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Effective Use of Insulin in Diabetes: Update for 2007 Thomas M. Flood, MD Director Georgia Center for Diabetes Atlanta, Georgia.

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Presentation on theme: "Effective Use of Insulin in Diabetes: Update for 2007 Thomas M. Flood, MD Director Georgia Center for Diabetes Atlanta, Georgia."— Presentation transcript:

1 Effective Use of Insulin in Diabetes: Update for 2007 Thomas M. Flood, MD Director Georgia Center for Diabetes Atlanta, Georgia

2 Key Question 1. Completely comfortable 2. Somewhat comfortable 3. Slightly comfortable 4. 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 Flood has no relevant financial relationships with any commercial interests to disclose.

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. OrganizationA1C Target (%) AACE<6.5 EASD<6.5 ADA<7 (general) <6* (individual patient)

6 Key Question What percentage of patients with diabetes achieve the AACE goal of A1C <6.5%? 1. 25% 2. 35% 3. 55% 4. 75% Use your keypad to vote now! ?

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

8 Diabetes Demographics in the United States Physician-Diagnosed Diabetes (%) Undiagnosed Diabetes (%) Male Female White Black Mexican Total Population Aged ≥20 Years Adapted from: National Center for Health Statistics. Health, United States, With Chartbook on Trends in the Health of Americans. Hyattsville, Md: 2006.

9 Adjusted Incidence per 1000 Person-Years (%) UKPDS = United Kingdom Prospective Diabetes Study. Stratton IM et al. BMJ. 2000;321: Epidemiologic Data From the UKPDS Updated Mean A1C (%) Myocardial infarction Microvascular end points ? AACE Goal No A1C Threshold in Type 2 Diabetes

10 *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: Patients (%) A1C <7% 44.3% NHANES III, n = BP <130/80 mm Hg TC <200 mg/dL 29.0% Good control* 7.3% 5.2% 33.9% 35.8% 37.0% P < % Risk Factor Control in Adults With Diabetes: NHANES III ( )/NHANES NHANES , n = 370

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

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

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

14 Oral Antihyperglycemic Monotherapy Maximum Therapeutic Effect on A1C Precose [PI]. West Haven, Conn: Bayer; 2003; Aronoff S et al. Diabetes Care. 2000;23: ; Garber AJ et al. Am J Med. 1997;102: ; Goldberg RB et al. Diabetes Care. 1996;19: ; Hanefeld M et al. Diabetes Care. 2000;23: ; Lebovitz HE et al. J Clin Endocrinol Metab. 2001;86: ; Simonson DC et al. Diabetes Care. 1997;20: ; Wolfenbuttel BH, van Haeften TW. Drugs. 1995;50: Acarbose Insulin Nateglinide Reduction in A1C (%) Glipizide GITS Glimepiride Repaglinide Pioglitazone Metformin Rosiglitazone Sitagliptin

15 UKPDS: Early Initiation of Insulin Therapy Improves A1C Control ULN = upper limit of A1C nondiabetic range. Wright A et al. Diabetes Care. 2002;25: Conventional therapy Insulin therapy Sulfonylurea ± insulin therapy A1C (%) ULN = 6.2% Years From Randomization

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

17 Key Question What are the barriers for your patients with type 2 diabetes regarding initiation of insulin therapy? 1. Concern that insulin use is “forever” 2. Fear of injection 3. Equating insulin use with worsening diabetes and complications 4. Fear of weight gain Use your keypad to vote now! ?

18 PerceptionReality Failing oral therapy 58% of patients believe using insulin means they have failed OAD therapy OAD failure is due to progressive nature of type 2 diabetes; insulin is best agent to control disease Needle phobia Fear associated with early experiences Current needles considered painless; easy-to-use injection systems are available Fear of complications Common association of insulin with diabetic complications Complications are due to uncontrolled, progressive disease; insulin actually results in reduction of vascular damage 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:

19 PerceptionReality Hypoglycemia is prevalent with insulin use Severe hypoglycemia is very uncommon in patients with type 2 diabetes, occurring at 10% the rate in patients with type 1 diabetes Insulin use increases atherosclerosis Studies indicate no exacerbation of cardiovascular disease There is weight gain with insulin use Weight gain is modest and can be controlled with diet and exercise Patients have a negative attitude regarding insulin use Insulin is a “positive” approach to achieving glycemic control Clinician Barriers to Insulin Use: Perception vs Reality Douek IF et al. Diabet Med. 2005;22: ; Malmberg K et al. J Am Coll Cardiol. 1995;26:57-65; Malmberg K et al. BMJ. 1997;314: ; Romano G et al. Diabetes. 1997;46: ; UKPDS Group. Lancet. 1998;352:

20  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) Information and Patient Education Links for Healthcare Professionals

21 Next Steps…  What do we do for the patient who has failed on 1 or 2 oral agents?

22 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: Nathan DM et al. Diabetes Care. 2006;29:

23 B = breakfast; D = dinner; L = lunch; T2DM = type 2 diabetes mellitus. Polonsky KS et al. N Engl J Med. 1988;318: GlucoseInsulin 6:0010:0018:0014:002:0022:006:00 Time 6:0010:0018:0014:002:0022:006:00 Time BLDBLD Normal T2DM mg/dL μU/mL Basal insulin Rationale for Basal Insulin Therapy: Insulin and Glucose Patterns

24 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 NPA = neutral protamine aspart; NPL = neutral protamine lispro. Analog premixes

25 Plank J et al. Diabetes Care. 2005;28: ; Rave K et al. Diabetes Care. 2005;28: ; Rosenstock J, Goldstein BJ, et al, eds. Textbook of Type 2 Diabetes. London, UK, and New York, NY: Martin Dunitz; 2003: Idealized Profiles of Human Insulin and Basal Insulin Analogs 0:00 2:004:006:008:00 10:00 12:0014:0016:0018:0020:0022:0024:00 Plasma Insulin Levels Time NPH Glargine Detemir

26 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: Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25) – Aspart Mix (70/30) 4:0016:0020:0024:004:00 BreakfastLunchDinner Insulin Action 8:00 12:008:00 Time Glucose levels Insulin levels

27 Open-Label, Twice-Daily Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n = 549) Blood Glucose (mg/dL) 3 AM Baseline (week 0) Endpoint (week 26) Baseline (week 0) Endpoint (week 26) Exenatide 5 μg bid 1st 4 weeks, then 10 μg bid Insulin Glargine 10 U/d, titrated to target FPG <100 mg/dL Prebreakfast Prelunch Predinner 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: AM Prebreakfast Prelunch Predinner

28 HS = at bedtime. Adapted with permission from Karl DM. Curr Diab Rep. 2004;4: 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 Glargine, Detemir, or NPH HS Weekly titration based on FPG All oral agents continued STEP 1 Above target Add insulin Main meal STEP 2 Above target Add insulin Next largest meal STEP 3 Above target Add insulin Last meal STEP 4

29 Case Study

30 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/m 2 ; 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.

31 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

32 Decision Point Which insulin would you use? 1. NPH at bedtime 2. Glargine once daily 3. Twice-daily premixed 4. Detemir at bedtime Use your keypad to vote now! ?

33 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: Hermansen K et al. Diabetes Care. 2006;29: ; Riddle MC et al. Diabetes Care. 2003;26: Mean self-monitored FPG values from preceding 2 days (mg/dL) Increase of insulin dosage (U/d) ≥ – – – 1202

34 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:

35 Insulin glargine NPH insulin :0022:0024:002:004:006:008:0010:0012:0014:0016:0018:00 Time B L D Basal insulin 20:00 Hypoglycemia by Time of Day Hypoglycemia Episodes (PG  72 mg/dL) Riddle MC et al. Diabetes Care. 2003;26: *P <.05 (between treatment). * * * * * * * Treat-to-Target Trial: Timing and Frequency of Hypoglycemia

36 Detemir vs NPH Insulin in T2DM (n = 476) *All reported events, including symptoms only. Hermansen K et al. Diabetes Care. 2006;29: Hypoglycemia Events* Detemir NPH A1C (%) Study Week Study Week Detemir NPH

37 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 detemir 2 FPG (mg/dL)  Insulin Dose (U/d) >1808 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. 1.Riddle MC et al. Diabetes Care. 2003;26: Hermansen K et al. Diabetes Care. 2006;29: Davies M et al. Diabetes. 2004;53(suppl 2):1980.

38 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

39 Decision Point What do you do now? 1. Keep increasing the insulin dose 2. Go to twice-daily premixed 3. Switch to exenatide 4. Send patient for gastric bypass consult Use your keypad to vote now! ?

40 Units Weeks in Study Total Daily Dose (U) N = 756. Riddle MC et al. Diabetes Care. 2003;26: Treat-to-Target Trial

41 Case Study (cont’d)  Patient is taking 75 U with FPG controlled ( 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

42  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 Case Study (cont’d)

43 Decision Point What do you do now? 1. Increase glargine 2. Switch to twice-daily premixed 3. Switch to 4-shot basal-bolus program 4. 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.

44  Because the patient’s FPGs are good and post- prandial glucose levels are high, the decision is made to switch to twice-daily premixed insulin  The patient is encouraged to increase daily monitoring to adjust insulin dose Case Study (cont’d)

45 PPG = postprandial glucose. Reprinted with permission from Monnier L et al. Diabetes Care. 2003;26: Contribution (%) A1C Quintile At Lower A1C Levels, PPG Contributes More to Overall A1C Than FPG 12345

46 Prandial Excursions Are Evident, Especially Around a Single Key Meal: Insulin Glargine vs Premixed (n = 209) 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: * Plasma Glucose (mg/dL) Week 28 Baseline Glargine Premixed † Time of Day BB B90BL L90 BD D90 Bed3 AM * * * *

47 Case Study (cont’d) BreakfastLunchDinnerMS Middle of Night Dose Blood Sugar Dose Blood Sugar Dose Blood Sugar Dose Blood Sugar Monday Tuesday Wednesday  Thursday Friday Saturday Sunday Daily Blood Glucose Diary March 24Week Ending

48 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: Twice-Daily Split-Mixed Regimens or Lispro Mix (75/25) – Aspart Mix (70/30) 4:0016:0020:0024:004:00 BreakfastLunchDinner Insulin Action 8:00 12:008:00 Time Glucose levels Insulin levels

49 *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: ; Plank J et al. Diabetes Care. 2005; 28: ; Rave K et al. Diabetes Care. 2005;28: Idealized Profiles: Rapid-Acting Insulin Analogs 0:00 2:004:006:008:00 10:00 12:0014:0016:0018:0020:0022:0024:00 Plasma Insulin Levels Time Regular insulin Rapid-acting Inhaled insulin*

50 Case Study (cont’d)  Decision is made to switch to basal-prandial therapy to reduce hypoglycemia and postprandial highs  60% of patient’s total daily insulin dose is given as basal insulin – 54 U glargine qhs titrated to FPG mg/dL  Before the main meal, a rapid-acting analog is added: glulisine, initiated at 5 units, up-titrated using a treat-to-target algorithm  Patient continues to self-monitor glucose

51 Meal Insulin: Rapid-Acting Analogs (Lispro, Aspart, Glulisine) vs Regular Hours RHI = regular human insulin. Adapted with permission from Howey DC et al. Diabetes. 1994;43: Insulin Activity RHI Timing of food absorbed Analog insulin

52 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: Becker RHA et al. Exp Clin Endocrinol Diabetes. 2005;113: *Heise T et al. Diabetes. 2005;54(suppl 1):A145.

53 Decision Point The best time to use a rapid-acting insulin analog is: 1. Before a meal 2. After a meal 3. Either works well Use your keypad to vote now! ?

54 Pre- and Postmeal Efficacy of Insulin Glulisine vs Regular Human Insulin Garg SK et al. Endocr Pract. 2005;11:11-17; Garg SK et al. Poster presented at ADA 64th Annual Scientific Sessions, June 4-8, 2004, Diabetes. 7:529P. Significant A1C reduction with premeal glulisine compared to premeal human insulin Significant reduction in A1C with pre- and postmeal glulisine Baseline Endpoint P <.05

55 Case Study (cont’d)  At 6-month follow-up patient is doing well with 70 U glargine and 10 U to 17 U glulisine at supper  Actual dose adjusted by  Meal carbohydrate content  Activity  Insulin supplement of additional 1 U for every 25 mg/dL above 130 mg/dL (prandial glucose)  A1C = 6.3%  He feels well, has infrequent “hypos,” and is pleased with his blood glucose control

56 Q & A

57 PCE Takeaways

58 PCE Takeaways: Basal-Prandial Insulin Replacement 1. An effective insulin treatment strategy provides both basal and postprandial insulin coverage 2. Initially, prandial insulin may be needed only at the largest meal of the day, with coverage at other meals added based on prandial glucose levels 3. Rapid-acting insulin analogs closely match normal mealtime insulin patterns

59 Key Question 1. Much more comfortable 2. Somewhat comfortable 3. Slightly comfortable 4. Not comfortable at all Use your keypad to vote now! ? How much more comfortable do you now feel you will be initiating insulin therapy in your patient population?


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