1. Concentrate! Key Takeaways of new insulin products
Sara Wettergreen, PharmD, BCACP
Assistant Professor of Pharmacotherapy
University of North Texas System College of Pharmacy

2. Learning Objectives: Pharmacists
Compare and contrast use of insulin pen devices
Identify patients who may benefit from use of new insulin products
Design a patient-specific treatment regimen using new insulin products

3. Learning Objectives: Technicians
Compare and contrast use of insulin pen devices
Define safety considerations related to insulin use
Assist patients with obtaining pricing discounts for new insulin products

4. Diabetes: A Growing Problem
29.1 million people in the United States have diabetes
About 1 in 4 of these are undiagnosed
37% of patients treated for diabetes use insulin
Center for Disease Control (CDC). National diabetes statistics report, 2014.

5. “Egregious Eleven” Schwartz et al. Dia Care 2016;39:179-186
Previously, ominous octet by Defronzo circa 2009; we have now moved to the egregious eleven by Schwartz
β-Cell–centric construct: the egregious eleven. Dysfunction of the β-cells is the final common denominator in DM. A: Eleven currently known mediating pathways of hyperglycemia are shown. Many of these contribute to β-cell dysfunction (liver, muscle, adipose tissue [shown in red to depict additional association with IR], brain, colon/biome, and immune dysregulation/inflammation [shown in blue]), and others result from β-cell dysfunction through downstream effects (reduced insulin, decreased incretin effect, α-cell defect, stomach/small intestine via reduced amylin, and kidney [shown in green]). B: Current targeted therapies for each of the current mediating pathways of hyperglycemia. GLP-1, glucagon-like peptide 1; QR, quick release.
Schwartz et al. Dia Care 2016;39:

6. Role of Insulin
American Diabetes Association Dia Care 2016;39:S52-S59

7. Role of Insulin
Reprinted with permission from American Association of Clinical Endocrinologists © 2016 AACE. Endocr Pract.2016;22:

8. New Insulin Products Insulin glargine U-100 equivalent (Basaglar®)
Became available December 15th, 2016
Insulin glargine U-300 (Toujeo®)
Insulin degludec U-100 and U-200 (Tresiba®)
Regular human insulin u-500 (Humulin R U-500 KwikPen®)
Insulin lispro U-200 (Humalog U-200 KwikPen®) .

9. Characteristics of an Ideal Basal Insulin
PK/PD profile that more closely mimics endogenous basal insulin secretion
Low risk of hypoglycemia
Minimal weight gain
Dosing flexibility
Easy for patients to administer

10. Advances with Basal Insulins
Glargine U-300
Degludec U-100, U-200
Less peak
Longer duration
Lower risk of hypoglycemia
Detemir
Glargine U-100
Glargine U-100 equivalent
Less peak
Longer duration
Lower risk of hypoglycemia
NPH
Peak
Shorter duration
Risk of hypoglycemia

11. Insulin Glargine U-100 Equivalent (Basaglar®)
Not considered a “biosimilar” as the Biologic License Application (BLA) pathway was not used, but is a follow-on biologic approved via the New Drug Application (NDA) pathway
Conversion from insulin glargine U-100 (Lantus®) is 1:1 dose
Non-inferior to insulin glargine U-100 (Lantus®)
Basaglar [Prescribing Information]. Indianapolis, IN: Eli Lilly and Company.
Rosenstock J, et al. Diabetes Obes Metab. 2015;17(8):

12. Insulin Glargine U-300 (Toujeo®)
U U-300
Surface Area
Volume
FDA approved February 2015
Available in disposable, prefilled SoloSTAR pen device
1/3 of injection volume compared with U-100
Reduces depot surface area by ½
Allows for a gradual, prolonged rate of absorption
Each pen contains 450 units
Maximum single injection dose = 80 units
TOUJEO® (insulin glargine) injection 300 units/mL [prescribing information]. Bridgewater, NJ: Sanofi-Aventis.

13. PK/PD of Insulin Glargine U-300 vs. U-100
Becker RHA. Diabetes Care 2015;38:

14. EDITION 1: Insulin Glargine U-300
Multicenter, open-label
T2D patients, A1C 7%–10%
Current basal therapy with ≥ 42 units/day of glargine or NPH + mealtime RAIA ± metformin
Insulin glargine U-100
Once daily using pen device
Adjusted no more than every 3 days to goal FPG 80–100 mg/dL
Insulin glargine U-300
Once daily using pen device
Adjusted no more than every 3 days to goal FPG 80–100 mg/dL
Primary Outcome: A1C change from baseline to month 6
Riddle MC. Diabetes Care 2014;37:

15. EDITION 1: Insulin Glargine U-300
Outcome
Glargine U-300
(n=404)
Glargine U-100
(n=403)
Change in A1C from baseline (%)
-0.83
Change in weight from baseline (kg)
+0.9
Daily basal insulin dose at end of study (units)
103 94
Confirmed or severe nocturnal hypoglycemic events (%) 36 46
Ending dose was 103 for U-300 and 94 for U-100
Confirmed = glucose less than 70
Met predefined noninferiority criteria.
Riddle MC. Diabetes Care 2014;37:

16. EDITION 2: Insulin Glargine U-300
Multicenter, open-label
T2D patients, A1C 7%–10%
Current basal therapy with ≥ 42 units/day of glargine or NPH + OADs
Insulin glargine U-100
Once daily using pen device
Adjusted no more than every 3 days to goal FPG 80–100 mg/dL
Insulin glargine U-300
Once daily using pen device
Adjusted no more than every 3 days to goal FPG 80–100 mg/dL
Primary Outcome: A1C change from baseline to month 6
Yki-Jarvinen H. Diabetes Care 2014;37:

17. EDITION 2: Insulin Glargine U-300
Outcome
Glargine U-300
(n=404)
Glargine U-100
(n=407)
Change in A1C from baseline (%)
-0.57
-0.56
Daily basal insulin dose at end of study (units) 91 82
Nocturnal hypoglycemic (%)
30.5
41.6
Confirmed or severe hypoglycemia (%)
21.6
27.9
Participants experiencing nocturnal hypoglycemia
Met predefined noninferiority criteria.
Yki-Jarvinen H. Diabetes Care 2014;37:

18. EDITION 3: Insulin Glargine U-300
Multicenter, open-label
T2D patients, A1C 7%–11%
Insulin naive using OADs
Insulin glargine U-100
Once daily using pen device
Adjusted no more than every 3 days to goal FPG 80–100 mg/dL
Insulin glargine U-300
Once daily using pen device
Adjusted no more than every 3 days to goal FPG 80–100 mg/dL
Primary Outcome: A1C change from baseline to month 6
Bolli GB. Diabetes Obes Metab 2015;17:

19. EDITION 3: Insulin Glargine U-300
Outcome
Glargine U-300
(n=439)
Glargine U-100
Change in A1C from baseline (%)
-1.42
-1.46
Daily basal insulin dose at end of study (units)
59.4 52
Nocturnal confirmed or severe hypoglycemic (%) 18 24
Participants experiencing nocturnal hypoglycemia
Met predefined noninferiority criteria.
Bolli GB. Diabetes Obes Metab 2015;17:

20. Insulin Glargine U-300: Summary
Smoother PK/PD profile than glargine U-100
Full 24-hour coverage; flexibility in dosing time
Less nocturnal hypoglycemia than glargine U-100
Smaller injection volume
1:1 conversion recommended when switching from glargine U-100
Higher doses (~10%) may be needed compared with insulin glargine U-100
TOUJEO® (insulin glargine) injection 300 units/mL [prescribing information]. Bridgewater, NJ: Sanofi-Aventis.

21. Insulin Degludec (Tresiba®)
Approved by FDA September 25, 2015
U-100 (Tresiba® 100 units/mL)
FlexTouch pen device
300 units per pen; max single dose = 80 units
Duration of action > 40 hours; allows for flexibility in dosing
Doses are selected in 1 unit increments
U-200 (Tresiba® 200 units/mL)
FlexTouch pen device; low volume
600 units per pen, max single dose = 160 units
Bioequivalent to degludec U-100; similar glucose lowering
Doses are selected in 2 unit increments
Zinman B. Diabetes Care 2012;35: ; Gough SC. Diabetes Care 2013;36:
Garber AJ. Lancet 2012;379:

22. Insulin Degludec PK/PD
Half life >25 hours
Duration of action: 42 hours
Steady state is reached within 3 days, thus dose titrations should occur on a weekly basis
Similar PK/PD between the U-100 and U-200 concentrations
Schematic representation of the hypothesis for the mode of retarded absorption of insulin degludec (IDeg). IDeg is injected subcutaneously as a zinc phenol formulation containing the IDeg di-hexamer in the T3R3 conformation. Rapid loss of phenol changes the IDeg hexamers to a T6 configuration and multi-hexamer chains form. With slow diffusion of zinc, these chains break down into dimers, which quickly dissociate into readily absorbed monomers.
Vora J, et al. Diabetes Research in Clinical Practice 2015;109:19-31.

23. Insulin Degludec Clinical Trial (Duration) Background Therapy
Comparator Arms
Change in A1C (%)
End of Trial Insulin Dose (units/kg)
Hypo-glycemia (episodes per pt-year)
Confirmed or Severe Nocturnal Hypoglycemia (per pt-year)
Zinman
(52 weeks)
Metformin (insulin naive)
IDeg U-100
-1.06
0.59
1.52
0.25*
Glargine
-1.19
0.60
1.85
0.39
Garber
Insulin ± OADs
-1.1
0.75
11.1*
1.4*
-1.2
0.69
13.6
1.8
Gough
(26 weeks)
Metformin ± DPP-4i
(insulin naive)
IDeg U-200
-1.22
0.53*
1.22
0.18
-1.42
1.42
0.28
GOUGH = lower FPG with U-200 than insulin glargine
Noninferiority criteria met.
*p<0.05.
Zinman B. Diabetes Care 2012;35: ; Gough SC. Diabetes Care 2013;36: ; Garber AJ. Lancet 2012;379:

24. Converting to Insulin Degludec
Vora J, et al. Diabetes Research in Clinical Practice 2015;109:19-31.

25. Patient Considerations with Insulin Degludec
Titration Frequency
TITRATE Study: Insulin determir was titrated by 3 units every 3 days
Titrations with insulin degludec should be made on a weekly basis due to the extended duration of action
Adherence
Flexibility in timing between doses with a minimum of 8 hours between doses
Minimal change is safety or efficacy with variability in timing of doses between 8 to 40 hours between doses
Vora J, et al. Diabetes Research in Clinical Practice 2015;109:19-31.

26. Insulin Degludec: Summary
Extended duration of action compared to other basal insulin products
Less nocturnal hypoglycemia with degludec U-100 than glargine U-100
1:1 conversion recommended when switching from other basal insulins
20% dose reduction may be considered if using twice daily dosing
Extended coverage; flexibility in dosing time; weekly titrations
Vora J, et al. Diabetes Research in Clinical Practice 2015;109:19-31.

27. Regular Human Insulin U-500 (Humulin R U-500 KwikPen®)
Nothing new about the insulin
Five times as concentrated as U-100 insulin
Used for severe insulin resistance (total daily dose >200 units/day)
The PEN is new!
1500 units per 3 mL pen
Doses are selected in 5 unit increments
No dose-conversions needed (compared to vial use)
Humulin R U-500 KwikPen [Prescribing Information]. Indianapolis, IN: Eli Lilly and Company.

28. Regular Human Insulin U-500
Continues to be available in a 20 mL vial (10,00 units of insulin)
U-500 syringe is recommended for use with the U-500 vial
Humulin R U-500 [Prescribing Information]. Indianapolis, IN: Eli Lilly and Company.

29. Regular Human Insulin U-500: Dosing Review
Conversion from U-100 products to U-500
A1c ≥ 8%: 1:1 conversion from U-100 to U-500 insulin total daily dose (TDD)
May decrease TDD by 10-20% if A1c<8%
The TDD is then divided
Required TDD (Units)
Route and Frequency
U-500 Insulin Dosage
Twice daily
50/50 or 60/40 before breakfast and supper
Three times daily
33/33/33 before meals
Four times daily
30/30/30/10 (mealtimes and bedtime)
>600
Segal AR, et al. Am J Health-Syst Pharm. 2010; 67:

30. Regular Human Insulin U-500: Dose Titration
Ballani P, et al. Diabetes Care. 2006; 29(11):

31. Characteristics of an Ideal Bolus Insulin
Low risk of hypoglycemia
Minimal weight gain
Dosing flexibility
Easy for patients to administer

32. Advances with Bolus Insulins
Lispro U-200
Decreased number of pens needed with high doses
Pen device
Rapid-acting insulin analogs
Faster onset
Shorter duration
Clinical outcomes
Pen devices
Regular
Slow onset
Longer duration
Risk of hypoglycemia

33. Insulin Lispro U-200 (Humalog U-200 KwikPen®)
The CONCENTRATION is new!
Twice as concentrated as U-100 insulin
1500 units per 3 mL pen
Doses are selected in 1 unit increments
1:1 unit conversion recommend when switching from insulin lispro U-100
Benefit is that patients on high bolus doses will use less pens
Humalog [Prescribing Information]. Indianapolis, IN: Eli Lilly and Company.

34. Ultra-Rapid Acting Insulin Aspart (NN1218)
Earlier time to 50% maximal concentration
Faster-acting insulin aspart: 20.7 minutes
Insulin aspart: 31.6 minutes
Application submitted to the FDA
October 7, 2016 – FDA response letter issued requesting additional information for the immunogenicity and clinical pharmacology data
Heise T, et al. Diabetes Obes Metab. 2015;17(7):

35. Discussion Question!
What patients may be good candidates for each of these new insulin products?
Insulin glargine U-300 (Toujeo®)
Insulin degludec U-100 and U-200 (Tresiba®)
Regular human insulin u-500 (Humulin R U-500 KwikPen®)
Insulin lispro U-200 (Humalog U-200 KwikPen®)

36. Cost Considerations Insulin product How supplied Total units/pen Cost
Cost/unit
Insulin glargine U-300
1.5 mL pens
450
$134
$0.30
Insulin glargine U-100
3 mL pens
300
$89
Insulin glargine U-100 equivalent
TBD
Insulin degludec U-200
600
$213
$0.36
Insulin degludec U-100
$107
Regular human insulin U-500 pen
1,500
$320
$0.21
Regular human insulin U-500 vial
20 mL vial
10,000
$1655
$0.16
Insulin lispro U-200
$236
$0.39
Insulin lispro U-100
$118
Table adapted from: Mospan CM.JAAPA. 2016; 29(6):16-18;
Pricing from as of October 2016

37. Drug Discount Programs
Insulin product
Program Details
Insulin glargine U-300
Discount cards are available
Card can reduce copay to $15, with a maximal discount of $200/pack
Can be used for the first 12 prescription fills
Sanofi Patient Connection Program
May be able to decrease drug price to $0 copay
Insulin degludec
U-200/U-100
Can decrease copayment to as low as $15 (maximal discount of $500 for each fill)
Can be used for the first 24 prescription fills
Regular human insulin
U-500 pen
Discount cards available
Card can reduce copay to $25, with a maximum of 7 KwikPen packs per prescription fills
Insulin lispro U-200
Can decrease copayment to as low as $25 (maximal discount of $100 for each fill)

38. Not Just an Outpatient Issue!
In the Inpatient Setting:
Insulin pens are preferred by nurses
Felt it was easier to teach patients to self-administer insulin using a pen device
Felt that the risk of a dosing error was lower with a pen device vs. syringe
Reduced waste from using insulin pens instead of vials may reduce cost
One study projected a cost savings of $36 per patient per hospital stay with insulin pen use instead of insulin vials
Haines ST, et al. Am J Health-Syst Pharm. 2016; 73(suppl 5):S4-16.

39. A Risky Situation…
2009: At a Texas hospital in 2009, 2,114 insulin-dependent patients with diabetes were exposed to disease transmission risk via used insulin pens
2011: Over 2,000 patients were exposed to used insulin pens at a Wisconsin hospital and outpatient clinic
2013: Over 700 patients at a New York hospital may have been exposed inadvertently to human immunodeficiency virus (HIV), hepatitis B, or hepatitis C because of the reuse of insulin pens on multiple patients

40. Discussion Question!
Are insulin pens used at your practice site? If so, how do you decrease the risk of reusing insulin pens?

41. Best Practices for Safe Use of Insulin Pen Devices in Hospitals
Recommendations have been made for each step in the medication-use process
Examples:
“Warning! Confirm patient. Insulin pens are for use in one patient only”
Require all health professionals to pass a competency assessment for insulin pens (at the time of hire and periodically thereafter)
Develop a system to prompt the proper disposal of insulin pens when the order is discontinued
Haines ST, et al. Am J Health-Syst Pharm. 2016; 73(suppl 5):S4-16.

42. Key Takeaways 37% of patients treated for diabetes use insulin
Many new insulin products are available, each with their own advantages
Cost may be a barrier to patient use, and drug discount programs are one method of assisting patients reduce costs
Addition of new insulin products can lead to further confusion with the various devices available, which has implications for both the inpatient and outpatient settings

43. Concentrate! Key Takeaways of new insulin products
Sara Wettergreen, PharmD, BCACP
Assistant Professor of Pharmacotherapy
University of North Texas System College of Pharmacy