1. Insulin Therapy and Other Management Issues in Type 1 Diabetes Mellitus Philip Raskin, MD Jaime A. Davidson, MD The University of Texas Southwestern Medical Center

2. Treatment Guidelines for Diabetes American Diabetes Association 1 –HbA1c <7.0% –Preprandial BG 70–130 mg/dL –Postprandial BG <180 mg/dL American Association of Clinical Endocrinologists 2 –HbA1c ≤6.5% –Preprandial BG <110 mg/dL –Postprandial BG <140 mg/dL International Diabetes Federation –HbA1c <6.5% 3,4 –Preprandial BG <110 mg/dL 3,4 –Postprandial BG <160 mg/dL 4 1. American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S11-S63. 2. AACE. Endocr Pract. 2011;17(suppl 2):1-53. 3. IDF. Global Guideline for Type 2 Diabetes. 2005. 4. IDF. Guideline for Management of PostMeal Glucose in Diabetes. 2011.

3. Type 1 Diabetes Mellitus Type 1 (immune-mediated beta cell destruction leading to absolute insulin deficiency) Dependent on exogenous insulin Prone to ketoacidosis Usually lean, but not always Recent weight loss Abrupt onset of symptoms, often before age 30 May occur at any age

4. Natural History of Type 1 Diabetes CELLULAR (T CELL) AUTOIMMUNITY LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) GLUCOSE INTOLERANCE (OGTT) HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD 65, IA 2 Ab, etc.) PUTATIVE ENVIRONMENTAL TRIGGER CLINICAL ONSET TIME BETA CELL MASS DIABETES “PRE”- DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY With permission from Skyler JS, et al. Diabetes. 2011;60:1-8.

5. As Early as Possible in the Course of Diabetes Metabolic Memory: Benefits of good diabetes control are long-lasting in both type 1 and type 2 diabetes 1,2 Intensive diabetes control in older diabetic individuals with long-standing Type 2 diabetes and well-established microvascular and macrovascular complications can result in bad outcomes (ACCORD, etc)? 3 When to Initiate Intensive Therapy in Type 1 Diabetes? 1.DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653. 2.UKPDS Group. N Engl J Med. 2008;359:1577-1589. 3. ACCORD Study Group. N Engl J Med. 2011;364:818-828.

6. DCCT Microvascular Complication Event Rates 1. DCCT Research Group. Ophthalmology. 1995;102:647-661. 2. DCCT Research Group. Kidney Int. 1995;47:1703-1720. 3. DCCT Research Group. Ann Intern Med. 1995;122:561-568. Retinopathy Progression 1 Laser Rx 1 Microalbuminuria 2 Albuminuria 2 Clinical Nephropathy 3

7. DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569. Further Retinopathy Progression Over 7 Years of EDIC from the Level at DCCT Closeout Even after intensive therapy was stopped at the end of DCCT, effects of intensive therapy persisted for >7 years Difference between conventional and intensive therapy accelerated even after the treatments ended After 7 years of EDIC –Risk reduction: 62% with intensive therapy (95% CI 51%-70%, P <.001)

8. Meta-analysis: Improved Glucose = Reduction in Macrovascular Events With reduction in glucose, there is greater improvement in macrovascular events in glucose T1DM vs T2DM* Stettler C, et al. Am Heart J. 2006;152:27-38. Combined incidence Any macrovascular event T1DM 0.38 (95% CI, 0.26–0.56) T2DM 0.81 (95% CI, 0.73–0.91) Cardiac events T1DM 0.41 (95% CI, 0.19–0.87) T2DM 0.91 (95% CI, 0.80–1.03) Peripheral vascular events T1DM 0.39 (95% CI, 0.25–0.62) T2DM 0.58 (95% CI, 0.38–0.89) Cerebrovascular events T1DM 0.34 (95% CI, 0.05–2.57) T2DM 0.58 (95% CI, 0.4–0.74) *Incidence rate ratios are shown for T1DM (based on 8 randomized studies) and T2DM (based on 6 randomized studies).

9. Insulin

10. Insulin Analog Insulin produced by technology that uses recombinant DNA to produce an insulin molecule that is slightly different from human insulin in structure as well as pharmacokinetic/ pharmacodynamic properties

11. Insulin Preparations Agents Regular, NPH Human 70/30 Insulin aspart, glulisine and lispro, insulin glargine and detemir Insulin lispro 75/25, 50/50 Biphasic insulin aspart 70/30 Class Human Insulin Premixed Human Insulin Insulin Analogs Premixed Insulin Analogs

12. Time Action Profiles of Insulin Products Rapid-acting insulin analogs (insulin aspart, insulin glulisine, insulin lispro) –Duration of action: 4–6 hours Regular insulin –Duration of action: 8–10 hours NPH insulin –Duration of action: 12–18 hours Long-acting insulin analogs (insulin glargine, insulin detemir) –Duration of action: 20–24 hours

13. Rapid-Acting Analogs vs Regular Human Insulin Insulin Level (  U/mL) 800 700 600 500 400 300 200 100 0 With permission from Woodworth, et al. Diabetes. 1993;42(suppl 1):54A. 012345678012345678 Time (hours) 0.05 U/kg (n = 6) 0.1 U/kg (n = 9) Regular Human Insulin 0.2 U/kg (n = 9) 0.3 U/kg (n = 3) 800 700 600 500 400 300 200 100 0 012345678012345678 Time (hours) Rapid-Acting Analogs Glucose Insulin Rate (mg/min)

14. Braak EW, et al. Diabetes Care. 1996;19:1437-1440. Rapid-Acting Analogues T max (hours)* Regular Human Insulin 1.0 0.77 1.0 3.8 1.3 3.1 * 0.2 U/kg sc. Comparison of Insulin Absorption by Injection Site

15. Management of Type 1 Diabetes

16. Intensive Diabetes Management Goals of Therapy Tools of Therapy Systems of Therapy Defined by

17. Intensive Diabetes Management Near-normal glycemia Near-normal glycohemoglobin Prevention of complications Absence of hypoglycemia Goals

18. Intensive Diabetes Management Multiple-component insulin regimen Daily blood glucose monitoring Careful balance of food intake, activity, and insulin dosage An action plan for patient adjustment of the above, and the use of insulin supplements Defined target blood glucose levels (individualized) Elements of Management

19. Intensive Diabetes Management Frequent contact between patient and health care providers Patient education and motivation Psychological support Assessment (glycohemoglobin) Elements of Management

20. Intensive Diabetes Management Basal Meal-related Components of Insulin Replacement

21. Basal Bolus Therapy

22. Plasma Insulin (  U/mL) Time 4:008:0012:0016:0020:0024:004:008:00 Breakfast Lunch Dinner Glargine/Detemir 75 50 25 0 Basal/Bolus Idealized Absorption of Analog Insulin Bedtime Lispro/Aspart/Glulisine Courtesy of Davidson JA.

23. Insulin Pumps

24. Time of Day 20 40 60 80 100 BLD 0600 0800 1800 12002400 Bolus Continuous infusion for basal delivery Bolus  U/mL Bolus Insulin Pump Delivery Rapid-Acting Analogs B=breakfast; L=lunch; D=dinner Courtesy of Davidson JA.

25. Insulin Pumps

26. Wearing the Insulin Pump

27. Intensive Diabetes Management Basal: 40%–60% Premeal: 40%–60% –If according to carbohydrate  0.8–1.2 units/gram carbohydrate –If according to % of total daily dose  15%–25% before breakfast  15% before lunch  15%–20% before dinner Insulin Dose Distribution

28. Insulin dosage Insulin timing Meal size Meal content Intensive Diabetes Management Preprandial Algorithms

29. Intensive Diabetes Management Supplements Adjustments Insulin Dose Changes

30. Intensive Diabetes Management Supplements –Compensatory –Anticipatory Insulin Dose Changes

31. Compensatory supplements –Based on prevailing blood glucose –Corrects blood glucose outside “target” range –Alters basic dose for that point in time Intensive Diabetes Management Insulin Dose Changes

32. Intensive Diabetes Management Blood glucose –<50 mg/dL – 51–100 mg/dL –101–150 mg/dL –151–200 mg/dL –201–250 mg/dL –251–300 mg/dL –>300 mg/dL Fast-acting insulin –Decrease 2 units –Decrease 1 unit –Take usual dose –Increase 1 unit –Increase 2 units –Increase 3 units –Increase 4 units Compensatory Supplements Per Dr. Raskin.

33. Intensive Diabetes Management What is my blood glucose now? Do I plan to eat more or less than usual? Will I be more or less active after eating? What has happened under these circumstances previously? Insulin Dose Changes Mealtime Questions

34. Insulin Dose Changes Adjustments –Based on pattern over several days –~10% increase or decrease in insulin component preceding BG measurement –Change one component at a time Intensive Diabetes Management

35. Insulin Timing Regular insulin usually 30–60 minutes before meals Rapid-acting analogs taken at mealtime or better yet 15 minutes before –Increase time interval if blood glucose above target (further from meal) –Decrease time interval if blood glucose below target (closer to meal) Intensive Diabetes Management

36. Meal Size or Carbohydrate Content Decrease if blood glucose above target or less activity planned Increase if blood glucose below target or more activity planned Intensive Diabetes Management

37. Criteria for Selection of Patients Suboptimal glycemic control Motivation to pursue intensive therapy Willing and able to perform frequent SMBG Sufficient education and ability Adequate psychological stability Appropriate financial resources Skilled medical staff available Intensive Diabetes Management

38. Contraindications Hypoglycemia unawareness Counterregulatory unresponsiveness Age Medical reasons, debilitated, short life expectancy, malignancy, etc Intensive Diabetes Management

39. Benefits of Insulin Pump Therapy Allows for flexibility in schedule More physiologic and reproducible Insulin delivery more predictable Less hypoglycemia (exercise) Intensive Diabetes Management

40. Self-Blood Glucose Monitoring Essential Component of Intensive Management Intensive Diabetes Management

41. Blood Glucose Monitoring Initially, check blood glucose before and 1.5–2 hours after each meal and at bedtimeInitially, check blood glucose before and 1.5–2 hours after each meal and at bedtime Weekly at 2:00 AM–3:00 AM Weekly at 2:00 AM–3:00 AM Four blood glucose checks before each meal after targets are achievedFour blood glucose checks before each meal after targets are achieved

42. Effect of Memory Meter on HbA1c in Patients with Type 1 Diabetes N = 22 intensively treated T1DM patients (using insulin pump or 4 daily insulin injections) Monthly mean HbA1c across 12 months –HbA1c 6.9% ± 0.12% before memory meter –HbA1c 6.4% ± 0.10% while a memory meter was used –P =.0004 –Difference in slopes P =.046 As the frequency of SMBG (tests/day) increased, HbA1c decreased: r = −0.61, P <.01 Strowig SM, Raskin P. Diabetes Care. 1998;21:1694-1698.

44. Hypoglycemia

45. Hypoglycemia Identify hypoglycemia patterns and relate to insulin peaksIdentify hypoglycemia patterns and relate to insulin peaks Look for causesLook for causes — Lifestyle issues — Lifestyle issues Exercise Exercise Food Food Alcohol Alcohol — Medical causes — Medical causes Altered kidney or liver function Altered kidney or liver function Hormonal deficiencies (eg, pituitary or adrenal) Hormonal deficiencies (eg, pituitary or adrenal) Rapid gastric emptying Rapid gastric emptying Hypoglycemia unawareness Hypoglycemia unawareness National Diabetes Information Clearinghouse (NDIC). Hypoglycemia. Accessed 1/29/13 at: http://diabetes.niddk.nih.gov/dm/pubs/hypoglycemia/#symptoms.

46. 46 15 g CHO as juice, soda, or glucose tablets

47. 47

48. Monitoring GLYCOHEMOGLOBIN 1 –1–2 MONTHS DURING STABILIZATION –2–4 MONTHS ROUTINELY BLOOD PRESSURE—every visit 1 –Probably should be measured in both supine and standing positions 2 URINE PROTEIN/MICROALBUMIN—annually 1,2 EYE EXAMS—annually 1,2 FOOT EXAMS—annually 1,2 LIPIDS—annually 1,2 1. American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S11-S63. 2. AACE. Endocr Pract. 2011;17(suppl 2):1-53.

49. Adherence

50. Adherence to Insulin in Pediatric Type 1 Diabetes Meta-analysis of 21 studies (N = 2492) Increased adherence is associated with decreased HbA1c values –Greater association pre-DCCT vs post- DCCT, possibly due to increased complexity of regimens Hood KK, et al. Pediatrics. 2009;124:e1171-e1179.

51. Adherence During Transition to Adolescence in Type 1 Diabetes 2-year longitudinal, multisite study of youth aged 9–11 (N = 225) HbA1c increased (8.2 to 8.6%, P <.001) Blood glucose monitoring frequency decreased (4.9 to 4.5/day; P <.02) Change in HbA1c associated with change in blood glucose monitoring frequency (P <.001) Rausch JR, et al. Diabetes Care. 2012;35:1219-1224.

52. Adherence to Insulin in Adults with Diabetes Internet survey of US adults (N = 502) 57% reported skipping insulin injections –20% regularly skip insulin injections Risk factors for intentional insulin omission –Type 2 vs type 1 diabetes –Higher number of injections –Perceived injection burden  Interference with daily activities  Pain  Embarrassment Peyrot M, et al. Diabetes Care. 2010;33:240-245.

53. Global Attitudes of Patients and Physicians in Insulin Therapy (GAPP) Study Multinational internet survey –1250 physicians –1530 patients age ≥18 (n = 180 with type 1 diabetes) Patients –Overall: 33.2% reported being nonadherent ≥1 day in previous month (mean 3.3 days) –US: 41.9% reported being nonadherent  2nd highest level among 8 countries in study Physicians –72.5% reported that some patients do not take insulin as prescribed Peyrot M, et al. Diabet Med. 2012;29:682-689.

54. Most Common Reasons for Insulin Omission/Nonadherence Was too busy Was traveling Skipped meals Stress or emotional problems Embarrassment Difficult to take it at the same time every day Peyrot M, et al. Diabet Med. 2012;29:682-689.

55. Conclusions People with T1DM require insulin on a daily basis for survival Intensive diabetes treatment can prevent the development and progression of microvascular complications in diabetes Because there is metabolic memory, intensive diabetes treatment should be initiated as early in the course of T1DM as is possible

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