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Effective Use of Insulin in Diabetes: Update for 2007

Effective Use of Insulin in Diabetes: Update for 2007. Kenneth S. Hershon, MD Director of Research North Shore Diabetes and Endocrine Associates New Hyde Park, New York Assistant Clinical Professor of Medicine Albert Einstein College of Medicine Bronx, New York. ?. Key Question.

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Effective Use of Insulin in Diabetes: Update for 2007

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  1. Effective Use of Insulin in Diabetes: Update for 2007 Kenneth S. Hershon, MD Director of Research North Shore Diabetes and Endocrine Associates New Hyde Park, New York Assistant Clinical Professor of Medicine Albert Einstein College of Medicine Bronx, New York

  2. ? Key Question • Completely comfortable • Somewhat comfortable • Slightly comfortable • Not comfortable at all Use your keypad to vote now! How comfortable are you with initiating insulin therapy in your patient population?

  3. Faculty Disclosure • Dr Hershon:honorarium, research support, speakers bureau: Eli Lilly and Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Pharmaceuticals Inc, Pfizer Inc, sanofi-aventis Group.

  4. Learning Objectives • State current management goals for diabetes • Identify barriers to optimal use of insulin, and how to overcome them • Discuss the roles of short-, intermediate-, and long-acting insulins in the management of diabetes

  5. A1C Targets Suggested by Different Organizations Optimal target:A1C <6% (normal range) *As close to normal (<6%) without significant hypoglycemia. AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes.

  6. State of Diabetes in America: Blood Sugar Control Across the United States as Measured by A1C National average = 67% above goal (A1C 6.5%) WA 68.4 ME 27.2 MT 55.2 ND 29.7 MN 59.3 VT = 26.7 NH = 20.4 MA = 29.5 CT = 28.4 RI = 29.5 NJ = 67.3 DE = 66.4 MD = 68.1 VT OR 64.2 NH ID 63.3 NY 71.1 W 24.2I SD 24.6 MA MI 65.4 WY 63.0 CT RI IA 58.9 PA 70.9 NE 56.5 NJ OH 71.7 NV 67.3 IL 72.6 IN 66.4 MD UT 72.4 DE CO 67.1 WV 69.5 CA 34.5 VA 67.7 KS 67.0 KY 66.8 MO 66.2 NC 65.7 TN 65.6 OK 65.6 AR 69.6 AZ 67.3 SC 66.3 NM 68.6 MS 72.8 AL 71.3 GA 69.3 LA 71.3 TX 67.7 FL 63.9 N >157,000 Top 10 Highest AACE. State of Diabetes in America. May 2005. Available at: http://www.aace.com/public/awareness/stateofdiabetes/DiabetesAmericaReport.pdf

  7. Diabetes Demographics in the United States Population Aged ≥20 Years Physician-Diagnosed Diabetes (%) Undiagnosed Diabetes (%) Adapted from: National Center for Health Statistics. Health, United States, 2006. With Chartbook on Trends in the Health of Americans. Hyattsville, MD: 2006.

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

  9. 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 44.3% P <.001 37.0% 40 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. BP = blood pressure; NHANES = National Health and Nutrition Examination Survey; TC = total cholesterol. Saydah SH et al. JAMA. 2004;291:335-342.

  10. Stages of Type 2 Diabetes: Criteria for Advancing to Next Stage? A1C not at target: 7.0% 100 Monotherapy 75 Combination oral therapy β-Cell Function (% β) 50 Insulin 25 Type 2 Diabetes Phase I Type 2 Diabetes Phase II Phase III 0 -12 -10 -6 -2 0 2 6 10 14 Years From Diagnosis Based on data of UKPDS 16. UKPDS Group. Diabetes. 1995;44:1249-1258.

  11. Biggest Clinical Hurdle? +Insulin +Oral combo + insulin + + +Oral combination + +Oral monotherapy Diet and exercise Stepwise Management of Type 2 Diabetes Adapted from Williams G. Lancet. 1994;343:95-100.

  12. ? Key Question What is the approximate amount that A1C can be lowered through use of oral agents? • 1% • 2% • 3% • 4% Use your keypad to vote now!

  13. Antihyperglycemic MonotherapyMaximum Therapeutic Effect on A1C Acarbose Nateglinide Sitagliptin Rosiglitazone Pioglitazone Repaglinide Glimepiride Glipizide GITS Metformin Insulin 0 -1.0 -1.5 -2.0 -0.5 Reduction in A1C (%) Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23:1605-1611; Garber AJ et al. Am J Med. 1997;102:491-497; Goldberg RB et al. Diabetes Care. 1996;19:849-856; Hanefeld Met al.Diabetes Care. 2000;23:202-207; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86:280-288; Simonson DC et al. Diabetes Care. 1997;20:597-606; Wolfenbuttel BH, van Haeften TW.Drugs. 1995;50:263-288.

  14. 9 8 7 A1C (%) ULN = 6.2% 6 5 0 0 1 2 3 4 5 6 Years From Randomization UKPDS: Early Initiation of Insulin Therapy Improves A1C Control Conventional therapy Insulin therapy Sulfonylurea ± insulin therapy ULN = upper limit of A1C nondiabetic range. Wright A et al. Diabetes Care. 2002;25:330-336.

  15. 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 8.6% 8.8% 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.

  16. ? Key Question What are the barriers for your patients with type 2 diabetes regarding initiation of insulin therapy? • Concern that insulin use is “forever” • Fear of injection • Equating insulin use with worsening diabetes and complications • Fear of weight gain Use your keypad to vote now!

  17. Patient Barriers to Insulin Use: Perception vs Reality OAD = oral antidiabetic drug. Meese J. Diabetes Educ. 2006;32:9S-18S; Peyrot M et al. Diabet Med. 2005;22:1379-1385.

  18. Clinician Barriers to Insulin Use: Perception vs Reality Douek IF et al. DiabetMed. 2005;22:634-640; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65; Malmberg K et al. BMJ. 1997;314:1512-1515; Romano G et al. Diabetes. 1997;46:1601-1606; UKPDS Group. Lancet. 1998;352:837-853.

  19. Information and Patient Education Links for Healthcare Professionals • American Association of Diabetes Educators (www.diabeteseducator.org) • American Association of Clinical Endocrinologists (www.aace.com) • American Diabetes Association (www.diabetes.org) • International Diabetes Federation (www.idf.org) • National Diabetes Education Initiative (www.ndei.org) • National Diabetes Education Program (ndep.nih.gov) • National Institute of Diabetes and Digestive and Kidney Diseases (www2.niddk.nih.gov)

  20. Next Steps… • What do we do for the patient who has failed on 1 or 2 oral agents?

  21. 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% often brought to goal by addition of basal insulin therapy to OADs • Easy and safe: patient-directed treatment algorithms with small risk of serious hypoglycemia • ADA and EASD recommended: “Although 3 OADs can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense” FPG = fasting plasma glucose. ADA. Diabetes Care. 2006:29(suppl 1):S4-S42; AACE position statement. Available at: http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Nathan DM et al. DiabetesCare. 2006;29:1963-1972.

  22. 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.

  23. 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 on doses” 1 Analog premixes NPA = neutral protamine aspart; NPL = neutral protamine lispro. 1. Nathan DM et al. Diabetes Care. 2006;29:1963-1972.

  24. 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, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY: Martin Dunitz; 2003:131-154.

  25. Breakfast Lunch Dinner Insulin Action 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25)–Aspart Mix (70/30) Glucose levelsInsulin levels Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.

  26. Open-Label, Twice-Daily Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n = 549) Insulin glargine 10 U/d, titrated to target FPG <100 mg/dL Exenatide 5 μg bid 1st 4 weeks, then 10 μg bid 240 240 220 220 200 200 Blood glucose (mg/dL) 180 180 160 160 140 140 Baseline (week 0) 120 120 Baseline (week 0) Endpoint (week 26) Endpoint (week 26) 100 100 Prelunch Prelunch Predinner Predinner 3 AM 3 AM Prebreakfast Prebreakfast Both medications lowered A1C from 8.2% to 7.1% from baseline Weight change: exenatide –2.3 kg, glargine +1.8 kg Nausea: exenatide 57.1%, glargine 8.6% Heine RJ et al. Ann Intern Med. 2005;143:559-569.

  27. STEP 4 STEP 2 STEP 1 STEP 3 Add insulin Last meal • Glargine, Detemir, • or NPH HS • Weekly titration based on FPG • All oral agents continued Add insulin and exenatide or pramlintide Next largestmeal Above target Add insulin Main meal Above target Above target Steps in Transition From Basal to Basal-Bolus Insulin Therapy in T2DM Above target: A1C >7.0% FPG >110 mg/dL A1C <7.0%, FPG <110 mg/dL HS = at bedtime. Adapted with permission from Karl DM. Curr Diab Rep. 2004;5:352-357.

  28. Case Study

  29. Case Study: Initiating Insulin Therapy • 60-year-old man: 10-year history of T2DM and hypertension • Current T2DM medications: metformin 1000 mg bid, rosiglitazone 8 mg AM, and glimepiride 8 mg qd • Hypertension medications: 40 mg lisinopril, 10 mg amlodipine, 12.5 mg HCTZ • Dyslipidemia medication: 10 mg atorvastatin • Physical exam: weight = 245 lb (10-lb increase); height = 6’0”; BMI = 34.2 kg/m2; waist circumference = 44 in; BP = 130/80 mm Hg • Laboratory: TC = 167 mg/dL; TG = 206 mg/dL; HDL = 35 mg/dL; LDL = 90 mg/dL • A1C = 8.9%; plasma glucose in the office = 198 mg/dL • Creatinine 1.1 mg/dL, normal LFTs HCTZ = hydrochlorothiazide; TG = triglycerides; HDL = high-density lipoprotein; LFTs = liver function tests; BMI = body mass index.

  30. Case Study (cont’d) • Patient agrees to basal insulin therapy, however: • Expresses feelings of failure at inability to control glycemia with OADs • Displays anxiety about injections • You explain the progressive nature of diabetes: • Convey that insulin injections are the best way to achieve glycemic control • Describe injection options (“painless” needles, injector pens, etc) • Indicate that you and the patient will be a “team” in getting to the A1C goal

  31. ? Decision Point Which insulin would you use? • NPH at bedtime • Glargine once daily • Twice-daily premixed • Detemir at bedtime Use your keypad to vote now!

  32. Treat-to-Target Trial: Oral Agents + Glargine or NPH at Bedtime • Patients (n = 756) with inadequate glycemic control (A1C >7.5%) taking 1 or 2 oral agents • Started with 10 U/d bedtime basal insulin and adjusted weekly to target FPG 100 mg/dL: Riddle MC et al. Diabetes Care. 2003;26:3080-3086.

  33. 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.

  34. Treat-to-Target Trial: Timing and Frequency of Hypoglycemia Hypoglycemia by Time of Day Basal insulin Insulin glargine 350 * * NPH insulin 300 * 250 * Hypoglycemia Episodes (PG 72 mg/dL) * 200 * * 150 100 50 B L D 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.

  35. 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.

  36. Case Study (cont’d) • 10 U glargine is added to OADs • Patient is sent home with the “2, 4, 6, 8 algorithm” with a target FPG goal of 100 to 110 mg/dL.1 Similar algorithm can be used with detemir2 FPG (mg/dL) Insulin Dose (U/d) 120-140 2 140-160 4 160-180 6 >180 8 Alternative strategy: Increase basal insulin dose by 2 units every 3 days until FPG 100 mg/dL*3 *Certain populations (children, pregnant women, and the elderly) require special considerations. • Riddle MC et al. Diabetes Care. 2003;26:3080-3086. • Hermansen K et al. Diabetes Care. 2006;29:1269-1274. • Davies M et al. Diabetes. 2004;53(suppl 2):A473. Abstract 1980-PO.

  37. Case Study (cont’d) • Patient is seen 1 month later • FPG still above 200 mg/dL, using up to 30 U daily • Patient is frustrated and feels the insulin does not work

  38. ? Decision Point What do you do now? • Keep increasing the insulin dose • Go to twice-daily premixed • Switch to exenatide • Send patient for gastric bypass consult Use your keypad to vote now!

  39. Treat-to-Target Trial 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 N = 756. Riddle MC et al. Diabetes Care. 2003;26:3080-3086. Weeks in Study

  40. Case Study (cont’d) • Patient is taking 75 U with FPG controlled (<100 mg/dL to rarely >110 mg/dL) since last visit 4 months ago • Patient’s last A1C = 6.9%, monitoring occasional postprandial blood sugars • Patient finds insulin injections painless and after speaking with you, feels that he is now a partner in his therapy program

  41. Case Study (cont’d) • Over the next 3 years, patient seen for routine follow-up every 3 to 4 months • Remains medically stable, with A1C values 6.5% to 7.2% • 3.25 years after adding basal insulin glargine, A1C has increased to 8.2%, however, FPG checks remain <120 mg/dL

  42. ? Decision Point What do you do now? • Increase glargine • Switch to twice-daily premixed • Switch to 4-shot basal-bolus program • Increase monitoring to AC and HS, and have patient report after 2 weeks Use your keypad to vote now! AC = before meals; HS = at bedtime.

  43. At Lower A1C Levels, PPG Contributes More to Overall A1C Than FPG Contribution (%) 1 2 3 4 5 A1C Quintile PPG = postprandial glucose. Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.

  44. Prandial Excursions Are Evident, Especially Around a Single Key Meal: Insulin Glargine vs Premixed (n = 209) 350 300 250 200 150 100 50 Premixed† Glargine Baseline Plasma Glucose (mg/dL) * * * * * Week 28 BB L90 D90 B90 BL BD Bed 3 AM Time of Day Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin (BIAsp 70/30) *Denotes statistically significant difference between treatment groups at specific times. †Premixed = BIAsp 70/30. Raskin P et al. Diabetes Care. 2005;28:260-265.

  45. Rapid-acting Inhaled insulin* Idealized Profiles: Rapid-Acting Insulin Analogs Regular insulin 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 *Inhaled dry human insulin (Exubera®) powder Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY: Martin Dunitz; 2003:131-154; Plank J et al. Diabetes Care. 2005; 28:1107-1112; Rave K et al. Diabetes Care. 2005;28:1077-1082.

  46. Breakfast Lunch Dinner Insulin Action 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25)–Aspart Mix (70/30) Glucose levelsInsulin levels Adapted with permission from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342-1349.

  47. Case Study (cont’d) Daily Blood Glucose Diary Week Ending July 24

  48. Analog insulin RHI Timing of food absorbed Meal Insulin: Rapid-Acting Analogs (Lispro, Aspart, Glulisine) vs Regular 10 8 6 Insulin Activity 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 0 Hours RHI = regular human insulin. Adapted with permission from Howey DC et al. Diabetes. 1994;43:396-402.

  49. Advantages of Rapid-Acting Analogs • Short duration of action—fewer between-meal “hypos” than regular insulin • Flexible mealtime dosing • More consistent kinetics • Day to day • Across anatomical sites • With large doses • Slightly faster onset of glulisine action (compared to lispro) in obese and morbidly obese subjects (independent of BMI)* Adapted from Hirsch IB. N Engl J Med. 2005;352:174-183. Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113:435-443. *Heise T et al. Diabetes. 2005;54(suppl 1):A145.

  50. ? Decision Point The best time to use a rapid-acting insulin analog is: • Before a meal • After a meal • Either works well Use your keypad to vote now!

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