First step into insulin therapy

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)

The breakthrough: Toronto 1921 – Banting & Best

Fears & concerns about insulin therapy

Normal physiologic patterns of glucose and insulin secretion in our body

How Is Insulin Normally Secreted?
Insulin is secreted continuously at low levels in a pulsatile fashion between meals and overnight to suppress hepatic glucose production (basal secretion). This is coupled with intense short bursts of secretion in response to meals and rising glucose concentrations to ensure that glucose concentrations remain within the normal range (prandial secretion) (Figure).[21] The rapid early rise of insulin secretion in response to a meal is critical, because it ensures the prompt inhibition of endogenous glucose production by the liver and disposal of the mealtime carbohydrate load, thus limiting postprandial glucose excursions. Basal insulin secretion accounts for approximately 50% of total insulin secreted each day, whereas the remaining 50% of insulin is secreted in response to meals.[22]

The rapid early rise of insulin secretion in response to a meal is critical,
because it ensures the prompt inhibition of endogenous glucose production by the liver disposal of the mealtime carbohydrate load, thus limiting postprandial glucose excursions.

When we wake up in the morning, our glucose level is not 0; there is continual basal glucose production by the liver overnight without a need to eat anything during the night. The extent of that basal glucose production is controlled by a certain amount of basal insulin secreted by the islet cells. Once we start to eat, we have increasing glucose absorption from the intestine so that glucose levels rise; almost immediately, there is a rise in islet cell insulin secretion, and this will then peak as the glucose levels peak. Then once the absorption of glucose from the intestine starts to fall, and glucose levels are starting to exit out of the bloodstream into the tissues as a result of adequate insulinization, then so does insulin secretion decrease from the pancreas, and levels come back down to baseline between meals. Again then it is time for lunch, insulin levels rise; again they fall between meals, only to rise again at dinner and with any snacks that we may eat during the day.

Bolous insulins (Mealtime or prandial)
Type Onset of action Peak of action Duration of action Human regular Short acting 30-60 minutes 2-4 hours 8-10 hours Insulin analogs (Lispro,Aspart,Glulisin) Rapid acting 5-15 minutes 1-2 hours 4-5 hours Inhaled insulin 10-20 minutes 2 hours 6 hours 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.

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

Basal insulins NPH Analogs Glargine (Lantus) Detemir (Levimir) by Novo
Humulin N (Eli Lilly) Insulatard (Novo) (also available as insulatard Novolet pen) Dongsulin N (Highnoon) Insuget N (Getz) =========================================== Analogs Glargine (Lantus) Lantus Solostar Pen (Sanofi Aventis) Detemir (Levimir) by Novo

Basal Insulins Insulin Type Onset of action Peak of action
Duration of action NPH Intermediate acting 1-2 hours 5-7 hours 13-18 hours Glargine (Lantus) Aventis Long acting Relatively flat Upto 24 hours Detemir (Levimir)Novo 2-4 hours 8-12 hours 16-20 hours 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.

Human Regular Humulin R (Eli Lilly) Actrapid (Novo) (Also available as Actrapid novolet pen) Dongsulin R (Highnoon) Insuget R (Getz) ========================================== Analogs Lispro (Humolog) by Eli Lilly Novorapid by Novo Aspart Glulisine (Apidra) by Sanofi Aventis

Type Onset of action Peak of action Duration of action Human regular Short acting 30-60 minutes 2-4 hours 8-10 hours Insulin analogs (Lispro,Aspart,Glulisine) Rapid acting 5-15 minutes 1-2 hours 4-5 hours 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.

Pre mixed 70/30 (70% N,30% R) Analogs Novomix 30 (Novo)
Humulin 70/30 (Eli Lilly) Mixtard 30 (Novo) (Also available as Mixtard 30 Novolet Pen) Dongsulin 70/30 (Highnoon) Insuget 70/30 (Getz) =================================== Analogs Novomix 30 (Novo) Humolog Mix 25(Lilly) Humolog Mix 50(Lilly)

Types of Insulin 1. Rapid-acting (Analogs) 2. Short-acting
3. Intermediate-acting 4. Premixed 5. Long-acting 6. Extended long-acting (Analogs) (Regular) (NPH) (70/30) Key Point There are six types of insulin available which differ in their time to onset of action and duration of action. (Lantus) 41

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

Proposed Algorithm of therapy for Type 2 Diabetes
Inadequate Non pharmacological therapy Severe symptoms Severe hyperglycaemia Ketosis pregnancy 2 oral agents 3 oral agents 1oral agent Add Insulin Earlier in the Algorithm

First step into Insulin therapy

What we have in our pockets?
Basal Insulins (NPH,Lantus) Bolus Insulins(Human Regular) Premixed (Human 70/30)

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

Touch Pad Question Currently, roughly ____ of my patients with type 2 diabetes are taking some form of insulin. 1. >80% % % % % 48

Touch Pad Question When it comes to first-line insulin, I tend to prescribe: 1. An intermediate-acting insulin with fast-acting insulin as needed 2. A long-acting or extended long-acting insulin with fast-acting insulin as needed 3.A premixed insulin 49

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 Key Points The effects of rapid-acting insulin analogues occur within roughly 10 to 15 minutes, peak at 1 to 1.5 hours, and last between 4 and 5 hours. Examples of rapid-acting insulin analogues include insulin aspart, lispro, and glulisine. The effects of short-acting human insulin occur within 30 to 60 minutes, peak at 2 to 4 hours, and last 5 to 8 hours. 50

Types of Insulin Premixed Onset 1-3 hr(s)
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 Key Points Intermediate-acting human insulin begins to exert its effect with 1 to 3 hours, peak at 5 to 8 hours, and can last up to 18 hours. Examples include NPH and lente insulin. Premixed insulin comes in a vial or cartridge and contains a fixed ratio of rapid- or short-acting to intermediate-acting insulin. Examples include 75% NPL with 25% lispro, 70% APS with 30% aspart, and 70% NPH with 30% regular insulin or NPH. 51

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) Key Points The onset of action for long-acting human insulin is 3 to 4 hours, the peak occurs at 8 to 15 hours, and the effects last 22 to 26 hours. Examples include ultralente insulin. Long-acting insulin analogues begins to exert its effect within 1.5 to 3 hours. The peak of action for insulin detemir is dose dependent, and insulin glargine has no peak. Both last up to 24 hours. 52

Inhaled Insulin Inhaled Insulin
Approved in the U.S. in 2006 for the treatment of type 2 diabetes However, published studies to date have not demonstrated whether inhaled insulin can lower HbA1c to ≤7%, either: As monotherapy or In combination with an injection of long-acting insulin Key Points Inhaled insulin was approved in the U.S. in 2006 for the treatment of type 2 diabetes. However, published clinical studies to date have not demonstrated whether inhaled insulin can lower HbA1c to 7% or lower, either as monotherapy or in combination with an injection of long-acting insulin. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 53

Advantages of Insulin Therapy
Oldest of the currently available medications, has the most clinical experience Most effective of the diabetes medications in lowering glycemia Can decrease any level of elevated HbA1c No maximum dose of insulin beyond which a therapeutic effect will not occur Beneficial effects on triglyceride and HDL cholesterol levels Key Points Insulin is the oldest of the currently available medications for the management of hyperglycemia in type 2 diabetes and has the most clinical experience. It is the most effective of diabetes medications in lowering glycemia: when used in adequate doses it can decrease any level of elevated HbA1c to, or close to, the therapeutic goal, and there appears to be no maximum dose beyond which a therapeutic effect will not occur. Insulin has also been shown to beneficially affect triglyceride and HDL cholesterol levels. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 54

Effect of Insulin on Triglyceride and HDL-C Levels
0.34 mmol/l (30mg/dl) p=0.07 n=15 2 1.5 0.22 mmol/l (19.4mg/dl) p=0.07 n=15 1.8 1.85 1.4 1.39 1.6 1.3 Tryglyceride level (mmol/l) HDL-C (mmol/L) 1.51 1.4 1.2 1.17 1.2 Key Point This slide illustrates the effect of insulin on triglycerides and HDL cholesterol levels in a randomized, double-blind, placebo-controlled, 9-month study in 31 patients with type 2 diabetes treated with NPH insulin (n=15) or glyburide (n=16). Reference: Nathan DM et al. Glyburide or insulin for metabolic control in non-insulin-dependent diabetes mellitus. A randomized, double-blind study. Ann Int Med 1988;108: 1.1 1 1 Baseline Month 9 Baseline Month 9 Triglycerides HDL-C Adapted from Nathan DM et al. Ann Int Med 1988;108: 55

Disadvantages of Insulin Therapy
Weight gain ~ 2-4 kg May adversely affect cardiovascular health Hypoglycemia However, rates of severe hypoglycemia in patients with type 2 diabetes are low… Type 1 DM: 61 events per 100 patient-years Type 2 DM: 1-3 events per 100 patient-years Key Points The disadvantages of insulin therapy include weight gain of roughly 2 to 4 kilograms, which is probably proportional to the correction of glycemia and owing predominantly to the reduction of glycosuria. This weight gain could adversely affect cardiovascular health. Insulin therapy is also associated with hypoglycemia; however, rates are much lower than in type 1 diabetes. In clinical trials aimed at normoglycemia and achieving a mean HbA1c of approximately 7%, severe hypoglycemic episodes (defined as requiring help from another person to treat) occurred at a rate of 61 per 100 patient-years in a type 1 diabetes trial (i.e., the DCCT intensive-therapy group), but occurred at a rate of just 1 to 3 per 100 patient-years in trials with type 2 diabetics. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 56

Balancing Good Glycemic Control with a Low Risk of Hypoglycemia…
Key Point Essentially, the key to good insulin therapy is to balance good glycemic control with a low risk of hypoglycemia. Hypoglycemia 57

Rates of Hypoglycemia for Premixed vs. Long-Acting Insulin
3.5 p<0.05 45 p<0.05 3.4 40 43 3 35 2.5 30 2 25 Episodes per patient-year % of subjects 1.5 20 15 1 16 Key Points Long-acting insulin has demonstrated lower rates of hypoglycemia than premixed insulin. Shown here are the results of a randomized, 28-week study in 233 insulin-naïve patients with type 2 diabetes treated with BIAsp 70/30 bid or units glargine at bedtime titrated to target blood glucose by algorithm-directed titration. Rates of minor hypoglycemia, both in terms of the number of episodes per patient-year and the percentage of patients experiencing minor hypoglycemia, were significantly lower with insulin glargine. Reference: Raskin P et al. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care 2005;28(2):260-5. 10 0.5 0.7 5 BIAsp 70/30 (n=117) Glargine (n=116) BIAsp 70/30 (n=117) Glargine (n=116) Adapted from Raskin P et al. Diabetes Care 2005;28(2):260-5. 58

Percentage of patients Percentage of patients
HbA1c 7% Without Hypoglycemia (Composite Endpoint) in Two Treat-to-Target Studies 35 35 p<0.05 33.2 30 30 25 26.7 25 p=0.008 26.0 20 20 Percentage of patients achieving HbA1c 7% Percentage of patients achieving HbA1c 7% 15 15 16.0 10 10 Key Points Compared with NPH insulin, long-acting insulin analogues have demonstrated higher rates of patients achieving HbA1c targets without hypoglycemia. More patients receiving once-daily insulin glargine or twice-daily insulin detemir achieved their glycemic targets without hypoglycemia versus patients receiving NPH in two randomized, open-label, parallel-group, 24-week multicenter trials of patients with inadequate glycemic control (HbA1c >7.5%) (n=756 and n=475, respectively). References: Riddle M et al. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26: Hermansen K et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetes Care 2006;29: 5 5 Insulin glargine NPH Insulin detemir NPH Once-daily dosing1 Twice-daily dosing2 Hypoglycemia definition: glucose levels ≤4 mmol/L (72 mg/dL) or requiring assistance 1. Riddle M et al. Diabetes Care 2003;26: 2. Hermansen K et al. Diabetes Care 2006;29: 59

Rates of Hypoglycemia for Premixed vs. Long-Acting Insulin + OAD
Mean number of confirmed hypoglycemic events per patient-year in a 28-week study 6 p=0.0009 5.73 5 Premixed insulin Insulin glargine + OADs 4 Events per patient-year 3 2.62 2 p=0.0449 p=0.0702 Key Points The combination of a long-acting insulin and oral antidiabetic (OAD) therapy has been shown to have a significantly lower risk of hypoglycemia than premixed insulin. Rates of symptomatic (p=0.0009), nocturnal (p=0.0449) and severe hypoglycemia (p=0.0702) were all lower in an open-label, 24-week, multicenter, parallel group clinical trial of 371 insulin-naïve patients with poor glycemic control (FBG 120 mg/dl, HbA1c %) on sulfonylurea plus metformin. Hypoglycemia was defined as blood glucose <60mg/dl (<3.3 mmol/l) and severe hypoglycemia as blood glucose <36mg/dl (<2.0 mmol/l). Reference: Janka HU et al. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care 2005;28:254-9. 1 1.04 0.05 0.00 0.51 Symptomatic Nocturnal Severe Adapted from Janka et al. Diabetes Care 2005;28:254-9. 60

Rate of event per patient-year
Rates of Hypoglycemia for Premixed vs. Long-Acting Insulin + OAD in Elderly Patients 12 Rate of event per patient-year Premixed (n=63) Glargine + OAD (n=69) p=0.01 10 8 p=0.008 6 p=0.06 4 2 Key Points This result was also seen in elderly patients. The overall rate of hypoglycemia (p=0.01), the rate of confirmed hypoglycemia (p=0.008), and the rate of confirmed symptomatic hypoglycemia (p=0.06) were lower with the combination of long-acting insulin and oral antidiabetic therapy (OAD) versus premixed insulin in a 24-week, multicenter, open, randomized trial of 364 poorly controlled patients aged ≥65 years with type 2 diabetes mellitus. Hypoglycemia was defined as blood glucose <60 mg/dl (<3.3 mmol/l). Reference: Janka HU et al. Combination of oral antidiabetic agents with basal insulin versus premixed insulin alone in randomized elderly patients with type 2 diabetes mellitus. J Am Geriatr Soc 2007;55(2):182-8. All episodes of hypoglycemia All confirmed episodes of hypoglycemia Confirmed symptomatic hypoglycemia Adapted from Janka HU et al. J Am Geriatr Soc 2007;55(2):182-8. 61

Rates of Nocturnal Hypoglycemia for NPH vs. Long-Acting Insulin
HbA1c and rates of nocturnal hypoglycemia at Week 28 40 p<0.02 glargine vs. NPH NPH (n=259) Insulin glargine (n=259) 30 4 Patients (%) 3 20 p<0.01 for both treatments vs. baseline 2 10 Adjusted mean change from baseline 1 Key Points Extended long-acting insulin has also shown lower rates of nocturnal hypoglycemia for similar HbA1c reductions versus NPH. In an open-label, 28-week, multicenter trial (n=518), both NPH and insulin glargine resulted in a significant (p<0.01) reduction in HbA1c from baseline, but rates of nocturnal hypoglycemia from Month 2 to the study endpoint were significantly lower with insulin glargine (p<0.02). Reference: Rosenstock J et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 2001;24(4):631-6. -1 -2 HbA1c (%) Nocturnal hypoglycemia (Month 2 to endpoint) Adapted from Rosenstock J et al. Diabetes Care 2001;24(4):631-6. 62

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

Initiating and Adjusting Insulin
Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) 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. Target range: mmol/L ( mg/dL) If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c 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) 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 Key Points Although initial therapy is aimed at increasing basal insulin supply, usually with intermediate- or long-acting insulin, patients may also require prandial therapy with short- or rapid-acting insulin as well. The ADA algorithm has been created to help guide physicians in determining a patient’s optimal insulin regimen. There are three steps to the algorithm. Each will be reviewed in turn. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c every 3 months Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin Nathan DM et al. Diabetes Care. 2006;29(8): 64

Step One… Target range: If HbA1c ≤7%... If HbA1c 7%...
Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) 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. Target range: mmol/L ( mg/dL) If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c 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) 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 Key Point Step one involves initiating insulin. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c every 3 months Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin Nathan DM et al. Diabetes Care. 2006;29(8): 65

Step One: Initiating Insulin
Start with either… Bedtime intermediate-acting insulin or Bedtime or morning long-acting insulin Insulin regimens should be designed taking lifestyle and meal schedules into account Key Point When initiating insulin, the ADA recommends beginning with either a bedtime intermediate-acting insulin or a bedtime or morning long-acting insulin. This can be initiated with 10 units or 0.2 units per kilogram. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 66

Step One: Initiating Insulin, cont’d
Check fasting glucose and increase dose until in target range Target range: mmol/l ( mg/dl) Typical dose increase is 2 units every 3 days, but if fasting glucose >10 mmol/l (>180 mg/dl), can increase by large increments (e.g., 4 units every 3 days) Key Points Fasting glucose should be checked daily via fingerstick and the dose should be increased, typically by 2 units every 3 days, until fasting levels are in the target range (i.e., mmol/l or mg/dl). If fasting glucose is over 10 mmol/l (i.e., over 180 mg/dl), doses can be increased in larger increments (for example, by 4 units every 3 days). All insulin regimens should be designed to take lifestyle and meal schedules into account. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 67

Step One: Initiating Insulin, cont’d
If hypoglycemia occurs or if fasting glucose < 3.89 mmol/l (70 mg/dl)… Reduce bedtime dose by ≥4 units or 10% if dose >60 units Nathan DM et al. Diabetes Care 2006;29(8): 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. Key Point If hypoglycemia occurs or if fasting glucose is over 3.89 mmol/l (i.e. 70 mg/dl), the bedtime dose should be reduced by at least 4 units or by 10% if the dose is above 60 units. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): While using basal insulin alone,never stop or reduce ongoing oral therapy 68

After 2-3 Months… If HbA1c is <7%... If HbA1c is ≥7%...
Continue regimen and check HbA1c every 3 months If HbA1c is ≥7%... Move to Step Two… Key Points HbA1c should be re-checked within 2 to 3 months. If it is below 7%, the current regimen should be continued with re-evaluation of HbA1c levels every 3 months. If it is 7% or higher, physicians should move to Step Two of the algorithm. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 69

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.

Step Two… Target range: If HbA1c ≤7%... If HbA1c 7%...
Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) 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. Target range: mmol/L ( mg/dL) If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c 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) 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 Key Point Step Two of the algorithm involves intensifying insulin therapy. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c every 3 months Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin Nathan DM et al. Diabetes Care. 2006;29(8): 72

Step Two: Intensifying Insulin
If fasting blood glucose levels are in target range but HbA1c ≥7%, check blood glucose before lunch, dinner, and bed and add a second injection: If pre-lunch blood glucose is out of range, add rapid-acting insulin at breakfast If pre-dinner blood glucose is out of range, add NPH insulin at breakfast or rapid-acting insulin at lunch If pre-bed blood glucose is out of range, add rapid-acting insulin at dinner Key Points If, after 2 to 3 months of initiating insulin therapy, fasting blood glucose levels are in target range but HbA1c is 7% or higher, the patient’s blood glucose should be checked before lunch, dinner, and bed, and a second injection should be added. If the patient’s pre-lunch blood glucose is out of range, rapid-acting insulin should be added at breakfast. If pre-dinner blood glucose is out of range, NPH insulin should be added at breakfast or rapid-acting insulin should be added at lunch. If pre-bed blood glucose is out of range, rapid-acting insulin should be added at dinner. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 73

Making Adjustments Can usually begin with ~4 units and adjust by 2 units every 3 days until blood glucose is in range Key Point For the second injection, physicians can begin with approximately 4 units of insulin and adjust by 2 units every 3 days until blood glucose is in range. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): When number of insulin Injections increase from 1-2………..Stop or taper of insulin secretagogues (sulfonylureas). Nathan DM et al. Diabetes Care 2006;29(8): 74

After 2-3 Months… If HbA1c is <7%... If HbA1c is ≥7%...
Continue regimen and check HbA1c every months If HbA1c is ≥7%... Move to Step Three… Key Points Again, HbA1c should be re-checked within 2 to 3 months. If it is below 7%, the current regimen should be continued with re-evaluation of HbA1c levels every 3 months. If it is 7% or higher, physicians should move to Step Three of the algorithm. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 75

Step Three… Target range: If HbA1c ≤7%... If HbA1c 7%...
Hypoglycemia or FG >3.89 mmol/l (70 mg/dl): Reduce bedtime dose by ≥4 units (or 10% if dose >60 units) 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. Target range: mmol/L ( mg/dL) If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c 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) 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 Key Point Step Three of the algorithm involves further intensifying insulin therapy. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): If HbA1c ≤7%... If HbA1c 7%... Continue regimen; check HbA1c every 3 months Recheck pre-meal BG levels and if out of range, may need to add another injection; if HbA1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial rapid-acting insulin Nathan DM et al. Diabetes Care. 2006;29(8): 76

Step Three: Further Intensifying Insulin
Recheck pre-meal blood glucose and if out of range, may need to add a third injection If HbA1c is still ≥ 7% Check 2-hr postprandial levels Adjust preprandial rapid-acting insulin Key Points If pre-meal blood glucose is out of range when rechecked, a third injection of insulin may be needed. If HbA1c is still 7% or higher, 2-hour postprandial levels should be checked and preprandial rapid-acting insulin adjusted. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 77

Premixed Insulin Not recommended during dose adjustment
Can be used before breakfast and/or dinner if the proportion of rapid- and intermediate-acting insulin is similar to the fixed proportions available Key Points Premixed insulin is not recommended during dose adjustment. However, it can be used conveniently, usually before breakfast and/or dinner, if the proportion of rapid- and intermediate-acting insulin is similar to the fixed proportions available. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 78

Key Take-Home Messages
Insulin is the oldest, most studied, and most effective antihyperglycemic agent, but can cause weight gain (2-4 kg) and hypoglycemia Insulin analogues with longer, non-peaking profiles may decrease the risk of hypoglycemia compared with NPH insulin Premixed insulin is not recommended during dose adjustment Key Points In conclusion: Insulin is the oldest, most studied and most effective antihyperglycemic agent but can cause weight gain (2-4 kg) and, in rare instances, hypoglycemia Insulin analogues with longer, non-peaking profiles may decrease the risk of hypoglycemia compared with NPH insulin Published studies have not demonstrated whether inhaled insulin can lower HbA1c to 7% or lower Premixed insulin is not recommended during dose adjustment 79

Key Take-Home Messages, cont’d
When initiating insulin, start with bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin After 2-3 months, if FBG levels are in target range but HbA1c ≥7%, check BG before lunch, dinner, and bed,and, depending on the results, add 2nd injection (stop sulfonylureas here) After 2-3 months, if pre-meal BG out of range, may need to add a 3rd injection; if HbA1c is still ≥7% check hr postprandial levels and adjust preprandial rapid-acting insulin. Key Points (continued from previous): When initiating insulin, patients should start with bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin After 2 to 3 months, if fasting blood glucose levels are in target range but HbA1c is 7% or higher, blood glucose levels should be checked before lunch, dinner and bed, and, depending on the results, a 2nd insulin injection should be added. After 2 to 3 months, if pre-meal blood glucose is out of range, a 3rd injection may be needed. If HbA1c is still 7% or higher, 2-hour postprandial levels should be checked and preprandial rapid-acting insulin adjusted accordingly. 80

Regimen # 2

First calculate total daily dose of insulin
Body weight in kgs / 2 e.g; an 80 kg person will require roughly about 40 units / day.

Dose calculation……..contd
Split the total calculated dose into 4 (four) equal s/c injections. ¼ of total dose as regular insulin s/c half-hour ( ½ hr ) before the three main meals with 6 hrs gap in between. ¼ total calculated dose as NPH insulin s/c at 11:00 p.m. with no food to follow.

Dose calculation: example
For example in an 80-kg diabetic requiring 40 units per day, start with: 08:00 a.m units regular insulin s/c ½ hr before breakfast. 02:00 p.m units regular insulin s/c ½ hr before lunch. 08:00 p.m units regular insulin s/c ½ hr before dinner. 11:00 p.m units NPH/ lantus insulin s/c

Dose adjustment For adjustment of dosage, check fasting blood sugar the next day and adjust the dose of night time NPH Insulin accordingly i.e. keep on increasing the dose of NPH by approximately 2 units daily until you achieve a normal fasting blood glucose level of mg/dl.

Control BSF by adjusting the prior the dose of NPH

Dose adjustment….contd.
Remember that the BSL (Blood Sugar Level) at any given time reflects the insulin / meal taken before the reading, and therefore, a raised level of fasting blood sugar requires a change in the dose of previously administered night time insulin and will NOT be controlled by adjusting the next insulin injection.

Dose adjustment…contd.
Once the fasting blood glucose has been controlled, check 6-Point blood sugar as follows: Fasting. 2 hours after breakfast. Before lunch (and noon insulin) 2 hours after lunch. Before dinner (AND EVENING INSULIN) 2 hours after dinner

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

Dose adjustment…contd.
Now control any raised random reading by adjusting the dose of previously administered regular insulin. For example: a high post lunch reading will NOT be controlled by increasing the dose of next insulin (as in sliding scale), rather adjustment of the pre-lunch regular insulin on the next day will bring down raised reading to the required levels.

Examples For the following profile: Blood sugar fasting = 100 mg/dl
We need to increase the dose of NPH at night to bring down baseline sugar level (BSF) to around 100 mg/dl after which the profile should automatically adjust as follows: Blood sugar fasting = 100 mg/dl Blood sugar 02 hrs after breakfast = 170 mg/dl Blood sugar pre-lunch = 110 mg/dl Blood sugar 2 hrs. after lunch = 190 mg/dl Blood sugar pre-dinner = 120 mg/dl Blood sugar 2 hrs. post dinner = 180 mg/dl For the following profile: Blood sugar fasting = 180 mg/dl Blood sugar after breakfast = 250 mg/dl. Blood sugar pre lunch = 190 mg/dl Blood sugar post lunch 270 = mg/dl Blood sugar pre dinner = 200 mg/dl Blood sugar post dinner 260 = mg/dl

Examples……contd. Blood sugar fasting = 130 mg/dl
Blood sugar after breakfast = 160 mg/dl Blood sugar pre-lunch = 130 mg/dl Blood sugar post lunch = 240 mg/dl Blood sugar pre-dinner = 180 mg/dl Blood sugar 2 hrs. post dinner = 200 mg/dl This patient needs adjustment of pre-lunch regular Insulin which will bring down post lunch and pre dinner readings within normal limits. 2 hrs post dinner blood sugar(200 mg/dl) will be brought down by adjusting pre dinner regular insulin.

Combinations In types 2 subjects, once the blood sugar profile is normalized and the patient is not under any stress, the total daily dose (morning + noon + night + NPH at 11 p.m) may be divided into two 12 hourly injections of premixed Insulin

Examples….contd. e.g-1; If a patient is stabilized on
10U R + 12U R + 10U R + 12U NPH; then he may be shifted to 44/2 = 22 units of 70/30 Insulin 12 hourly s/c ½ hr before meal. e.g-2; If the adjusted Insulin is 14U R+16U R+12U R+8U NPH, then split the total dose: 30 U 70/30 before breakfast and 20U 70/30 before dinner to compensate for the high morning and lunch Insulin.

Combinations………contd.
Problem: Remember that BD dosing usually fails to cover lunch, especially if it is heavy. So: Always check for post lunch hyperglycemia when using this regimen. Solution: Patients can be advised to take their lunch (heavier meal) at breakfast; and breakfast (lighter meal) at lunch. Adding Glucobay with lunch some times provides a reasonable control. An alternate combination to overcome the problem is regular insulin for morning and noon, with premixed insulin at night.

Example 10U R before breakfast + 12U R before lunch + 22U 70/30 before dinner. Insulin will be injected exactly 6 hrs apart as in the QID regimen.

Choice of regimens R+ R+ R+ L**** R+ R+ R+ N ***
R+ R+ premixed insulin** BD premixed insulins*

Regimen # 3 (Pre mixed)

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%

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

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

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.

The prandial insulins

Limitations of Regular Human Insulin
Slower onset of activity that requires injections to be given 30 to 45 minutes before meals Patient inconvenience Safety concerns if the meal is not eaten when scheduled A prolonged duration of action (up to 12 hours of activity) Late postprandial hypoglycemia (4 to 6 hours after a meal) Risk of hyperinsulinemia

How to add and titrate prandial insulins?
In a large cohort study of more than 8000 patients managed by primary care physicians, more than 34% of patients were not initiated on insulin until A1C exceeded 10.0%,[47] representing a population with greater insulin resistance and greater insulin deficiency. Basal insulin can be introduced as the initial insulin strategy, as described above; however, patients with such elevated baseline A1C levels despite oral therapy are likely to require prandial insulin replacement in addition to basal insulin.[48] Most of the clinical data on basal-prandial insulin regimens involve patients with type 1 diabetes; however, considering the high prevalence of type 2 diabetes, more clinical studies are needed in this population to assist physicians with treatment decisions (Starting Insulin in Patients With A1C > 10.0%)

Regular insulin and Rapid acting analogues(Lispro)

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

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 .

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 U for a large meal plus additional units of insulin, if needed, based on the pre -meal self-monitoring blood glucose level reading

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

Titration of regular insulin and analogues

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…………………..

How to start pre mixed (70/30) Insulin

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; Step 3:Give 2 parts in the morning and 1 part in the evening; Morning=20U Evening=10 U

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

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…………………..

Advantages and disadvantages of premixed insulins

Advantages: Easy to administer for the physician
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.

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

How to solve the problem of dosage flexibility

Regimen # 4

Disadvantage of split- mixed regimen
Mid-night hypoglycemia

How to solve the problem of nocturnal hypoglycemia

Somogyi phenomenon Solution: Due to Night insulin taken early
excess dose of night time insulin, or Night insulin taken early Peaks at 3:00 a.m: hypoglycemia Counter regulatory hormones released in excess: Resulting in over correction of hypoglycemia: Fasting hyperglycemia Solution: Check BSL AT 3 :00 a.m Give long acting at 11:00 p.m so peak comes later Reduce dose of night time insulin

Dawn phenomenon Solution
Growth hormone surge at dawn raises insulin requirement. Night time insulin taken early, fades out before dawn. Fasting hyperglycemia Solution Give long acting insulin not before 11 :00 p.m May need to increase dose of night time insulin

More physiologic regimens

Using a twice-daily injection of basal insulin combined with a rapid-acting insulin prior to each meal offers a nice, predictable pattern that offers more precise coverage than some of the less physiologic programs.

(Concept of early insulinization)
Remember Insulin No miracle drug Has definite indications As delivery route follows reverse physiology: Good control is achieved only if residual pancreatic function is preserved to a certain extent i-e: Starting insulin on time is vital (Concept of early insulinization)

Pearls for practice Never try to control diabetes with oral hypoglycemic drugs / insulin without first ensuring strict diet control. Always bring fasting sugar to normal before trying to control post prandial / random blood sugar. Control any underlying infection/stressful condition vigorously. Keep meal timings regular with 6 hrs between the three meals. Do not inject NPH before 11 p.m. Keep number of calories during the meals same from day to day. The quantity and quality of diet should be same at same timings. Do not use sliding scale to calculate the dose of insulin. Use proper technique to inject s/c insulin. Ensure proper storage of insulin.

Common Problems

Problems can be avoided
Adherence to time table is all that is required to avoid problems: Regular meals Regular injections Regular excercise

Choosing an Insulin with a Lower Risk of Hypoglycemia
Insulin analogues with longer, non-peaking profiles may decrease the risk of hypoglycemia… Key Point An effective way of lowering the risk of hypoglycemia is to choose an insulin analogue with a longer, non-peaking profile. Reference: Nathan DM et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8): Nathan DM et al. Diabetes Care 2006;29(8): 146

Injection Techniques

Sites of injection Arms  Legs  Buttocks  Abdomen 

Sites of injection…….contd.
Preferred site of injection is the abdominal wall due to Easy access Ample subcutaneous tissue Absorption is not affected by exercise.

Injection technique

Technique Tight skin fold Spirit…. X Appropriate needle size
90 degree angle Change site to avoid lipodystrophy

Injection technique…….contd.
INSTRUCTIONS: Keep the needle perpendicular to skin in order to avoid variability in absorption (fig-A) Insert needle upto the hilt (fig-A) Distribute daily injections over a wide area to avoid lipodystrophy and other local complications (fig-B)

Storage Injections: refrigerate Pens: do not refrigerate

Shelf life One month once opened

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

First step into insulin therapy

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