1. Davida F. Kruger, MSN,APN-BC,BC-ADM Certified Nurse Practitioner Division of Endocrinology, Diabetes, Bone and Mineral Disorders Henry Ford Health System Detroit, Michigan

2. John S.  48 year old, white male  Married. Wife has type 2 diabetes  Works as a mechanic  Reports packing lunch of sandwich, fruit, chips and a few healthy snacks  Has seen dietian, working on portion size and carbohydrate content of meal ( was consuming 200 grams per meal)  BMI 42  Not physically active  SMBG 2-4 times daily, records in diary

3. Pertinent History Medical History:  Hypertension (20 years)  Dyslipidemia (20 years)  Recent MI (2010)  Stent December (2010) Social History  Married, children grown  Never smoked  Social drinker (rare)

4. Diabetes Management  Basal Insulin 200 units in divided dose, 100 units at breakfast and 100 units at 10 pm  Meal time insulin: 50 units at breakfast, 40 units at lunch, 50 units at dinner  A1c 9.8  Blood glucose monitoring consistent with A1c

5. Blood Glucose Diary DateBBABBLALBDADBT Sun379343398 Mon298251377 Tues263276285 Wed303317414 Thur187268 FRI256198343 Sat345341

6. What Are This Patient’s Options ?  Add more basal insulin ?  Add more meal time insulin ?  Switch to an insulin pump ?  Switch to U-500 insulin ?

7. What About the Need for More CONCENTRATED Insulins?  For more resistant patients, U-100 insulin both impractical and inconvenient When over 100 units (1mL) required at one time, would need more than one injection When over 100 units (1mL) required at one time, would need more than one injection Large volume of insulin painful Large volume of insulin painful Large depot of insulin impedes absorption making it unpredictable (a more concentrated insulin should be more predictable at these doses) Large depot of insulin impedes absorption making it unpredictable (a more concentrated insulin should be more predictable at these doses)

8. Insulin Resistant Conditions to Consider U-500 Insulin  Non-Syndromic Insulin Resistance Obesity with T2DM requiring > 200 u/day Obesity with T2DM requiring > 200 u/day Post-op or post-transplant state Post-op or post-transplant state High-dose steroids or pressors High-dose steroids or pressors Systemic infection Systemic infection Pregnancy with underlying T2DM Pregnancy with underlying T2DM

9. Most Recent PK/PD U-500 Data  Duration of action was shown to be prolonged for U-500 vs. U-100; mean late tRmax50 was 3.4 hr longer than at the 100-U dose (p<0.001)  The longer duration of effect of U-500 compared to U-100 suggests that multiple daily injections of U-500 without use of a basal insulin may be a plausible treatment option for insulin-resistant patients with type 2 diabetes

10. So Is U-500 Regular Insulin a Basal or a Prandial Insulin?  It is BOTH!  Lag times never studied, but it only makes sense that when used as mealtime insulin timing between injection and eating is even more important than with U-100 regular (or analogue)  Main secret for success with U-500 insulin FREQUENT SMBG! FREQUENT SMBG!

11. Communicating U-500 Dosing  Two ways: “units” on a U-100 insulin syringe or volume (mL) on a tuberculin syringe  Ideally, would be nice if everyone used both; most patients will discuss this in units  My compromise with patients and in charting: always note U-500.

12. Example  Patient is taking 10 units of U-500 insulin at breakfast (the equivalent of 50 units of U-100 regular) and it is decided to increase the dose to 14 units U-500 I tell the patient to increase the dose to 14 units U-500 in his U-100 syringe I tell the patient to increase the dose to 14 units U-500 in his U-100 syringe I chart the dose was increased to 14 units of U-500 (which is 70 units of U-100 regular) I chart the dose was increased to 14 units of U-500 (which is 70 units of U-100 regular)

13. Example  This can also be done in tuberculin syringes and only discussed in terms of volume of insulin  In the US tuberculin syringes only available in 27G needles  So 10 units of U-500 insulin would be 0.10 mL of insulin  An increase to 14 units would be 0.14 mL of insulin  My observation: patients and Health Care Providers prefer “units”

14. In-Patient Issues with U-500  Major concern for error “units” or mL? “units” or mL?  Many hospitals use both “Give 10 units U-500 (0.10 mL) 30 min prior to breakfast” “Give 10 units U-500 (0.10 mL) 30 min prior to breakfast”

15. Implementing U-500 Insulin  150-300 units/day U-500 has been shown effective with or without traditional basal insulin U-500 has been shown effective with or without traditional basal insulin Without basal insulin, U-500 can be split into ac breakfast and dinner shots (60/40) or ac TID (40/30/30 or 40/35/20) Without basal insulin, U-500 can be split into ac breakfast and dinner shots (60/40) or ac TID (40/30/30 or 40/35/20) Many continue basal insulin, esp. during transition from U-100 Many continue basal insulin, esp. during transition from U-100 Like most insulin management, what we do with U-500 is generally anecdotal. The good news: these patients don’t generally get hypoglycemic!

16. Sidebar: Understanding Basal Insulin 1.5 units/k g 2.0 units/kg 0.5 units/kg placebo 1.0, 1.5, and 2.0 units/kg > GIR than 0.5 units/kg, but not than each other! 1.0 units/kg GIRs for different doses of glargine injected into the abdomen Wang Z. Diabetes Care. 2010;33:1555-1560

17. Sidebar: Basal Insulin in This Population  No data comparing HS glargine, detemir, or NPH in these severely insulin resistant patients  Anecdote: the “peak” of the HS NPH often seems to improve fasting BGs better than the analogues  Another anecdote (“trick”): injecting a smaller volume of the NPH into two sites can improve efficacy of the insulin and improve glucose Inject 40 units of NPH into two different sites instead of one large depot of 80 units (same with analogues?) Inject 40 units of NPH into two different sites instead of one large depot of 80 units (same with analogues?)

18. This Patient:  Tally his total daily insulin intake of u-100 insulin:  Basal 200 units plus 140 units of meal time insulin: 340 of u-100 insulin  340./. 5 = 68 units of u-500 insulin  Start by providing half at breakfast and half at dinner  34 units of u-500 insulin at breakfast and dinner using a u-100 syringe

19. What Does The Patient Need to Know  Explain the difference between u-100 and u-500 insulin  Refer For MNT, diabetes education  Frequent blood glucose monitoring, charted for review  Treatment of hypoglycemia  Injection technique, site rotation  U-500 insulin only comes in a vial

20. Follow up Blood Glucose Diary DateBBABBLALBDADBT Sun197234247 Mon219218273 Tues186199201 Wed238176239 Thu211200253175 FRI193195217 Sat245223263224

21. What Do You see ?  Fasting blood glucose remain elevated  Before lunch, after lunch and before dinner blood glucose elevated  After dinner and bed time blood glucose elevated

22. Next Steps  Increase the following:  Dinner u-500 insulin 1-2 units (5-10 u-100) Corrects bed and fasting blood glucose  Breakfast u-500 insulin 1-2 units (5-10 u- 100) Corrects after breakfast, before lunch and perhaps after lunch and before dinner.  Add lunch time injection. Start with 2-4 units u-500 insulin (10-20 units u-100) Corrects after lunch and before dinner blood glucose

23. What About Cost?  U-500: 1 vial = $320/20 mL vial (mean of 3 pharmacies since not available at drugstore.com)  U-100 regular insulin (Drugstore.com): $73/vial (34% increase in the past 3 years)  Insulin lispro and insulin glargine: $126 and $119/vial (18% increase in past 3 years)  Insulin lispro-5 pens (15 mL) = $226 (13% increase in past 3 years)  Insulin glargine-5 pens = $220 (14% increase in past 3 years)  Insulin detemir -5 pens = $224 (13% increase in past 3 years)

24. What is the Cost/Unit of Insulin? cents From drugstore.com, 4/27/11* *U-500 cost at 3 pharmacies

25. Pearls  U-500 insulin can be taken 15-30 min before meals and at bed time to control blood glucose  Small volume provides a more comfortable injection with better absorption  U-500 insulin works as both a basal and bolus insulin  Go slow and be sure patient is comfortable with insulin adjustments  Education, frequent blood glucose monitoring will help patient be successful