1. PRACTICAL INSULIN USE PRACTICAL INSULIN USE or, how to think like a pancreas Oliver Z. Graham, MD Department of Internal Medicine Virtual Endocrinologist

2. “Truly understanding issues such as when to use regular insulin, when it would be better to use insulin lispro or aspart… simply requires a great deal of experience.” --Irl Hirsch, MD, UC San Diego, Clinical Diabetes 2001

3. “It tends to be more difficult to manage a patient on insulin if you don’t really understand what you’re doing.” --Oliver Z. Graham, MD, reflecting on personal Experience, Pittsburgh Health Center

4. Types of Insulin

6. Types of Insulin: Lispro and Aspart (Humalog/Novolog) Fast acting (works within 5 min) Better matches carbohydrate intake to insulin dose Can take right before meals

7. Types of Insulin: Regular Slower onset and later peaking Must take 30-45 min before meals Doesn’t really match blood sugar levels, especially with high carbo meals May lead to hyperglycemia immediately after meals with hypoglycemia several hours thereafter

8. Types of Insulin: NPH Long acting, with peak at 6-10 hours May be used for AM dosing to cover midday meals, used in PM to cover overnight Commonly used BID as 70/30

9. Types of Insulin: Glargine (Lantus) A true basal insulin with a 24 hour, peakless, predictable effect Simulates basal pancreatic insulin secretion

10. 70/30 (NPH/Regular) BID

11. 2 Injections/day (ie 70/30) using regular/NPH Postprandial glucose levels for breakfast/dinner covered by short acting insulins, lunch and overnight sugars covered by NPH Advantage: 2 Injections/day Disadvantage: –NPH given at supper does not last until breakfast, leading to high AM BS –NPH in AM does not cover lunch BS well

12. Lispro/Glargine

13. 4 Injections/day using Lispro/Glargine One dose basal insulin during day and overnight, with rapid/short acting insulin covering meals Advantage: –Allows for meal to meal adjustments of insulin in accordance to food intake, preprandial blood glucose levels, and exercise. –With lispro, probably offers the tightest control of BS given its physiologic simulation of insulin secretion (the “poor man’s insulin pump”) Disadvantage: –Its 4 injections

14. Case Study #1 See your handout for details

15. Question 1: How would you go about improving John’s glycemic control?

17. Question #2: If you choose insulin, should you start a long acting/short acting or both?

19. Relative contribution of fasting and postprandial glucose to A1C.

20. Starting Insulin 101 For HA1C > 9, FIX FASTING FIRST –Self monitoring on fasting glucose is easier for most patients –Fasting glucose is primarily influenced by stage of disease and meds Diet and activity have limited influence on fasting BS –Controlling postprandial BS is difficult with poorly controlled fasting sugars

21. Starting Insulin 101 As you near target A1C (<7), post prandial control gets more important

22. Question #3: If basal insulin, how/which do you start? –Lantus (glargine)? –NPH?

23. Lantus vs. NPH Equally efficacious when added to orals in achieving HA1c value Lantus associated with 41% lower risk of severe hypoglycemia (BS < 51)

24. How to start insulin gently Continue oral agents at same dosage –Consider d/c sulfonyurea Add single dose at 10 U or 0.15 U/kg –NPH at bedtime –Glargine anytime

25. How to start insulin gently, continued Have patient adjust dose by fasting BG every 3-5 days –Increase 4 U if FBG > 140 –Increase 2 U if FBG 120-140 –No change if FBG < 120 –Decrease dose by 2 U if FBG < 72 or sx hypoglycemia Check in by phone in 1-2 weeks

26. Question #3: What about Byetta (exanatide)? Would that be a reasonable alternative to insulin?

27. Byetta (exanatide) Naturally occurring component of Gila Monster Saliva Stimulates insulin release from pancreas, slows gastric emptying, inhibits glucagon release

28. Why use Byetta? Most patients gain weight with DM tx –Insulin tx  4 lb increase for every 1% A1c reduction With Byetta  WEIGHT LOSS –12 pound loss at 2 years tx A1c reduction about 1.1% ? Animal studies suggest beta cell regeneration

29. Why not use Byetta? Expensive (1 year -- $2700) Long term data not available (lessons from Avandia & Rezulin…) Nausea very common (50-60%) Because slows gastric emptying CONTRAINDICATED in GASTROPARESIS 2 injections/day

30. Who might get Byetta? Obese patients not at A1C target who are already on metformin, sulfonyurea or both or glitazone +/- metformin Not FDA approved for pts on 3 oral agents or on insulin

31. How to use Byetta Start 5 mcg BID prior to meals, titrate up to 10 mcg BID as tolerated at one month

32. Question #4: Should John get Byetta?

33. Case study, continued John has titrated up his Glargine to 40 U daily, and his A1c decreased to 7.8%. He then missed his next appointment, and comes back 6 months later.

34. Case study, continued Current meds: –Lantus 40 U daily –Metformin 1000 BID –Glipizide 10 mg BID HA1c 8.5% What do you do now? Are “lifestyle” changes still worthwhile?

35. Exercise and DM Studies show regular exercise –reduced A1c from 8.3  7.65%

36. Diet and DM Caloric restriction and weight loss (even 5-10% of body weight) can lead to: –Improved glucose control –Improved sensitivity to insulin –Improved lipid profiles and BP

37. Case study, continued Current meds: –Lantus 40 U daily –Metformin 1000 BID –Glipizide 10 mg BID HA1c 8.5% He says his knees hurt and he doesn’t want to start an exercise program. His diet is reasonable, but he is unable to lose more weight. How would you adjust his insulin at this time?

39. How to initially dose prandial insulin –1 unit for every 10 g carb (needs to learn carb counting) OR –5 units for a small meal –8-10 units for a large meal OR –Start with 4 units largest meal, titrate up every three days (see algorithm) OR –Calculate insulin needs (0.1 U/kg prior to each meal) AND –1 unit additional correction factor for every 30-50 mg/dl above 100 mg/dl preprandial (see handout)

40. Case Study, continued John really doesn’t want to do more than 2 injections/day. How do you manage his insulin now?

41. Insulin Regimens: 2 Injections/ day Postprandial glucose levels for breakfast/dinner covered by short acting insulins, lunch and overnight sugars covered by NPH Advantage: 2 Injections/day Disadvantage: –NPH given at supper does not last until breakfast, leading to high AM BS –NPH in AM does not cover lunch BS well

42. Transition From One Regimen to Another

43. Case continued John comes in two weeks later on the following DM meds: –70/30 20 U BID –Metformin 1000 BID –Glipizide 10 mg BID AM BS – 100, 90, 120, 111, 110 PM BS -- 150, 144, 179, 180, 168 What is your next step?

44. 70/30 (NPH/Regular) BID

45. Dosage Titration for Once-Daily or Twice-Daily Insulin Regimens

46. Case Study #2 RR is a 32 year old type I diabetic who was first diagnosed at age 12. Her HgA1c have ranged between 10-12 over the past ten years, and she is now legally blind from diabetic retinopathy and has a creatinine of 2.6. Her current insulin regimen is N 22 (AM) N 18 (PM) as well as sliding scale regular prior to meals. There have been 3 episodes of hypoglycemia in the past 2 weeks. She now comes to your clinic for the first time in 6 months without a blood sugar log book and wants you to “fix her diabetes” as well as signing some paperwork for in home support services and giving her some vicodin for her neuropathy. What do you think her target blood sugars should be?

47. Glycemic Goals for Intensive Insulin Therapy Preprandial: 90-130 1-2 Hours Postprandial: 160-180 Target HbA1c < 6.5 - 7

48. Intensive Insulin Therapy: Relative Contraindications Individuals with hypoglycemia awareness Individuals with recurrent, severe hypoglycemic episodes Individuals with severe emotional disorders or psychosocial stressors Individuals with alcohol or drug abuse problems Individuals with advanced, end stage diabetic complications Individuals with medical conditions that can be aggravated by hypoglycemia, I.e. cerebrovascular disease, angina, or cardiac arrhythmia Intensive Diabetes Management, 1998

49. Intensive Insulin Therapy: Relative Contraindications, cont Individuals unable or unwilling to commit to the personal effort and involvement required for intensive diabetes management Individuals with concurrent illness and/or conditions that would functionally limit intensive management I.e. debilitating arthritis or severe visual impairment Individuals with a relatively short life expectancy Individuals who live alone Intensive Diabetes Management, 1998

50. Glycemic Goals for not-so- Intensive Insulin Therapy “Good control”: HbA1c<8 “Fair control”: pre-meal BG<200 “Do no harm control”: Avoid hyper/hypoglycemic symptoms only One blood sugar target does not fit all

51. Feel proud of any HgA1c reduction From “horrible control” to “poor control” – pat yourself on the back!!

52. Focus on the ABC’s A1c Blood Pressure Cholesterol

55. Organizational Guidelines – the consensus…. Per American Diabetes Association, JNC 7, California Department of Health Services, National Kidney Foundation, Singapore Ministry of Health, Scottish Intercollegiate Guidelines Network and many others IF DM GOAL BP < 130/80

56. Results From Statin Trials for Patients With Diabetes

58. ARE YOU LISTENING??? ARE YOU LISTENING??? Another Case Study A 29 year old patient has a very hectic life with two children and also works part time at a drug store. Her time of meals, length of workday and levels of physical activity are variable.

59. Her current insulin regimen is 4R + 10N (8 AM), 8R + 14 N (Before dinner) What could account for the variability of the readings?

60. What affects Blood Sugars? Foods Inconsistent eating habits –overeating or skipping meals –Altering timing of meals when on a fixed dose insulin schedule –variations in the carbohydrate load, glycemic index or fat content

61. DM and carbohydrates The amount of carbohydrates directly affects post-prandial blood sugars. To achieve good control, patients either need to learn: Carbohydrate Consistency: Eat the same amount of carbs at every meal for predetermined insulin dosage Carbohydrate Counting: Count up the amount of carbohydrates in the meal, and adjust insulin dosage accordingly

62. DM Nutrition 101 Increase activity Decrease calories for weight loss Whole grains instead of refined grains and starches Low saturated and hydrogenated fats Carb/meal consistency or carb counting

63. ARE YOU LISTENING??? ARE YOU LISTENING??? A Case Study A patient who has been treated for type 1 DM for 6 years is on N25 R10 (8 AM), N15 R10 (6 PM). His BS are: How would you change his regimen?

64. Adjusting Insulin If glucose levels are out of target at Check coverage provided by Postbreakfast/prelunchPrebreak short insulin Postlunch/presupperPrelunch short insulin and/or AM NPH Postsupper/bedtimePresupper short insulin MidafternoonMorning NPH or long acting insulin Early morningEvening NPH or long acting insulin

65. ARE YOU LISTENING??? ARE YOU LISTENING??? A Case Study A patient who has been treated for Type I DM for 14 years has the following regimen: N42 + R12 (8 AM), N21 + R 15 (6 PM) How would you change his insulin regimen? How do you account for the blood sugar outliers?

66. ARE YOU LISTENING??? ARE YOU LISTENING??? A Case Study His regimen :N42 + R12 (8 AM), N21 + R 15 (6 PM) Avg AM – 172 (excluding 95) Avg lunch 172 Avg dinner 129 (excluding 275) Avg QHS 225 Change evening to N24 + R18, should improve daytime values

67. Adjusting insulin Insulin adjustments should be based on average blood glucose readings, not the outliers Changes should be made based on numbers over several days to over 1-2 weeks Except for severe hypo/hyperglycemia, changes should be made in 10-20% increments (about 1-5U at a time)