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2. Dr. Ghadiri, MD Assistance professor of endocrinology Shahid Sadoughi University of Medical Sciences 2

3. The importance of glycemic control in minimizing complications related to diabetes has been well established in type 1 diabetes. United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that strict glycemic control in patients with type 2 diabetes results in a similar reduction in risk of microvascular disease. 3

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5. Initial therapy should begin with diet, weight reduction, and exercise, which may induce normoglycemia if compliance is optimal. Metformin therapy may be initiated, concurrent with lifestyle intervention, at the time of diabetes diagnosis. 5

6. Oral agents become less effective as beta cell function declines. The therapeutic options for patients who fail initial therapy with lifestyle intervention and metformin are to add a second oral or injectable agent, including insulin, or to switch to insulin. There is no consensus on which option is most effective. However, insulin is the preferred second-line medication for patients with A1C >8.5 percent or with symptoms of hyperglycemia despite metformin titration. 6

7. NORMAL PATTERNS OF INSULIN SECRETION Insulin is secreted in a pulsatile manner; pulses occur under basal conditions and in response to meals. Basal insulin secretion represents approximately 50 percent of 24-hour insulin production, with the remainder accounted for by prandial (mealtime) excursions. 7

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9. In person without diabetes, the pancreas delivers a small amount of insulin continuously to cover the body’s non-food related insulin needs. Basal Insulin 9

10. The amount of insulin required to cover the food you eat. Rapid-acting or Short-acting insulin works as a Bolus Insulin Bolus Insulin 10

11. Intensive insulin therapy has been used to describe complex regimens that separate basal insulin delivery (given as one to two daily injections of intermediate or long-acting insulin) with superimposed doses of short or rapid-acting insulins three or more times daily. 11

12. INSULIN PREPARATIONS In type 2 diabetes, insulin is generally provided in two ways: Basal supplement to suppress hepatic glucose production and maintain near normoglycemia in the fasting state. Pre-meal bolus dose of short-acting or rapid-acting insulin to cover the extra requirements after food is absorbed. 12

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14. For many patients with type 2 diabetes, a basal supplement is often adequate for good glycemic control as endogenous insulin secretion will control the post-prandial excursions. Some patients with type 2 diabetes will require additional premeal boluses, similar to treatment for type 1. 14

15. Premixed insulin preparations Most premixed (biphasic) preparations contain an intermediate acting insulin and either a short or a rapid-acting insulin. intermediate acting insulin Some patients who require pre-meal insulin in addition to basal insulin prefer premixed insulins for convenience. 15

16. Premixed preparations offer little glycemic advantage compared with adequately titrated basal and bolus insulin. In a meta-analysis of trials comparing rapid- acting/intermediate premixed insulin preparations with other treatments (premixed regular/NPH insulin, long-acting insulin, and non-insulin agents), premixed rapid-acting preparations were similarly effective in reducing A1C levels as premixed regular insulin preparations.regular insulin 16

17. Compared with other insulin therapy (long-acting or regular/NPH mix), premixed rapid-acting insulin preparations were more effective in reducing postprandial blood glucose levels but less effective in reducing fasting blood glucose. Premixed rapid-acting preparations were more often associated with minor hypoglycemia and weight gain than long-acting insulin or oral agents. 17

18. Premixed insulin preparations are sometimes used in type 2 diabetics, but we almost never use them in patients with type 1 diabetes. For patients with type 2 diabetes who require prandial insulin, the goal is to adjust the dose of fast-acting insulin immediately prior to a meal, and therefore, we prefer to keep basal and premeal insulin injections separate and adjust them independently. 18

19. COMBINATION ORAL AGENT AND INSULIN THERAPY Patients with persistent hyperglycemia despite oral hypoglycemic therapy may add insulin to oral medication or may stop the oral drug(s) and begin insulin. The rationale for combination oral hypoglycemic drug and insulin therapy is that, by suppressing hepatic glucose production, the patient can retain the convenience of oral agents, while minimizing total insulin requirements. 19

20. Many studies have shown that glycemia improves with insulin combination therapy. In some studies, target A1C goals (≤7 percent) were achieved in 60 to 70 percent of subjects. 20

21. Choice of insulin When insulin is combined with oral agents, a basal (long- or intermediate-acting) rather than a short- acting premeal (prandial) insulin is a reasonable first choice. The addition of basal insulin will improve nocturnal and fasting blood sugar, whereas premeal bolus insulin will decrease postprandial glucose excursions. 21

22. Basal insulin While intermediate-acting NPH insulin has been used commonly at bedtime to supplement oral hypoglycemic drug therapy, longer acting insulins, such as insulin glargine (once daily) and detemir (once or twice daily), added to oral agents are equally effective for reducing A1C values and may cause less nocturnal hypoglycemia.insulin glargine 22

23. In contrast to NPH, the time-action profile for insulin glargine has virtually no peak,which makes it an acceptable basal insulin preparation for intensive insulin therapy.insulin glargine 23

24. Insulin detemir : Insulin detemir Long-acting insulin analog; a fatty acid side chain that allows albumin binding results in prolongation in action. However, its duration of action appears to be substantially shorter than that of insulin glargine. 24

25. Meta-analyses of trials in patients with type 2 diabetes comparing once-daily insulin glargine or detemir to once or twice-daily NPH insulin report similar glycemic control between groups.insulin glargine Insulin glargine and detemir may have some relatively modest clinical advantages over NPH (less symptomatic and nocturnal hypoglycemia) with the important disadvantage of high cost. 25

26. Premeal (prandial) bolus insulin For patients with type 2 diabetes, a basal supplement is often adequate for good glycemic control, but for others, premeal (prandial or preprandial) boluses are necessary as they are in type 1 diabetes. 26

27. The newer rapid-acting insulins may have a minor glycemic advantage over short-acting (regular) insulin in patients with type 1 diabetes, but they do not have a clinically significant advantage in patients with type 2 diabetes. No significant differences were seen in serum A1C concentrations or the number of hypoglycemic episodes. 27

28.  However, the ability to inject the rapid-acting insulins immediately before meals, as opposed to the 30 to 45 minutes before the meal recommended for short acting insulins, may provide improved convenience for patients. 28

29. Comparison of insulin regimens A number of randomized trials have evaluated different insulin regimens in patients with type 2 diabetes. These trials primarily used glycemic control as the endpoint; data are more limited on cardiovascular outcomes. 29

30. Basal versus prandial Both basal and prandial regimens are similarly effective in reducing A1C concentrations when insulin doses are aggressively titrated to achieve glycemic goals. 30

31. This was illustrated by a randomized trial of once daily insulin glargine versus prandial insulin lispro in 415 patients who were inadequately controlled with metformin and a sulfonylurea. insulin glargineinsulin lispro metformin There were similar improvements in A1C and target A1C concentrations between 6.5 and 7.0 percent were achieved by 27 and 30 percent of subjects, respectively. Basal insulin was associated with greater patient satisfaction and less hypoglycemia. 31

32. Basal or prandial versus premixed Premixed insulin regimens with fixed combinations of short or rapid acting insulin with long or intermediate acting insulin claim to provide two peaks of insulin activity from just one injection, although in practice the peaks from the rapid acting and intermediate acting insulins tend to merge together and form a single peak of insulin action.intermediate acting insulin 32

33. In a three-year trial, 708 patients with type 2 diabetes who were suboptimally controlled with metformin and a sulfonylurea were randomly assigned to premixed biphasic insulin aspart (twice daily), prandial insulin aspart (three times daily), or basal insulin detemir (once or twice daily).There was no difference in median A1C levels among the three groups, but significantly more patients in the basal and prandial groups achieved an A1C level of ≤6.5 percent than in the biphasic premixed group.metformininsulin aspartinsulin detemir Patients in the basal group had the fewest episodes of hypoglycemia. 33

34. Conclusion : Whether a basal or a prandial (premeal) bolus strategy is more effective in improving important diabetes endpoints (microvascular and macrovascular complications) remains uncertain. In the absence of such data, we prefer initiating basal insulin, rather than prandial insulin, in patients who are poorly controlled on oral agents. For patients who require prandial insulin, we prefer to keep basal and prandial insulin injections separate and adjust them independently. 34

35. Insulin dose Basal Bedtime dose of NPH, detemir, or glargine insulin is being added to oral drug therapy: 10 units or 0.2 units per kg (taken at 10:00 PM). Fasting blood glucose (FBG) should be measured every day. An increase of 2 to 4 units in the bedtime insulin dose should be made periodically (approximately every three days) if the mean FBG is above 130 mg/dL during this time. 35

36. In this way, the bedtime insulin dose can be titrated over a period of several weeks or months. If fasting glucose levels are very elevated (>250 mg/dL), or if a patient is known to be very insulin resistant, initial doses can be higher and titration more aggressive. 36

37. Bolus If premeal bolus insulin needs to be added, the optimal dose depends upon many factors, including current and target blood glucose values, carbohydrate content of the meal, and activity. A typical starting dose is approximately 4 to 6 units. The dose can be increased by 2 to 3 units every three days until the postprandial blood glucose target is achieved. 37

38. Optimal timing of insulin dose For patients with type 2 diabetes on combination therapy (oral hypoglycemics and once-daily insulin), the optimal timing of the insulin dose depends in part upon the type of insulin. NPH insulin may be most effective if given at bedtime. Bedtime NPH : Less weight gain 38

39. In contrast, a morning rather than a bedtime dose of insulin glargine may provide better glycemic control in patients with type 2 diabetes who are also treated with an oral agent. insulin glargine Nocturnal hypoglycemia was less frequent with morning and bedtime insulin glargine than with bedtime NPH.insulin glargine 39

40. For patients with type 2 diabetes taking an oral hypoglycemic agent, the optimal timing is once- daily NPH or detemir at bedtime or once-daily insulin glargine in the morning or bedtime. insulin glargine 40

41. SWITCHING TO INSULIN MONOTHERAPY Patients with persistent hyperglycemia despite oral hypoglycemic therapy may stop the oral drug and begin insulin monotherapy. This approach is cheaper than combined therapy (although generic metformin is relatively inexpensive), but results in more weight gain and more episodes of hypoglycemia.metformin 41

42. Starting dose The initial dose of insulin in patients with type 2 diabetes switching to monotherapy is similar to the starting dose described above for patients adding insulin to oral hypoglycemic therapy. 42

43. Among patients who are taking insulin and have A1C values above the desired target, diet and exercise patterns should first be reviewed. Insulin doses should then be adjusted to achieve target levels of glycemia. Patients should measure blood glucose two to four times daily and should only reduce their insulin dose if hypoglycemia develops. 43

44. In general, dietary indiscretion and/or inadequate doses of insulin underlie the apparent failure of many patients treated with insulin regimens. Daily insulin doses typically exceed 65 to 100 units per day, and may sometimes be much higher, before obese type 2 diabetic patients can achieve near-normal glycemia. 44

45. Once-daily regimens For patients receiving insulin monotherapy, a once- daily dose of intermediate- or long-acting insulin is sometimes sufficient. As an example, insulin glargine is effective when used alone for once-daily therapy in patients with type 2 diabetes and may be associated with less nocturnal hypoglycemia and less weight gain than NPH.insulin glargine 45

46. However, serum insulin concentrations over a 24-hour period may be more stable in patients taking two doses daily, when the insulin preparation is NPH or detemir. 46

47. Twice-daily regimens If the goal is control of persistent hyperglycemia with a regimen that is simple, then twice-daily NPH insulin will be effective in many patients. If excessive postprandial rises in blood glucose are a concern, then a short- or rapid- acting insulin must be added. Injection of regular plus NPH insulin before breakfast and before dinner results in four peaks of insulin action, covering the morning, afternoon, evening, and overnight. However, the peaks tend to merge. Furthermore, with the common practice of drawing up both insulin preparations in the same syringe, serum insulin peaks become less distinct. 47

48. Intensive insulin Use of an intensive insulin regimen (similar to that used in T1DM) results in higher serum insulin concentrations and better glycemic control than that achieved with either an oral drug or conventional insulin therapy alone. A potential problem is the weight gain (8.7 kg in one study) that can occur with intensive regimens that achieve near normal glycemia. This weight gain may in some instances result in partial noncompliance with therapy, particularly in women. 48

49. INSULIN AS INITIAL THERAPY An alternative that may be beneficial, but is not widely used, is a brief period (two to four weeks) of intensive insulin treatment at the onset of type 2 diabetes.By inducing near normoglycemia with intensive insulin therapy, both endogenous insulin secretion and insulin sensitivity improve. The improvement in insulin secretion is presumably due to the elimination of the deleterious effects of hyperglycemia on beta cell secretory function, and in some patients, it results in better glycemic control that can then be maintained with diet and exercise for many months thereafter. 49

50. Insulin should be particularly considered for patients presenting with A1C >10 percent, fasting plasma glucose >250 mg/dL, random glucose consistently >300 mg/dL, ketonuria, or with unplanned weight loss in association with hyperglycemia. 50

51. Continuous subcutaneous insulin infusion (insulin pump) With pump therapy, basal insulin is supplied in the form of a continuous infusion (comprising between 40 and 60 percent of the total daily dose) with pre-meal bolus doses given to minimize postprandial glucose excursions. 51

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53. Choice of insulin Only short-acting insulin (regular) or rapid-acting insulins are used with continuous therapy. In a double- blind crossover trial, insulin lispro, compared with regular insulin, resulted in greater reduction in postprandial blood glucose concentrations,lower A1C,fewer episodes of hypoglycemia, and less weight gain.insulin lispro regular insulin Rapid-acting insulin analogs are typically preferred over regular insulin for continuous insulin therapy. 53

54. In general, approximately one-half of the total daily dose is administered as basal rate. For most patients, basal rates are in the range of 0.01 to 0.015 units per kg per hour (60 kg woman approximately 0.6 to 0.9 units per hour). The basal rates are adjusted empirically based on glucose monitoring results. 54

55. Certain time periods during the day may require higher, while other periods may require lower, infusion rates depending on individual factors including lifestyle. Most pumps allow for pre-programmed changes in basal rate to accommodate these requirements. 55

56. The premeal bolus dose should be based upon the carbohydrate content of the intended meal and the blood glucose level immediately before the meal. 56

57. Advantages CSII is increasingly used in the pediatric population. A randomized trial in 32 children and adolescents (aged 8 to 21 years) with type 1 diabetes showed that lower A1C and premeal glucose levels were more achievable with continuous subcutaneous insulin infusion than with an insulin regimen using once daily insulin glargine and premeal insulin aspart. insulin glargineinsulin aspart 57

58. In some children with type 1 diabetes who have frequent and severe nocturnal hypoglycemia, use of an insulin pump at nighttime only (with pre-breakfast NPH insulin and three pre-meal doses of insulin lispro during the day) can improve overall glycemic control and reduce hypoglycemia.insulin lispro 58

59. Another advantage of insulin pump therapy is that it allows more flexibility in the timing of meals. If someone has taken NPH insulin before breakfast, its action is likely to be maximal around lunchtime or early afternoon. Thus, delaying lunch can lead to hypoglycemia. With continuous therapy, the steady basal infusion should maintain normoglycemia but not induce hypoglycemia. 59

60. In addition, insulin absorption with pump therapy is less variable from day to day,and therefore blood glucose profiles may be more predictable. Both the small subcutaneous depot and the constancy of the injection site and depth for the two to three days with each catheter contribute to the relative consistency of absorption. 60

61. Continuous subcutaneous insulin has also been used in conjunction with a continuous glucose monitoring (CGM) device to give the patient more information about their blood glucose levels and allow them to make better informed decisions about insulin dosing. This approach is known as sensor-augmented insulin pump therapy. CSII in conjunction with continuous glucose monitoring may effectively improve glycemia while limiting the rise in hypoglycemia that often accompanies improved glycemic control. 61

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63. Disadvantages The costs of the pump and supplies are higher than those of ordinary syringes and needles. Superficial infection. System failure is usually due to blockage or leakage in the syringe or the infusion set or connectors, causing an interruption of infusion flow. Since the subcutaneous depot is so small, any interruption in continuous flow leads very quickly to hypoinsulinemia, hyperglycemia, and possibly diabetic ketoacidosis. 63

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66. Finally, many patients prefer not to have to wear a device and be "tethered" to the pump at all times. Pump-treated patients can take off the pump for brief periods. Doing so for one hour or less does not usually lead to loss of blood glucose control. For longer periods (such as overnight), a subcutaneous dose of intermediate-acting insulin should be given in a dose 1.5 to 2 times the calculated basal infusion rate for that period. Some patients also like to stop pump therapy and use multiple daily injection therapy for more prolonged periods, such as summer vacations, to allow water activities. These transitions are usually easy to make if planned ahead of time. 66

67. The overnight rate can be adjusted to maintain the pre-breakfast blood glucose in the target range. When changing the subcutaneous basal insulin infusion rate, a delay in the actual increase or decrease in plasma insulin levels must be taken into account, based on the kinetics of absorption and time to reach a new steady state.Therefore, basal rates of rapid-acting insulin should be changed about two to four hours before the change in plasma level is required. 67

68. When converting a patient from a multiple daily insulin regimen to continuous insulin therapy, the pre- pump level of chronic glycemia will help determine the pump basal rate and pre-prandial scales chosen. Patient who has been well controlled on his previous multiple injection regimen (A1C <7.0 percent), the initial total daily dose of insulin administered by pump may be 10 to 20 percent less than the total daily dose of the previous regimen. Conversely, patients with inadequate glycemic control may be started with the same total daily dose as they had been using with their injection regimens. 68