Insulin Therapy in DM

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?

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.

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

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

Basal insulins NPH 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 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

Bolous insulins (Mealtime or prandial) 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

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

Pre mixed 70/30 (70% N,30% R) 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 2. Short-acting 3. Intermediate-acting 4. Premixed 5. Long-acting 6. Extended long-acting (Analogs) (Regular) (NPH) (70/30) (Lantus)

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

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

F i rst step i nto 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

Touch Pad Question Currently, roughly ____ of my patients with type 2 diabetes are taking some form of insulin. 1. >80% 2. 60-80% 3. 40-60% 4. 20-40% 5. 0-20%

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

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

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

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)

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 HbA 1c to ≤7%, either: As monotherapy or In combination with an injection of long-acting insulin Nathan DM et al. Diabetes Care 2006;29(8):1963-72. Inhaled Insulin

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 HbA 1c No maximum dose of insulin beyond which a therapeutic effect will not occur Beneficial effects on triglyceride and HDL cholesterol levels Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

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

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 Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

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

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

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

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

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

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)

The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin

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%...

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%...

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 Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Step One: Initiating Insulin , cont’d Check fasting glucose and increase dose until in target range Target range: 3.89-7.22 mmol/l (70-130 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) Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

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 Step One: Initiating Insulin , cont’d Nathan DM et al. Diabetes Care 2006;29(8):1963-72. While using basal insulin alone, never stop or reduce ongoing oral therapy 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.

If HbA 1c is <7%... Continue regimen and check HbA 1c every 3 months If HbA 1c is ≥7%... Move to Step Two… After 2-3 Months… Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

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… 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%...

Step Two: Intensifying Insulin If fasting blood glucose levels are in target range but HbA 1c ≥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 Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Making Adjustments Can usually begin with ~4 units and adjust by 2 units every 3 days until blood glucose is in range Nathan DM et al. Diabetes Care 2006;29(8):1963-72. When number of insulin Injections increase from 1-2………..Stop or taper of insulin secretagogues (sulfonylureas).

If HbA 1c is <7%... Continue regimen and check HbA 1c every 3 months If HbA 1c is ≥7%... Move to Step Three… After 2-3 Months… Nathan DM et al. Diabetes Care 2006;29(8):1963-72 .

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%...

Step Three: Further Intensifying Insulin Recheck pre-meal blood glucose and if out of range, may need to add a third injection If HbA 1c is still ≥ 7% Check 2-hr postprandial levels Adjust preprandial rapid-acting insulin Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

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 Nathan DM et al. Diabetes Care 2006;29(8):1963-72 .

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 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 HbA 1c ≥7%, check BG before lunch, dinner, and bed,and, depending on the results, add 2 nd injection ( stop sulfonylureas here ) After 2-3 months, if pre-meal BG out of range, may need to add a 3 rd injection; if HbA 1c is still ≥7% check 2-hr postprandial levels and adjust preprandial rapid-acting insulin.

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. --- 10 units regular insulin s/c ½ hr before breakfast. 02:00 p.m . --- 10 units regular insulin s/c ½ hr before lunch. 08:00 p.m. --- 10 units regular insulin s/c ½ hr before dinner. 11:00 p.m. --- 10 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 80-110 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 = 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 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

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 *

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.

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? (Starting Insulin in Patients With A1C > 10.0%)

Regular insulin and Rapid acting analogues(Lispro)

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

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 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

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; 10+10+10 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. 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

Disadvantage of split- mixed regimen Mid-night hypoglycemia

How to solve the problem of nocturnal hypoglycemia

Somogyi phenomenon Due to 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 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

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.

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… Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

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.

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

Thank you all For Sparing your valuable time & Patient listening

Insulin Therapy in DM

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