002966 Level 1c

25. Glitazones Mechanism of action Decrease insulin resistance at peripheral sites and liver Decrease hepatic glucose production Adverse Effects Fluid retention and heart failure Retrospective study 5,441 patients DM-2 on glitazones vs. 28,103 controls Mean follow-up 9 months CHF 2.3% treatment group vs. 1.4% controls NNH 111 Diabetes Care 2003;26(11):2983-9 Level 2b

26. Glitazones Adverse Effects Hepatotoxicity Extracted to some degree from data on troglitazone and case reports Review 22 studies >6,000 patients LFT measured q4weeks x3 months then q6-12 weeks ALT Levels >3x ULN 0.32% rosiglitazone 0.17% placebo 0.4% sulfonylurea, metformin, insulin Diabetes Care 2002;25(5):815-21 Level 2b

27. Glitazones Adverse Effects Macular Edema case reports usually in patients with peripheral edema 1 Drug Interactions Gemfibrozil inhibits metabolism or rosiglitazone and possibly pioglitazone Randomized crossover trial 10 health volunteer 2 1- FDA MedWatch 2006 Jan5 Level 4 2- Diabetologia 2003;46(10):1319-23 Level 2c

28. Alpha-glucosidase inhibitors Works by inhibiting post-prandial absorption of glucose Side effects Flatulence, cramps, abdominal distention, borborygmus, diarrhea May interfere with glucose therapy for hypoglycemia 2 Improved glycemic control and insulin levels No effect on lipids or body weight Unknown effectiveness on morbidity and mortality 1 1- Cochrane Library 2005 Issue 2:CD003639 Level 1c 2- The Medical Letter 1996;38(967):9

29. Pramlintide Symlim Synthetic analog of human amylin Use with insulin therapy Injected prior to major meals Mechanism of action Modulates gastric emptying Increases feeling of satiety Injection medication Adverse effects Hypoglycemia especially in DM-1 or gastroparesis Should not be used in pt unable to determine when blood sugar is low Nausea, vomiting, abdominal pain, headache, fatigue, dizziness FDA Talk Paper 2005 March 17

30. Pramlintide Drug Interactions May decrease absorption of oral drugs Not recommended with anticholinergics, acarbose, or miglitol Cost AWP $79.50 per month Am J Health Syst Pharm 2005;62(8):816-22 Level 2b

31. Exenatide Byetta Used with metformin or sulfonylurea or both Injected prior to morning and evening meal Mechanism of action Incretin mimetic, stimulates glucagon-like peptide-1 receptor Stimulates production of insulin in the presence of high blood glucose Inhibits release of glucagon Slows gastric emptying Associated appetite suppression and weight loss Prescribers Letter 2005 Detail Document 210603

32. Exenatide Adverse Effects Hypoglycemia seen in patients on sulfonylurea (14.4-35.7% dose dependent) Nausea, vomiting, diarrhea, dizziness, headache, dyspepsia Withdrawal due to adverse effects 7% vs. 3% May alter absorption of oral medications Cost $147-172 per moth Prescribers Letter 2005 Detail Document 210603

33. Insulin Therapy Bedtime NPH with sulfonylurea Better than NPH alone for control Allows for lower insulin dose Based on metanalysis of 16 studies 1 Metformin as well reduces weight gain 2 Addition of PNH vs.. 70/30 reduces hypogylcemia, reduces weight gain, not as effective 3 1- Arch Intern Med 1996;156:259 [Level 1c] 2- Cochrane 2004:CD003418 [Level 1a] 3- J Fam Pract 2004;53:393 [Level 2a]

34. Insulin Therapy Long acting glargine insulin With sulfonylurea/metformin may be better than NPH for glycemic control 1 Second study 70/30 associated with improved control vs. glargine but more hypoglycemic episodes 2 1- Diabetes Care 2005;28:254 [Level 3] 2- Diabetes Care 2005;28:260 [Level 3]

35. Inhaled Insulin Exubera Inhaled 10 minutes prior to meal dosed in milligrams 0.05 mg/kg rounding down 1mg 3 units regular & 3mg 8 units Three 1mg doses is not equal to one 3mg dose Mechanism of action Small particle size 1-3 microns dry powder Deposited in alveoli Absorbed into capillary bloodstream 6-10% of inhaled insulin reached systemic circulation Prescribers Letter 2006 Detail Document 220308

36. Inhaled Insulin Adverse Effects Hypoglycemia Related to rate of absorption and duration of action Similar rate to injection insulin Cough Mild and non-productive Occurs within second to minutes Decreases with continued use Dry Mouth Mild to moderate severity Prescribers Letter 2006 Detail Document 220308

37. Inhaled Insulin Contraindications Hypersensitivity to human insulin Smoking within the last 6 months Unstable or poorly controlled lung disease Speed of onset similar to rapid acting insulin Prescribers Letter 2006 Detail Document 220308

38. Aspirin Prospective 5.2 year follow up on 2,368 pts with CAD and DM-2 Observational study Cardiac mortality 10.9% those taking Aspirin Cardiac Mortality 15.9% for those not taking aspirin Am J Med 1998;105(6):494-9 Level 2c

39. ACE Inhibitors Reduce albumin excretion rate in normotensive diabetics but no evidence of effect on ESRD, glomerular filtration rate, or side effects 1 Enalipril has long term reduction of frequency and severity of albuminuria and reduces the rate of rise of creatinine 2 HOPE trial discloses that ACE inhibitors help with a wide range of morbidity and mortality 3 1- Cochrane 2001;1:CD002183 [Level 1a] 2- Arch Intern Med 1996;156:286 [Level 1c] 3- Lancet 2000;355:253 [Level 1c]

40. Cardiovascular Disease Prevention Meta-analysis of placebo controlled RCTs 7 lipid lowering trials 6 hypertension trials 5 glucose control trial Results for risk reduction combined outcome coronary heart disease death and non-fatal MI Lipid lowering 0.75 (0.61-0.93) Hypertension control 0.73 (0.57-0.94) Glucose control 0.87 (0.74-1.01) 69-300 person-years of Lipid tx or HTN tx to prevent one cardiovascular event Am J Med 2001;111(8):633-42 Level 1a

41. American College of Physicians EB guidelines Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes. Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors. Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin. Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances. Ann Intern Med 2004;140(8):644-649 Level

42. Lipid Management Statin therapy for patients with DM-2 Coronary artery disease (Grade A) Age >40 plus CV risk factors LDL>100 with lifestyle changes (Grade A) Routine use in others (Grade C) Am Fam Physician 2005;72(5):866 FPIN questions

43. Lipid Management 2,838 Patients 40-75 with DM-2 for 6 months LDL <161.5 mg/dL 1 other risk factor, no prior CAD RCT of Atorvastatin 10 mg vs. placebo Median f/u 3.9 years Risk Reduction Tx vs. placebo 3.6% vs. 5.5% for composite (MI, USA, CHD Death, Cardiac arrest) 1.7% vs. 2.4% coronary revascularization 1.5% vs. 2.8% stroke 5.8% vs. 9% primary end point (any of above) NNT31 Lancet 2004;364(9435):685-96 Level 1c

44. Control the Blood Pressure Aggressive blood pressure control pays off for diabetics 1 Goal of less than 135 and less than 80 Decreases clinically relevant macrovascular events Decreases clinically relevant microvascular events Prolongs life 1- Ann Intern Med 2003;138:593 [Level 1a]

45. Blood pressure and Lipids Meta-analysis of 18 trials looking at Lipid control, HTN control, and Glucose control Primary aggregate end point (CHD, death non-fatal MI) Lipid management RR 0.75 NNT 106 HTN management RR 0.87 NNT 157 Glucose management RR0.87 NS Am J Med 2001;111:633-42 Level 1a

46. Control the Blood Pressure We do not intend to suggest that glycemic control is an ineffective intervention, but rather that treatment of hypertension should be prioritized and stressed as the most important intervention for the average population of persons with type 2 diabetes 1- Ann Intern Med 2003;138:593 [Level 1a]