The document discusses guidelines for initiating insulin therapy in patients with type 2 diabetes not controlled on oral antidiabetic drugs (OADs). It recommends starting with either bedtime intermediate-acting insulin or bedtime or morning long-acting insulin, beginning at a dose of 10 units or 0.2 units/kg. The insulin dose is then titrated up based on fasting blood glucose levels until the target range is achieved. Additional injections of rapid-acting insulin may be added if pre-meal blood glucose levels remain out of range.

1. First step into insulin therapy (How to start insulin in a patient not controlled on OADs) By Dr.Muhammad Tahir Chaudhry B.Sc.M.B;B.S(Pb).C.diabetology(USA)

2. The breakthrough: Toronto 1921 – Banting & Best

24. Fears & concerns about insulin therapy

29. Normal physiologic patterns of glucose and insulin secretion in our body

30. How Is Insulin Normally Secreted?

34. Bolous insulins (Mealtime or prandial) The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only. 6 hours 2 hours 10-20 minutes Rapid acting Inhaled insulin 4-5 hours 1-2 hours 5-15 minutes Rapid acting Insulin analogs ( Lispro ,Aspart,Glulisin) 8-10 hours 2-4 hours 30-60 minutes Short acting Human regular Duration of action Peak of action Onset of action Type Insulin

35. Pre-mixed Insulins NovoMix 30 Humolog Mix 25 Humolog Mix 50 (25% lispro75%IAA) (50% lispro 50%IAA) Humulin 70/30 Dongsulin 70/30 Mixtard 70/30 70% NPH 30% Regular NPH-Regular Examples Composition Insulin 30% rapid acting aspart + 70 % intermediate acting aspart(IAA) Rapid acting aspart ( Free and soluble ) + Intermediate acting aspart ( protaminated-crystallized Example Composition Insulin

37. Basal Insulins The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only. 16-20 hours 8-12 hours 2-4 hours Long acting Detemir (Levimir)Novo Upto 24 hours Relatively flat 1-2 hours Long acting Glargine (Lantus) Aventis 13-18 hours 5-7 hours 1-2 hours Intermediate acting NPH Duration of action Peak of action Onset of action Type Insulin

39. Bolous insulins (Mealtime or prandial) The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only. 4-5 hours 1-2 hours 5-15 minutes Rapid acting Insulin analogs ( Lispro ,Aspart, Glulisine ) 8-10 hours 2-4 hours 30-60 minutes Short acting Human regular Duration of action Peak of action Onset of action Type Insulin

43. Indications for Insulin Use in Type 2 Diabetes Pregnancy (preferably prior to pregnancy) Acute illness requiring hospitalization Perioperative/intensive care unit setting Postmyocardial infarction High-dose glucocorticoid therapy Inability to tolerate or contraindication to oral antiglycemic agents Newly diagnosed type 2 diabetes with significantly elevated blood glucose levels (pts with severe symptoms or DKA) Patient no longer achieving therapeutic goals on combination antiglycemic therapy

45. F i rst step i nto Insulin therapy

47. The ADA Recommendations on the Use of Insulin in Type 2 Diabetes

50. Types of Insulin Rapid Acting (e.g., aspart, lispro, glulisine) Short Acting (e.g., regular insulin) Onset 10-15 mins 30-60 mins Peak 60-90 mins 2-4 hrs Duration 4-5 hrs 5-8 hrs

51. Types of Insulin Intermediate Acting (e.g., NPH, lente) Premixed (e.g., 75% NPL / 25% lispro, 70% APS / 30% aspart, 70% NPH / 30% regular/NPH) Onset 1-3 hr(s) One vial or cartridge with a fixed ratio of rapid- or short-acting to intermediate-acting insulin Peak 5-8 hrs Duration Up to 18 hrs

52. Types of Insulin Long Acting (e.g., ultralente) Long-Acting Analogues (glargine, detemir) Onset 3-4 hrs 1.5-3 hrs Peak 8-15 hrs No peak with glargine, dose-dependent peak with detemir Duration 22-26 hrs 9-24 hrs (detemir); 20-24 hrs (glargine)

55. Effect of Insulin on Triglyceride and HDL-C Levels Adapted from Nathan DM et al. Ann Int Med 1988;108:334-40. 1 1.1 1.2 1.3 1.4 1.5 Baseline Month 9 1 1.2 1.4 1.6 1.8 2 Baseline Month 9 Tryglyceride level (mmol/l) HDL-C (mmol/L) 0.22 mmol/l (19.4mg/dl) p=0.07 n=15 1.85 1.17 1.51 1.39 HDL-C Triglycerides 0.34 mmol/l (30mg/dl) p=0.07 n=15

57. Balancing Good Glycemic Control with a Low Risk of Hypoglycemia… Hypoglycemia Glycemic control

58. Rates of Hypoglycemia for Premixed vs. Long-Acting Insulin Adapted from Raskin P et al. Diabetes Care 2005;28(2):260-5. 0 0.5 1 1.5 2 2.5 3 3.5 BIAsp 70/30 (n=117) 0 5 10 15 20 25 30 35 40 45 Glargine (n=116) BIAsp 70/30 (n=117) Glargine (n=116) Episodes per patient-year % of subjects p<0.05 p<0.05 3.4 0.7 43 16

59. HbA 1c  7% Without Hypoglycemia (Composite Endpoint) in Two Treat-to-Target Studies Hypoglycemia definition: glucose levels ≤4 mmol/L (72 mg/dL) or requiring assistance 1. Riddle M et al. Diabetes Care 2003;26:3080-6. 2. Hermansen K et al. Diabetes Care 2006;29:1269-74 . 0 5 10 15 20 25 30 35 Once-daily dosing 1 Twice-daily dosing 2 p<0.05 Percentage of patients achieving HbA 1c  7% 33.2 26.7 Insulin glargine NPH NPH Insulin detemir 0 5 10 15 20 25 30 35 Percentage of patients achieving HbA 1c  7% p=0.008 26.0 16.0

60. Rates of Hypoglycemia for Premixed vs. Long-Acting Insulin + OAD Adapted from Janka et al. Diabetes Care 2005;28:254-9 . Mean number of confirmed hypoglycemic events per patient-year in a 28-week study 0 1 2 3 4 5 6 Symptomatic Nocturnal Severe Premixed insulin Insulin glargine + OADs 5.73 2.62 1.04 0.51 0.05 0.00 Events per patient-year p=0.0009 p=0.0449 p=0.0702

61. Rates of Hypoglycemia for Premixed vs. Long-Acting Insulin + OAD in Elderly Patients Adapted from Janka HU et al. J Am Geriatr Soc 2007;55(2):182-8. Rate of event per patient-year p=0.01 p=0.008 p=0.06 0 2 4 6 8 10 12 Premixed (n=63) Glargine + OAD (n=69) All episodes of hypoglycemia All confirmed episodes of hypoglycemia Confirmed symptomatic hypoglycemia

62. Rates of Nocturnal Hypoglycemia for NPH vs. Long-Acting Insulin Adapted from Rosenstock J et al . Diabetes Care 2001;24(4):631-6 . HbA 1c and rates of nocturnal hypoglycemia at Week 28 NPH (n=259) Insulin glargine (n=259) 4 3 2 1 0 -1 -2 40 30 20 10 0 Adjusted mean change from baseline Patients (%) p<0.01 for both treatments vs. baseline p<0.02 glargine vs. NPH HbA 1c (%) Nocturnal hypoglycemia (Month 2 to endpoint)

63. The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin

64. Initiating and Adjusting Insulin Continue regimen; check HbA 1c every 3 months If fasting BG in target range, check BG before lunch, dinner, and bed. Depending on BG results, add second injection (can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range) Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA 1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin If HbA 1c  7%... Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) Continue regimen; check HbA 1c every 3 months Target range: 3.89-7.22 mmol/L (70-130 mg/dL) Nathan DM et al. Diabetes Care. 2006;29(8):1963-72. If HbA 1c ≤ 7%... Bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin (initiate with 10 units or 0.2 units per kg) Check FG and increase dose until in target range. Pre-lunch BG out of range: add rapid-acting insulin at breakfast Pre-dinner BG out of range: add NPH insulin at breakfast or rapid-acting insulin at lunch Pre-bed BG out of range: add rapid-acting insulin at dinner If HbA 1c ≤ 7%... If HbA 1c  7%...

65. Step One… Continue regimen; check HbA 1c every 3 months If fasting BG in target range, check BG before lunch, dinner, and bed. Depending on BG results, add second injection (can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range) Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA 1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin If HbA 1c  7%... Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) Continue regimen; check HbA 1c every 3 months Target range: 3.89-7.22 mmol/L (70-130 mg/dL) Nathan DM et al. Diabetes Care. 2006;29(8):1963-72. If HbA 1c ≤ 7%... Bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin (initiate with 10 units or 0.2 units per kg) Check FG and increase dose until in target range. Pre-lunch BG out of range: add rapid-acting insulin at breakfast Pre-dinner BG out of range: add NPH insulin at breakfast or rapid-acting insulin at lunch Pre-bed BG out of range: add rapid-acting insulin at dinner If HbA 1c ≤ 7%... If HbA 1c  7%...

70. With the addition of basal insulin and titration to target FBG levels, only about 60% of patients with type 2 diabetes are able to achieve A1C goals < 7%. [36] In the remaining patients with A1C levels above goal regardless of adequate fasting glucose levels, postprandial blood glucose levels are likely elevated.

72. Step Two… Continue regimen; check HbA 1c every 3 months If fasting BG in target range, check BG before lunch, dinner, and bed. Depending on BG results, add second injection (can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range) Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA 1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin If HbA 1c  7%... Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) Continue regimen; check HbA 1c every 3 months Target range: 3.89-7.22 mmol/L (70-130 mg/dL) Nathan DM et al. Diabetes Care. 2006;29(8):1963-72. If HbA 1c ≤ 7%... Bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin (initiate with 10 units or 0.2 units per kg) Check FG and increase dose until in target range. Pre-lunch BG out of range: add rapid-acting insulin at breakfast Pre-dinner BG out of range: add NPH insulin at breakfast or rapid-acting insulin at lunch Pre-bed BG out of range: add rapid-acting insulin at dinner If HbA 1c ≤ 7%... If HbA 1c  7%...

76. Step Three… Nathan DM et al. Diabetes Care. 2006;29(8):1963-72. Continue regimen; check HbA 1c every 3 months If fasting BG in target range, check BG before lunch, dinner, and bed. Depending on BG results, add second injection (can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range) Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA 1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin If HbA 1c  7%... Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) Continue regimen; check HbA 1c every 3 months Target range: 3.89-7.22 mmol/L (70-130 mg/dL) If HbA 1c ≤ 7%... Bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin (initiate with 10 units or 0.2 units per kg) Check FG and increase dose until in target range. Pre-lunch BG out of range: add rapid-acting insulin at breakfast Pre-dinner BG out of range: add NPH insulin at breakfast or rapid-acting insulin at lunch Pre-bed BG out of range: add rapid-acting insulin at dinner If HbA 1c ≤ 7%... If HbA 1c  7%...

86. Control BSF by adjusting the prior the dose of NPH

89. Control random sugar level by adjusting the prior dose of regular insulin

99. Adding basal insulin to oral agents is simple to implement, well tolerated, and highly effective -- particularly for patients with A1C levels between 7.0% and 10.0%

100. The dose of this basal insulin should be adjusted every 3-5 days to reach a target fasting glucose level of ≤ 120 mg/dL, provided that nocturnal hypoglycemia does not occur. Reduction in overnight and fasting glucose levels achieved by adding basal insulin may be sufficient to reduce postprandial elevations in glucose during the day and facilitate the achievement of target A1C concentrations

104. This should also be adjusted every 3-5 days to target FBG.

106. Theoretically, people with type 2 diabetes have a predominance of postprandial hyperglycemia, which may increase macrovascular risk. Thus, there is a rationale for early initiation of prandial coverage as well. However, with patient and caregiver reluctance to utilize injected insulin before meals, this approach is not often taken. However, once a patient develops clear insufficiencies in insulin secretory capacity, full-day insulin coverage is clearly required. This circumstance raises a philosophical question about taking the next step in treatment design. When converting from bedtime insulin treatment, one option would be to start with a conventional insulin program using a twice-daily premixed insulin or a custom-designed split mix. This will often eventually evolve into a full physiologic program. Or, it is also possible to go right to the full physiologic coverage approach, using a long-acting insulin at bedtime to provide basal coverage plus premeal rapid-acting insulin. At the crux of this decision is whether or not the patient is willing to take the additional premeal injections and monitoring in exchange for more lifestyle flexibility. The more physiologic approach has many advantages, but the frequent injections are often a deterrent. Thus, at this juncture, a clinician should determine the patient's interest, and if they are willing to move to a physiologic program right away, it is the best option medically. While the more conventional therapies are simpler, they do not optimally mimic natural patterns of insulin release, and postprandial coverage is often suboptimal. Hypoglycemia is more likely because insulin levels do not match the glucose levels from food intake. They are also less flexible if there are alterations to meal times or amounts.

109. The prandial insulins

113. How to add and titrate prandial insulins? (Starting Insulin in Patients With A1C > 10.0%)

114. Regular insulin and Rapid acting analogues(Lispro)

115. 1.Pre-meal plasma glucose levels and 2. meal size (carbohydrate content) prandial insulin dosing depends upon

116. A usual starting dosage for patients with type 2 diabetes is 1 U of rapid-acting insulin for every 10 g of carbohydrate eaten plus an additional 1 U for every 30 mg/dL above the target self-monitoring blood glucose level of 100 mg/dL. For example, a patient who had a premeal self-monitoring blood glucose level of 160 mg/dL, and was planning to eat a meal containing 30 g of carbohydrate, would take a prandial insulin dose of 5 U .

117. If the patient is uncomfortable counting carbohydrates, the physician can recommend a range of insulin dosages empirically based on the size of the meal I.e, 5 U of a rapid-acting analog for a small meal and 8-10 U for a large meal plus additional units of insulin, if needed, based on the pre -meal self-monitoring blood glucose level reading

118. A simple way to introduce prandial insulin is to start with 1 dose at the main meal (ie, 5-10 U).

119. Titration of regular insulin and analogues

120. You can increase or decrease the dose of regular insulin and analogues by 20 % i.e If the patients is using, 1-10 units…………….+/- 2 unit 11-20 units……………+/- 4 units 21-30 units……………+/- 6units 31-40 units……………+/- 8 units…………………..

121. How to start pre mixed (70/30) Insulin

122. For pre mixed insulins(70/30 preparations) Step1:First calculate the total daily starting requirement of insulin; body weight(kg)/2 eg, For a 60kg patient,total daily dose =30 units Step 2:Then devide this dose into 3 equal parts; 10+10+10 Step 3:Give 2 parts in the morning and 1 part in the evening; Morning=20U Evening=10 U

123. Dose titration of Pre-mixed(70/30) preparations

124. You can increase or decrease the dose of pre-mixed insulin by 10 % i.e If the patients is using, 1-10 units…………….+/- 1 unit 11-20 units……………+/- 2 units 21-30 units……………+/- 3 units 31-40 units……………+/- 4 units…………………..

125. Advantages and disadvantages of pre- mixed insulins

126. Advantages: Easy to administer for the physician. Easy to fill and inject by the patient. Provides both basal and bolus coverage with fewer number of injections.

127. Disadvantage: No dose flexability If u increase/decrease the dose of one component ,the dose of other component is also changed un desirably

128. How to solve the problem of dosage flexibility

129. Regimen # 4

131. Disadvantage of split- mixed regimen Mid-night hypoglycemia

132. How to solve the problem of nocturnal hypoglycemia

136. More physiologic regimens

144. Common Problems

147. Injection Techniques

150. Injection technique

155. Thank you all For Sparing your valuable time & Patient listening