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Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008

2008. Symposia Series 2. Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008. The Case for Earlier Insulin Use in Type 2 Diabetes. Charles F. Shaefer Jr, MD Assistant Clinical Professor of Medicine Medical College of Georgia Augusta, Georgia. Faculty Disclosure.

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Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008

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  1. 2008 Symposia Series 2 Radisson Hotel at Opryland Nashville, Tennessee May 31, 2008

  2. The Case for Earlier Insulin Use in Type 2 Diabetes Charles F. Shaefer Jr, MD Assistant Clinical Professor of Medicine Medical College of Georgia Augusta, Georgia

  3. Faculty Disclosure • Dr Shaefer:consultant: Pfizer Inc, sanofi-aventis; speakers bureau: Daiichi Sankyo, Inc., Forest Pharmaceuticals, Inc., Pfizer Inc, sanofi-aventis, Takeda Pharmaceuticals, Inc

  4. 7 What percentage of your patients areusing basal insulin after failure of 2 OADs? • 0%-15% • 15%-25% • 25%-40% • >40% Use your keypad to vote now!

  5. Learning Objectives • Explain the importance of tight glycemic control for patients with type 2 diabetes • Apply the most recent treatment algorithm to identify next steps in the management of patients with type 2 diabetes • Select the appropriate short-, intermediate, or long-acting insulins in the management of type 2 diabetes

  6. Diabetes Demographics in the United States Population Aged ≥20 Years Adapted from National Center for Health Statistics. Health, United States, 2006. With Chartbook on Trends in the Health of Americans. Hyattsville, Md: 2006.

  7. Estimated 2007 Direct and Indirect Costs of Diabetes in the United States Increase of $42 billion (32%) compared with 2002 In 2007, 1 of every 5 healthcare dollars spent on a person diagnosed with diabetes In 2007, 1 of every 10 healthcare dollars spent on diabetes Cost of Diabetes in Billions: Total: $174 Billion Indirect: $58 Billion ↑ Absenteeism ↓Productivity Unemployment due to disability ↓ Productivity due to early mortality Direct: $116 Billion Diabetes care DM complications Excess general medical costs DM = diabetes mellitus. ADA. Diabetes Care. 2008;31:1-20.

  8. Case Study

  9. Case History and Physical Findings • 58-year-old Hispanic man presents with complaints of fatigue and unusual hunger. He checked his blood glucose with his cousin’s meter and it was 143 mg/dL after lunch. The cousin insisted the patient seek medical attention • History of high BP; taking ramipril 10 mg daily • Claims to be otherwise healthy • Physical examination • BP: 126/72 mm Hg • Weight: 195 lb; waist circumference: 41 in; height: 5 ft 9 in • Blood glucose in the office is 136 mg/dL; patient ate light breakfast before his morning appointment • Point-of-care A1C = 6.1% • A1C = glycosylated hemoglobin; BP = blood pressure.

  10. Laboratory Results BUN = blood urea nitrogen; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TC = total cholesterol; TG = triglyceride. • BUN: 29 • Creatinine: 0.9 • HDL: 23 mg/dL • LDL: 106 mg/dL • TC: 234 mg/dL • TG: 287 mg/dL • Urinalysis: negative • Other labs are unrevealing

  11. 7 What is your diagnosis for this patient? • Type 2 diabetes • Pre-diabetes • Impaired fasting glucose • Don’t know Use your keypad to vote now!

  12. Diagnosis: Type 2 Diabetes • Blood glucose values measured by a 2-hour glucose tolerance test: • Prescreen: 103 mg/dL • Fasting: 106 mg/dL • 2 hour: 236 mg/dL • Patient presents at your office 2 hours after eating and reports self-monitored blood glucose (SMBG) of 213 mg/dL • You explain to the patient that he has type 2 diabetes

  13. ADA Criteria for the Diagnosis of Diabetes • FPG ≥126 mg/dL (7.0 mmol/L)* OR • Symptoms of hyperglycemia and a casual plasma glucose ≥200 mg/dL (11.1 mmol/L) OR • 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT* *In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day. ADA = American Diabetes Association; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.

  14. Natural History of Type 2 Diabetes Severity of Glucose Intolerance IGT Frank Diabetes NGT Insulin Secretion Postprandial Blood Glucose Fasting Blood Glucose Normal Blood Glucose Years to Decades Typical Diagnosis of Diabetes Insulin Resistance Progressive b-cell Dysfunction Microvascular Complications Macrovascular Complications IGT = impaired glucose tolerance; NGT = normal glucose tolerance. Leahy JL. Diabetes Care. 1990;13:992-1010.

  15. Suboptimal Management May Leadto Poor Outcomes in Diabetes Care • Delayed initiation of therapies to prevent long-term complications is common in general practice settings worldwide, especially in the United States, India, and Japan • Most primary care practitioners (50%-55%) delay insulin therapy until “absolutely necessary” • Delay of OAD = strongest correlate of insulin delay • Barely half (49.2%) of healthcare providers believe that earlier insulin use would decrease overall cost of diabetes care Peyrot M, et al. Diabetes Care. 2005;28:2673-2679; Skovlund S, et al. Diabetes Spectrum.2005;18:136-142.

  16. Diabetic Comorbidities Heart disease and stroke: death rate 2-4 times higher in adults with diabetes 80% with T2DM will have stroke or MI 60% will die of first event Blindness: diabetes is leading cause in persons aged 20 to 74 Kidney failure: diabetes is leading cause of new cases (44%) in 2002 Neuropathy: in 60%-70% of persons with diabetes Amputations: causes >60% of lower-limb amputations Periodontal disease: twice the risk in young adults with diabetes; severe gum disease in one third of persons with diabetes Maternal/neonatal health: poorly controlled diabetes causes major birth defects in 5%-10% of pregnancies, spontaneous abortions in 15%-20% NDIC. National Diabetes Statistics. Available at: www.diabetes.niddk.nih.gov/dm/pubs/statistics. Accessed April 29, 2008.

  17. No A1C Threshold in Type 2 Diabetes Epidemiologic Data From the UKPDS 80 Myocardial infarction Microvascular end points 60 Adjusted Incidence/1000 Person-Years (%) AACE Goal 40 20 ? 0 5 6 7 8 9 10 11 Updated Mean A1C (%) AACE = American Association of Clinical Endocrinologists ; UKPDS = United Kingdom Prospective Diabetes Study. Stratton IM, et al. BMJ. 2000;321:405-412.

  18. EPIC Study: Relative Risk of CVD Events by A1C Concentration CVD = cardiovascular disease; EPIC = Expanding Patient Involvement in Care; RR = relative risk. Khaw KT, et al. EPIC. Ann Intern Med. 2004;141:413-420.

  19. Tight Glycemic Control: Recommended A1C Targets Optimal target: A1C <6% (normal range) *As close to normal (<6%) as possible without significant hypoglycemia. Prospective data on A1C and macrovascular disease are less conclusive than on AIC and microvascular disease. EASD = European Association for the Study of Diabetes.

  20. STAGE 2 SBP 160 mm Hg or DBP 100 mm Hg Treatment recommended STAGE 1 SBP 140-159 mm Hg or DBP 90-99 mm Hg Consider treatment in those with diabetes or renal disease who fail lifestyle modification PREHYPERTENSION SBP 120-139 mm Hg or DBP 80-89 mm Hg NORMAL SBP <120 mm Hg and DBP <80 mm Hg JNC 7 Classification of Blood Pressure DBP = diastolic blood pressure; JNC 7 = Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure; SBP = systolic blood pressure. Chobanian AV, et al, for the NHBPEPCC. Seventh Report of the Joint National Committee on Prevention Bethesda, Md: NHLBI; 2004. NIH Publication No. 04-5230. Available at: www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. Accessed April 29, 2008.

  21. NCEP ATP III Lipid Classifications NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III. NCEP ATP III. JAMA. 2001;285:2486-2497.

  22. STENO2: Effect of Intensive Multifactorial Intervention on Number of CV Events (13.3-year mean follow-up) Total Mortality on Intensive Rx Reduced by 46% Number of CV Events Death FromCV Causes Stroke MyocardialInfarction CABG PCI Revascu-larization Amputation CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention. Gaede P, et al. N Engl J Med. 2008;358:580-591.

  23. Clinical Inertia: “Failure to Advance Therapy When Required” Last A1C Value Before Abandoning Treatment 10 9.6% 9.1% Mean A1C at Last Visit (%) 9 8.8% 8.6% 8 ADA Goal 7 Sulfonylurea Combination Diet/Exercise Metformin 2.5 Years 2.9 Years 2.2 Years 2.8 Years Brown JB, et al. Diabetes Care. 2004;27:1535-1540.

  24. Risk Factor Control in Adults With Diabetes: NHANES III (1988-1994)/NHANES 1999-2000 NHANES III, n = 1204 NHANES 1999-2000, n = 370 48.2% 50 P <.001 44.3% 40 37.0% 35.8% 33.9% 29.0% 30 Patients (%) 20 10 7.3% 5.2% 0 A1C <7% BP <130/80 mm Hg TC <200 mg/dL Good Control* *Achieved all 3 indicated goals. NHANES = National Health and Nutrition Examination Survey. Saydah SH, et al. JAMA. 2004;291:335-342.

  25. 7 What is the first step in managing this patient’s condition? • Institute lifestyle changes • Re-evaluate in 3 months • Refer for comprehensivediabetes education • Start an oral antihyperglycemic agent • 1, 2, and 3 • 1, 2, 3, and 4 Use your keypad to vote now!

  26. A1C ³7% A1C ³7% A1C ³7% A1C ³7% A1C ³7% A1C ³7% Yes* Yes* Yes* Yes* Yes* Yes* No No No No No No ADA/EASD Consensus Algorithm for Type 2 Diabetes Diagnosis Lifestyle Intervention + Metformin Add Sulfonylurea (least expensive) Add Glitazone (no hypoglycemia) Add Basal Insulin (most effective) Add Basal Insulin Intensify Insulin Add Glitazone† Add Sulfonylurea† Add Basal or Intensify Insulin Intensive Insulin + Metformin ± Glitazone *Check A1C every 3 months until <7% and then at least every 6 months; †3 oral agents can be used, but initiation and intensification of insulin therapy is preferred based on effectiveness and expense.Nathan DM , et al. Diabetes Care. 2006;29:1963-1972.

  27. Advancing Therapy • Metformin is started and titrated over several weeks to 1000 mg twice daily, which the patient tolerates well • He starts regular appointments with the certified diabetes educator (CDE) in a comprehensive program of lifestyle change and nutrition, as well as pharmacologic management • At 3-month follow-up the patient reports he is exercising and following the CDE’s dietary recommendations • Weight = 183 lb (loss of 12 lb) • A1C = 5.8%

  28. 1 Year Later… • A little more than a year later the patient returns. He has gained 25 lb and is exercising sporadically. He admits his diet isn’t good • After starting treatment, the patient missed his next appointment because he felt he was doing well • He missed a number of CDE visits and eventually stopped altogether • Physical findings • BP: 134/82 mm Hg • Weight: 208 lb (25-lb weight gain) • TC: 156 mg/dL; TG: 143 mg/dL; HDL: 32 mg/dL; LDL: 79 mg/dL • A1C: 8.1%

  29. Advancing Therapy • The patient is very reluctant to start insulin and requests an oral drug • Because of cost, he strongly prefers glyburide, which is started at 5 mg daily • 3-month follow-up: A1C = 6.8% • The patient is happy with his therapy despite occasional mild hypoglycemia • Agrees to come back every 3 to 4 months for examination and A1C determination

  30. Failure of 2 OADs The patient keeps his follow-up appointments, but about 18 months later • A1C: 7.6% • BP: 118/72 mm Hg • Body weight: 200 lb • TC: 122 mg/dL; TG: 122 mg/dL, HDL: 39 mg/dL; LDL: 76 mg/dL • Current Rx: metformin + glyburide, plus ramipril, amlodipine, atorvastatin, aspirin, niacin

  31. 7 What is your next treatment recommendation? • Increase lifestyle measures • Add a third OAD • Initiate insulin • Discuss gastric bypass Use your keypad to vote now!

  32. Percent Reaching A1C Goal: TZD Added to Metformin and SFU P <.001 A1C Achieved at 6 Months (%) A1C Achieved at 12 Months (%) SFU = sulfonylurea; TZD = thiazolidinedione. Yale JF, et al. Ann Intern Med. 2001;134:737-745.

  33. ADA and EASD Recommendation After Failure of 2 OADs • The authors of the ADA treatment algorithm discourage the use of >2 OADs: “Although 3 OADs can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense” • Thanks to his comprehensive diabetes education, the patient understood that one day insulin would be needed • It’s no surprise to him that basal insulin is to be started. He expresses concern about hypoglycemia and a general sense of losing control. He wants to be part of the decision-making process AACE. Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement. Available at: www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed April 29, 2008; ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; Nathan DM, et al. DiabetesCare. 2006;29:1963-1972.

  34. Basal Insulin Therapy • Usual first step when beginning insulin therapy • Continue OAD and add basal insulin to optimize FPG • A1C of up to 9.0% may best be reduced to goal by addition of basal insulin therapy to OADs • Easy and safe: patient-directed treatment algorithms with small risk of serious hypoglycemia AACE. Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement. Available at: www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed April 29, 2008; ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; Holman RR, et al. N Engl J Med. 2007;357:1716-1730; Nathan DM, et al. DiabetesCare. 2006;29:1963-1972.

  35. Rationale for Basal Insulin Therapy:Insulin and Glucose Patterns Basal Insulin Normal T2DM Glucose Insulin 400 120 100 300 80 μU/mL mg/dL 200 60 40 100 20 6:00 10:00 14:00 18:00 22:00 2:00 6:00 6:00 10:00 14:00 18:00 22:00 2:00 6:00 B L D B L D Time Time B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus. Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239.

  36. UKPDS: Early Initiation of Insulin Therapy Improves A1C Control 9 8 7 A1C (%) ULN = 6.2% 6 5 0 0 1 2 3 4 5 6 Years From Randomization Conventional therapy Insulin therapy Sulfonylurea ± insulin therapy ULN = upper limit of A1C nondiabetic range. Wright A , et al. Diabetes Care. 2002;25:330-336.

  37. Options for Initiating Insulin Therapy Basal insulin NPH insulin (at bedtime) Insulin detemir (once or twice daily) Insulin glargine (once daily) Premixed insulin preparations 70/30 NPH insulin/regular insulin 50/50 NPL insulin/insulin lispro 70/30 NPA insulin/insulin aspart 75/25 NPL insulin/insulin lispro “Premixed insulins are not recommended during adjustment of doses”1 Analog premixes NPA = neutral protamine aspart; NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.

  38. ADA/EASD Algorithm: Avoid Premixed Insulin in Dose Adjustment Phase Breakfast Lunch Dinner Insulin Action 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Glucose levelsInsulin levels Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. NY: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.

  39. Idealized Profiles of Human Insulinand Basal Insulin Analogs NPH Plasma Insulin Levels Detemir Glargine 2:00 4:00 6:00 8:00 12:00 14:00 16:00 18:00 20:00 22:00 24:00 0:00 10:00 Time Plank J, et al. Diabetes Care. 2005;28:1107-1112; Rave K, et al. Diabetes Care. 2005;28:1077-1082; Rosenstock J, et al, eds. Textbook of Type 2 Diabetes. London, NY: Martin Dunitz; 2003:131-154.

  40. Treat-to-Target Trial: Oral Agents + Glargine or NPH at Bedtime (n = 756): Efficacy Results In both groups, FPG decreased from 194 or 198 mg/dL to 117 or 130 mg/dL, respectively, by study end, and A1C decreased from 8.6% to 6.9% by 18 weeks. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.

  41. Treat-to-Target Trial: Timing and Frequency of Hypoglycemia Hypoglycemia by Time of Day Basal Insulin B L D 350 * Insulin glargine * 300 NPH insulin 250 * * Hypoglycemia Episodes (PG ≤72 mg/dL) 200 * * * 150 100 50 0 20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 Time *P <.05 (between treatment). Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.

  42. Detemir vs NPH Insulin in T2DM (n = 476) Detemir NPH 400 350 300 250 200 150 100 50 0 A1C (%) 10.0 9.0 8.0 7.0 6.0 Detemir NPH Hypoglycemia Events* 8 20 24 0 2 12 16 4 8 20 24 -2 0 12 16 4 Study Week Study Week *All reported events, including symptoms only. Hermansen K, et al. Diabetes Care. 2006;29:1269-1274.

  43. 7 What will you select as the basal insulin for this patient? • Detemir • Glargine • NPH • Premixed analog 70/30 Use your keypad to vote now!

  44. 7 How will you initiate insulin therapy? • Calculate an initial dose based on weight • Start 10-U glargine and patient adjusts daily • Start 10-U glargine and patient adjusts every 3 days • Start 10-U glargine and patient makes weekly adjustments Use your keypad to vote now!

  45. Choice of Algorithms for Self-Titration • 2-4-6-8 Treat to Target1 • Add 2, 4, 6, or 8 units to basal insulin dose weekly depending on average FBS • PREDICTIVE 3032 • Add 3 units of basal insulin every 3 days until average FBS = 100 mg/dL • 1-1-100 INSIGHT3 • Add I unit of basal insulin daily until FBS = 100 mg/dL • 3-2-1 ATLANTUS4 • Add 2 units of basal insulin every 3 days until average FBS = 100 mg/dL FBS = fasting blood sugar; INSIGHT = Implementing New Strategies With Insulin Glargine for Hyperglycemia Therapy; PREDICTIVE = Predictable Results and Experience in Diabetes Through Intensification and Control to Target: an International Variability Evaluation. 1. Riddle M, et al. Diabetes Care. 2003;26:3080-3086; 2. Meneghini L, et al. Presented at 67th Annual Scientific Session of the ADA. June 2007. Chicago Ill; 3. Gerstein HC, et al. Diabet Med. 2006;23:736-742; 4. Davies M, et al. Diabetes Care. 2005;28:1282-1288.

  46. Strategy: Increase Basal Insulin by 1 Unit/Day to FPG ≤100 mg/dL INSIGHT Study: Oral Agents + Insulin Glargine *Estimates of the likelihood of achieving and maintaining the indicated outcome based on Cox regression before and after adjustment for baseline A1C, baseline oral agent use, and site. Gerstein HC, et al. Diabet Med. 2006;23:736-742.

  47. 7 Patient starts with 1-1-100 algorithm andtitrates up to 30 U. FBG averages 140 mg/dL.How will you adjust the insulin dose? • Change to premixed insulin • Add mealtime insulin • Continue to titrate glargine • Intensify lifestyle measuresincluding diet Use your keypad to vote now!

  48. Treat-to-Target Trial: Forced Weekly Titration to Target FPG ≤100 mg/dL 50 45 Units Total Daily Dose (U) 42 37 40 33 28 30 21 20 10 10 0 21 0 1 2 3 4 5 6 7 8 10 12 15 18 Weeks in Study N = 756 Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.

  49. Follow-Up After Starting Insulin • During 6 months of follow-up • Dose advances to 49-U glargine daily • FBG averages 103 mg/dL • A1C = 6.4% • Patient feels a sense of ownership • At 2-year follow-up • Average FBG 140 mg/dL • A1C = 7.2%

  50. 7 Are you satisfied with the patient’s results? • Yes • No Use your keypad to vote now!

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