1. Diabetes Mellitus Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University isales@ksu.edu.sa

2. Insulin

3. Normal Physiologic Insulin Secretion The Basal/Bolus Concept Insulin Effect B L D HS B

4. Basal/Bolus Concepts: Mimicking Natural Physiology Insulin Secretion 12:006:0018:0024:00 Time Basal Insulin Secretion 6:00

5. Basal/Bolus Concepts: Mimicking Natural Physiology Insulin Secretion 12:006:0018:0024:00 Time 6:00 Bolus Insulin Secretion SupperBreakfastLunch

6. Basal/Bolus Concepts: Mimicking Natural Physiology Insulin Secretion 12:006:0018:0024:00 Time 6:00 Bolus Insulin Secretion Basal Insulin Secretion BreakfastLunchSupper

7. Basal/Bolus Concepts: Mimicking Natural Physiology Characteristics of Healthy Basal Insulin Secretion Endogenous secretion over 24 hours Relatively constant insulin release with no pronounced peaks Suppresses glucose production between meals and over night 50% of daily needs Predictable absorption pattern in healthy individuals without diabetes

8. Basal/Bolus Concepts: Mimicking Natural Physiology Characteristics of Healthy Bolus Insulin Secretion Endogenous secretion in response to a meal stimulus Limits hyperglycemia after meals Rapid insulin release with an immediate rise and sharp peak at 1 hour Relatively short duration of action 10%-20% of the total daily insulin requirement at each meal Predictable absorption pattern in healthy individuals without diabetes

9. Bolus Short-Acting Insulin OnsetPeakDuration Short Acting Regular (Humulin R ® / Novolin R ® ) 30-60 min2-4 hrs6-10 hrs

10. Bolus Short-Acting Insulin Regular BSLHS Insulin Effect B Regular Insulin

11. Short-Acting Insulin Analogues OnsetPeakDuration Rapid Acting Lispro (Humalog ® ) Aspart (NovoLog ® ) Glulisine (Apidra ® ) 5-15 min30-90 min3-5 hrs

12. Short-Acting Insulin Analogues Lispro/Aspart/Glulisine BSLHS Insulin Effect B Insulin lispro/aspart/glulisine

13. Short-Acting Insulin Analogues 400 350 300 250 200 150 100 Meal SC injection 50 0 03060 Time (min) 90120180210150240 Lispro Regular Human 500 450 400 350 300 250 150 50 200 100 0 050100 Time (min) 150200300250 Aspart Regular Human Plasma Insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506. Lispro and Aspart: Plasma Insulin Profiles

14. Short-Acting Insulin Analogues Faster onset & shorter duration of action Allows for patient to “dose and eat” Patients with BG < 70mg/dL at mealtime may inject after a meal to avoid hypoglycemia Postprandial hyperglycemia following high fat meals (pizza) due to short duration of insulin action & sustained increase in blood glucose cause by the food Ideal for individuals: Night-time hypoglycemia Unpredictable schedules Eat out often Infants/toddlers with unpredictable consumption of calories Lispro/Aspart/Glulisine: Clinical Features

15. Basal Long-Acting Insulin NPH Onset of Action 1-2 hours Peak Effect 4-8 hours Duration of action 10-20 hours

16. Basal Long-Acting Insulin NPH BSLHS Insulin Effect B 6-23

17. Basal Long-Acting Insulin Analogue Insulin detemir Onset of Action 2-4 hours Peak Effect 4-14 hours Duration of action 12-24 hours * * Depending on dose

18. Basal Long-Acting Insulin Analogue BSLHS Insulin Effect B 6-25 Detemir

19. Basal Long-Acting Insulin Analogue Insulin glargine Onset of Action 2-4 hours Peak Effect Flat/No Peak Duration of action 24 hours

20. Basal Long-Acting Insulin Analogue BSLHS Insulin Effect B 6-25 Glargine

21. Basal Insulin Glargine 6 5 4 3 2 1 0 010 Time (h) After SC Injection End of observation period 2030 Glargine NPH Glucose Utilization Rate (mg/kg/h) Lepore, et al. Diabetes. 1999;48(suppl 1):A97. Pharmacokinetics of Lantus: A Time Action Profile

22. Basal/Bolus Concepts: Mimicking Natural Physiology BSLHS Insulin Effect B 6-25 Glargine Lispro/Aspart/Glulisine Inhaled insulin

23. Basal/Bolus Concepts: Mimicking Natural Physiology Insulin Secretion 12:006:0018:0024:00 Time 6:00 Bolus Insulin Secretion Basal Insulin Secretion BreakfastLunchSupper

24. Insulin Profiles 0 2468 10 12141618202224 Plasma Insulin Levels Regular ( 6–10 hr ) NPH ( 10–20 hr ) Time (hr) Glargine ( ~24 hr ) Aspart, Lispro, Glulisine, Inhaled insulin (4 –5 hr ) Rosenstock J. Clin Cornerstone. 2001;4:50-61. Please see accompanying prescribing information Detemir (~12-24 hr)

25. Premixed Insulin Basal and Bolus Effect Brand NameComponents Humulin® 50/50 50% NPH insulin/ 50% regular insulin Humulin® 70/30, Novolin® 70/30 70% NPH insulin/ 30% regular insulin Novolog 70/30 Novolog ® 70/30 70% insulin aspart protamine/ 30% insulin aspart Humalog Mix 50/50 Humalog ® Mix 50/50 50% lispro protamine/ 50% lispro insulin Humalog Mix 75/25 Humalog ® Mix 75/25 75% lispro protamine/ 25% lispro insulin

26. Insulin Injection Sites Rate of absorption (Quickest to slowest) Abdomen Arm Hip Thigh/buttocks

27. Factors Affecting Onset and Duration of Insulin Absorption – Increased SQ blood flow can increase absorption rates of regular and short acting insulin minimal effects on intermediate and long-acting insulin – Site of injection: the rate of absorption is fastest from abdomen, intermediate from arm, and slowest from thigh/buttocks. – Exercise of the injected area within 1 hr may increase absorption rate (regular and short acting affected more so than intermediate acting insulins) – Temperature: heat can increase absorption while cold decreases absorption – Massaging the injected area can increase the absorption of insulins – Smoking may/may not decrease absorption rates due to vasoconstriction – Insulin absorption is delayed from lipohypertrophic sites – Lower doses of insulin are absorbed more rapidly & have shorter duration of action than larger doses

28. Insulin Mixing Appropriate insulin mixtures Humulin R can be mixed with Humulin N without any clinical difference from the equivalent amounts of insulin given as separate injections Humalog/Novolog/Apidra can be mixed and injected with Human NPH insulin

29. Insulin Mixing Inappropriate insulin mixtures Lantus should not be mixed with any other insulin products and should be administered alone. Levemir should not be mixed with any other insulin products and should be administered alone.

30. Insulin Dosing Step 1: Determine Between Intensive Insulin Therapy or Conventional Insulin Therapy Intensive Insulin Therapy (IIT) By definition, IIT attempts to mimic the body’s normal release of insulin and therefore, generally includes more than two injections per day using insulin with different action profiles. The goal of IIT is achieving near normal biochemical markers of glycemic control. Conventional Insulin Therapy (CIT) CIT involves one or two injections per day using intermediate- acting insulin with less-than-normal biochemical markers of glycemic control as a goal of therapy. The major goal of CIT is avoiding the symptoms of hyper- and hypoglycemia.

31. Insulin Dosing Step 1: Determine Between Intensive Insulin Therapy or Conventional Insulin Therapy Candidates for Intensive Insulin Therapy (IIT) Women with diabetes planning to conceive Pregnant women Poorly controlled on conventional therapy Highly motivated and compliant patients willing to test blood glucose 4 times daily and inject at least 3 doses of insulin daily Technical ability to test glucose Intellectual ability to interpret test results and adjust insulin Younger patients

32. Insulin Dosing Step 1: Determine Between Intensive Insulin Therapy or Conventional Insulin Therapy Patients to avoid or use cautiously Intensive Insulin Therapy (IIT) Counter-regulatory insufficiency (hypoglycemic unawareness) Type 1 diabetes for 15 years or more (not all patients) Beta-blocker therapy (mask symptoms of hypoglycemia) Autonomic insufficiency Adrenal or pituitary insufficiency Patients with coronary or cerebral vascular disease (counter- regulatory hormones may adversely effect these patients) Unreliable, noncompliant patients including those abusing alcoholor drugs and patients with psychiatric disorders Patients with severe diabetic complications Children that have not yet reached puberty

33. Insulin Dosing Step 2: Determine Daily Insulin Requirement Diabetes Type Dosage in U/kg Actual Body Weight Type 1  Initial Dose0.5-0.6  Honeymoon Phase0.1-0.4 Type 2  Initial Dose0.2-0.6  With Insulin Resistance0.7-2.5

34. Natural History of Type 1 DM 34

35. Honeymoon Period Patients may experience apparent remission within days or weeks after the initial diagnosis and treatment – Decreased blood glucose concentrations – Decreased insulin requirements May last for only a few weeks to months Increasing exogenous insulin requirements should be anticipated 35

36. Insulin Dosing Step 3: Develop a Dosing Schedule (Base Dose) Method Number of InjectionsMorning Before Breakfast Noon Before Lunch Evening Before Supper Bedtime Method 1 1 Injection Not Recommended N Method 2 2 Injections N (2/3) N (1/3) Method 3 2 Injections N&R (2/3) 2:1 or 1:1* N&R (1/3) 1:1 Method 4 3 Injections N&R (2/3) 2:1 or 1:1* R (1/6) N (1/6) Method 5 3 Injections N&R (2/5) 1:1 R (1/5) N&R (2/5) 1:1 Method 6 4 Injections R (1/4) R (1/4) R (1/4) R (1/4) Method 7 4 Injections R (1/4) R (1/4) R (1/4) N (1/4) Method 8 4 Injections lispro/aspart/glulisine/ Inhaled (16%) lispro/aspart/glulisine/ Inhaled (17%) lispro/aspart//glulisine/ Inhaled (17%) Glargine/Detemir (50%)

37. Method 1 NPH BSLHS Insulin Effect B 6-23

38. Method 1 (Alternative) BSLHS Insulin Effect B 6-25 Glargine

39. Method 2 NPH BSLHS Insulin Effect B 6-23

40. Method 3 NPH BSLHS Insulin Effect B 6-23 Regular

41. Method 4 NPH BSLHS Insulin Effect B 6-23 Regular.

42. Method 5 NPH BSLHS Insulin Effect B 6-23 Regular

43. Method 6 BSLHS Insulin Effect B 6-25 Regular

44. Method 7 BSLHS Insulin Effect B 6-25 Regular NPH.

45. Method 8 BSLHS Insulin Effect B 6-25 Glargine/Detemir Lispro/Aspart/Glulisine Inhaled Insulin

46. Insulin Dosing Step 3: Develop a Dosing Schedule (Base Dose) Method Number of InjectionsMorning Before Breakfast Noon Before Lunch Evening Before Supper Bedtime Method A Method A 2 1 Injection 2 Injections NPH Method B 1 Injection Glargine Method C 1 Injection Detemir Method D 2 Injections Detemir *May be used in patients with Type 2 DM to increase basal insulin levels ** Often used in combination with oral agents to increase total insulinization *** Starting dose is often 5-10 units HS

47. One Injection of Basal Insulin4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Plasma Insulin Levels Normal Physiologic Insulin Secretion

48. One Injection of Basal Insulin4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Plasma Insulin Levels Type 2 Diabetes Characterized by Reduced Insulin Secretion

49. One Injection of Basal Insulin4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal insulin Plasma Insulin Levels

50. One Injection of Basal Insulin4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal insulin Plasma Insulin Levels Increasing Doses of

51. One Injection of Basal Insulin4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal insulin Plasma Insulin Levels Increasing Doses of

52. One Injection of Basal Insulin4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal insulin Plasma Insulin Levels Increasing Doses of

53. Insulin Dosing Step 4: Adjustments to Base Insulin Dose Only adjust the base insulin dose if a pattern (similar glucose concentrations 3 or more days) is seen with a stable diet and exercise program Unless all values are > 200mg/dL, adjust one portion of insulin at a time (e.g. NPH in the PM, etc.) Fix the Fasting First. If adjustments are needed, start with the insulin component affecting fasting blood glucose If needed, adjust the base insulin dose by 1-2 units for every 30- 50 mg/dL above your glycemic goal.

54. Insulin Dosing Step 4: Adjustments to Base Insulin Dose Out of Range Blood Glucose Value (Not explained by food, illness, exercise, or stress) Pattern Adjustment Algorithms FBS High Low ↑ PM or Bedtime N, glargine, detemir * ↓ PM or Bedtime N, glargine, detemir Before Lunch High Low ↑ Morning Short-Acting Insulin ↓ Morning Short-Acting Insulin Before Dinner High Low ↑ Morning N or Lunchtime Short-Acting Insulin ↓ Morning N or Lunchtime Short-Acting Insulin Before Bedtime High Low ↑ Dinnertime Short-Acting Insulin ↓ Dinnertime Short-Acting Insulin During the NightLow↓ Evening N or Move Dinnertime N to Bedtime * Rule out Somogyi Effect with a 2-3 AM Blood Glucose

55. Basal Insulin Dose Titration Adjust basal insulin to reach blood glucose goal Type 1 – may increase dose 1-2 units every 2-3 days Type 2 – may have larger dose increases (2-10 units) ideally every 3-4 days, but at least every 7 days if starting at 10 units

56. Basal Insulin Dose Titration Insulin Detemir 303 Dosing Average glucose over 3 days If FBG above goal, increase by 3 units If FBG below goal, decrease by 3 units If FBG is at goal, no change Goal glucose 80-110mg/dL http://www.novomedlink.com/products/Levemir/about-dosing.aspx

57. Basal Insulin Dose Titration Insulin Glargine Increase 1 unit every day until fasting blood glucose < 100mg/dL OR Average 2 days fasting blood glucose, every 2 days – If ≥ 180mg/dL increase by 8 units – If 140-179mg/dL increase by 6 units – If 120-139mg/dL increase by 4 units – If 100-119mg/dL increase by 2 units – If < 100mg/dL no change in dose http://www.lantus.com/hcp/dosing.aspx

58. Insulin Dosing Step 4: Supplemental Insulin Dose Once the base insulin dose is stable, supplemental doses of short-acting insulin can be used to correct occasional excessive preprandial glucoses Algorithms (sliding scales) based on generalized patient response 1500 Rule: 1500/Patient’s total daily dose of all insulin = *(Blood glucose points)* Represents the number of points blood glucosewill be lowered by adding 1unit of Regular insulin to the normal pre-meal insulin dose 1800 Rule: 1800/Patient’s total daily dose of all insulin = *(Blood glucose points) * Represents the number of points blood glucose will be lowered by adding 1unit of Lispro, Aspart, or Glulisine insulin to thenormal pre-meal insulin dose

59. Bolus Insulin Dose Titration Ideal to base dose off of 2-hour post-prandial blood glucose readings Dose adjustments usually in 1-2 unit increments – Type 1 diabetes a 1-2 unit increase will decrease blood glucose ~ 30-50 mg/dL – Type 2 diabetes affect not as predictable due to insulin resistance

60. Insulin Dosing Step 4: Anticipated Insulin Dose The base insulin dose is increased or decreased based upon anticipated effects from diet and physical activity Insulin coverage of extra food: Begin with an additional 1 unit of short-acting insulin for every 10-15 grams of additional carbohydrate ingested above what isnormally consumed at meals (e.g. Holiday meal) Insulin-Carbohydrate ratio (500-rule): Divide 500 by the total daily dose of insulin (short-acting analogues); 450 for regular insulin. The result is the number of grams of carbohydrate covered by 1 unit of short-acting insulin

61. Coordinating Insulin Injections Proper timing of bolus insulin administration with regards to meals is crucial to optimize the action of insulin, achieve better glycemic control, and reduce the risk of adverse reactions Regular insulin (30 minutes) Lispro/Aspart/Glulisine (Fork in one hand needle in the other)

62. Special Issues With Insulin Somogyi Effect – Characterized by normoglycemia at bedtime and hypoglycemia around 2:00-3:00 AM – Usually results in a rebound hyperglycemia the following morning due to excessive hepatic glucose output activated by the counter-regulatory hormones (glucagons, epinephrine etc.) – Often times patients have nightmares and wake in the middle of the night with profuse perspiration

63. Special Issues With Insulin Somogyi Effect Therapeutic options: (after documenting low 3:00 AM blood glucose) – Decrease the evening insulin by 2-4 units and continue to watch 3:00 AM blood glucose to see if the situation resolves – Move the evening NPH insulin from pre-dinner to bedtime. This will shift the peak action of the NPH to near breakfast time when the patient is awake and ready to eat.

64. Special Issues With Insulin Dawn Phenomenon – Characterized by a rise in blood glucose occurring between 4-8 AM – The rise in glucose cannot be blamed on counter- regulatory hormones due to a hypoglycemic event, but may be secondary to a rise in growth hormone levels – It is not consistent from day to day. It is often difficult to tell if hyperglycemia is due to insufficient NPH (insulin waning) or the dawn phenomenon

65. Special Issues With Insulin Dawn Phenomenon Therapeutic options: – In either case, (insufficient evening NPH or the Dawn phenomenon), the dose of evening NPH should be increased – Since it not consistent from day to day, need to continue to monitor 3 a.m. blood sugars to prevent nocturnal hypoglycemia

66. Special Issues With Insulin Sick Day Management – Patients should be instructed to take their normal dose of insulin even if they are not eating well or have episodes of nausea and vomiting – Blood glucose may need to be monitored more frequently (e.g. every ½ hour) – Supplemental doses of short-acting insulin may be required – Test urine for ketones – Drink plenty of fluids (1/4 cup/hr for adults) and maintain caloric intake (Jello, crackers, soup, soft drinks, etc.) – Call physician if blood glucose remains greater than 240mg/dl or urine ketones remain after 2-3 doses of supplemental insulin

67. Insulin Storage Refrigerate unopened injectable insulin – do not freeze Use unopened insulin by manufacturer’s expiration date Opened insulin expire based on type & delivery device – may be kept at room temperature (15-30˚C or 59- 86˚F) for ~ 4 weeks. Inspect before use for clumping, precipitates, discoloration, etc.

68. Diabetes Mellitus Ibrahim Sales, Pharm.D. Assistant Professor of Clinical Pharmacy King Saud University isales@ksu.edu.sa