Insulin therapy Niloufar Ansari, Pharm. D. South Tehran Health Center, Tehran University of Medical Sciences

The breakthrough: Toronto 1921 – Banting & Best

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

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

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):1963-72. Nathan DM et al. Diabetes Care 2006;29(8):1963-72. 9 9

Types of Insulin 1. Rapid-acting (Lispro, Aspart) 2. Short-acting 3. Intermediate-acting 4. Premixed 5. Long-acting 6. Extended long-acting (Lispro, Aspart) (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) 10 10

Pharmacokinetics of Current Insulin Preparations Effective Onset Peak Duration Insulin lispro <15 min 1 hr 3 hr Regular 0.5-1 hr 2-3 hr 3-6 hr NPH/Lente 2-4 hr 7-8 hr 10-12 hr Ultralente 4 hr Varies 18-20 hr Insulin glargine* 1-2 hr Flat/Predictable 24 hr *Investigational Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:1463-1495. Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.

Summary of available insulin preparations Agent Type / Administration Glucose lowering Basal Post-meal NPH Intermediate-acting human Once or twice daily at bedtime ± breakfast  Detemir Long-acting analogue Glargine Once daily at bedtime or before breakfast Premixed Human or analogue mix Twice daily before breakfast and dinner Regular Fast-acting human Before meals Aspart, glulisine, lispro Rapid-acting analogue Inhaled insulin Rapid-acting human

Insulin Pens NovoMix®30 NovoRapid® Insulatard® 30% insulin aspart in a soluble fraction and 70% insulin aspart crystallised with protamine NovoRapid® Insulin aspart Insulatard® NPH

Insulin Pens

Intelligent Devices Pumps Smart Phones Meters A central reporting station where data is filtered for minor versus major problems and who is to be alerted (user, guardian, MD/RN) Intelligence can be built into a wide range of devices. Part of the control solution has to come from a centralized monitoring station. This would involve computers and people who monitor real time or near real time BG and other data. Communication methods such as Bluetooth, telephone, and internet will be required.

We are here! HCP Self Management Automation I n s u l i n D e l i v e r y Insulin & syringes We are here! Pumps Pens Closed Loop Connectivity Open Loop Data Management Advice/Feedback M o n i t o r i n g Home Monitors We are on a peth to automated blood glucose control. The workload of health care personnel will stay high through the current “self-management” stage. Only when useful devices which assist the user in making critical day to day control decisions become widely available will the medical workload begin to diminish. Clinic Monitoring HCP Self Management Automation

Injection Techniques

Sites of injection Arms  Legs  Buttocks  Abdomen  Easy access Ample subcutaneous tissue Absorption is not affected by exercise.

Side Effects Hypoglycaemia 2. Allergy: 3. Lipodystrophy - 15-15-15 rule - Dextrose 50% - Glucagon 2. Allergy: - Local allergy: redness, swelling and itching at the site of injection General allergic reaction: sweating, vomiting, breathing difficulties, rapid heart beat, feeling dizzy 3. Lipodystrophy

The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin 20

Normal physiologic patterns of glucose and insulin secretion in our body

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. 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.

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: 3.89-7.22 mmol/L (70-130 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):1963-72. 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):1963-72. 24

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: 3.89-7.22 mmol/L (70-130 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):1963-72. 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):1963-72. 25

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):1963-72. Nathan DM et al. Diabetes Care 2006;29(8):1963-72. 26

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) 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., 3.89-7.22 mmol/l or 70-130 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):1963-72. Nathan DM et al. Diabetes Care 2006;29(8):1963-72. 27

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):1963-72. 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):1963-72. While using basal insulin alone,never stop or reduce ongoing oral therapy 28

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

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%. 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: 3.89-7.22 mmol/L (70-130 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):1963-72. 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):1963-72. 31

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):1963-72. Nathan DM et al. Diabetes Care 2006;29(8):1963-72. 32

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):1963-72. 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):1963-72. 33

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 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):1963-72. Nathan DM et al. Diabetes Care 2006;29(8):1963-72. 34

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: 3.89-7.22 mmol/L (70-130 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):1963-72. 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):1963-72. 35

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):1963-72. Nathan DM et al. Diabetes Care 2006;29(8):1963-72. 36

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):1963-72. Nathan DM et al. Diabetes Care 2006;29(8):1963-72. 37

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 38

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 2-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. 39

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

Monitoring 1. Fasting hyperglycemia: - Check NPH bedtime dose - Down Phenomenon - Somogyi Effect  Use Regular before dinner and NPH at bedtime

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

Monitoring, cont’d 2. Midmorning hyperglycemia: - Check fasting blood glucose 3. Sick day management:  Do not reduce insulin dose

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.

References Koda-Kimble MA, Carlisle BA. Diabetes Mellitus. Applied Therapeutics, The Clinical Use of Drugs. McCulloch DK. General principles of insulin therapy in diabetes mellitus. UpToDate. Evans M, Schumm-Draeger PM, Vora J, King AB. A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvements and limitations. Diabetes Obes Metab 2011; 13:677. Swinnen SG, Hoekstra JB, DeVries JH. Diabetes Care. 2009 Nov;32 Suppl 2:S253-9. Diabetes Care. 2009;32 (Suppl 2):S253-9. Roach P. New insulin analogues and routes of delivery: pharmacodynamic and clinical considerations. Clin Pharmacokinet. 2008;47:595-610. http://www.novonordisk.com/diabetes/public/insulinpens/flexpen/default.asp

For Sparing your valuable time Thank you all For Sparing your valuable time & Patient listening Abr jungle, Shahroud, Iran