1. Injectable Medications for Treatment of Diabetes
Getting to the Point
Stephanie Lewis, PharmD
PGY-1 Resident University of New England – Hannaford Pharmacy – Martin’s Point Health Care

2. Objectives
Describe the mechanism of action, indications for use, dosages, stability, and adverse effects for each injectable product used to treat types 1 and 2 diabetes mellitus (DM)
Review insulin administration techniques and emergency use of glucagon
Identify drugs currently in the pipeline and the future of injectable therapies used to treat DM

3. Injectable Products

4. Pramlintide (Symlin ®)
MOA
Synthetic version of amylin; ↓ glucagon release from pancreatic alpha cells, ↓ GER
Dosing
Type 1 DM:
- Initial: 15 mcg SC immediately prior to main meals
- Maintenance: titrate at 15 mcg increments  up to 60 mcg as tolerated
Type 2 DM:
- Initial: 60 mcg SC immediately prior to main meals
- Maintenance: 120 mcg as tolerated
Contraindications
Gastroparesis, patients unable to detect hypoglycemia
Adverse Effects
Significant hypoglycemia, abdominal pain, n/v, headache, dizziness
Monitoring
FBG, A1C
Interactions
Slows gastric emptying time  reduced extent and rate of absorption of orally administered drugs
Clinical pearls
Used only as adjunct tx
Reduce mealtime insulin by 50% with concomitant use
Available as SC pen (expires 30 days after opening)
0.5-1 % ↓ in A1C

5. Pramlintide (continued…)
Generally not favored due to modest efficacy, dosing frequency, and side effects
Per 2016 ADA Guidelines
American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. 2016; 32(S1): S1-S112.

6. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA)
↑ glucose-dependent insulin & amylin secretion, ↓ glucagon, ↓ gastric emptying, ↑ satiety

8. GLP-1 RAs: Dosing Drug Initial Titrate Max Dose Adjustments
Exenatide IR (Byetta®)
5 mcg BID within 60 mins of a meal
(> 6H between doses)
↑ to 10 mcg after 1 month
10 mcg
Renal impairment: CrCl mL/min: use caution; CrCl < 30 mL/min not recommended
Hepatic impairment: not studied
Exenatide ER (Bydureon®)
2 mg once weekly
N/A
Liraglutide (Victoza®)
0.6 mg once daily
1.2 mg once daily per week
1.8 mg once daily
Renal & hepatic impairment: use caution – limited experience
Albiglutide (Tanzeum®)
30 mg once weekly
↑ to 50 mg once weekly if inadequate response
50 mg once daily
Renal impairment: use caution when initiating or escalating doses
Hepatic impairment: not studied, unlikely required
Dulaglutide (Trulicity®)
0.75 mg once weekly
↑ to 1.5 mg once weekly if inadequate response
1.5 mg once weekly
Hepatic impairment: use with caution

9. Missed Dose Information
GLP-1 RAs: Dosing
Switching from exenatide IR to ER
Begin ER 1 day after d/c IR; may have ↑ BG levels for ~ 2wks
Missed Dose Information
Exenatide IR (Byetta®)
Exenatide ER (Bydureon®)
Liraglutide (Victoza®)
Albiglutide (Tanzeum®)
Dulaglutide (Trulicity®)
Take as soon as you remember, skip dose if near next scheduled dose
If > 3 days since last dose, restart treatment, then once weekly
If >3 days w/o meds, re-initiate at 0.6 mg once daily
If > 3 days skip missed dose and resume at next regularly scheduled weekly dose

10. GLP-1 RA Contraindications
Family hx of medulary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2*
Black Box Warning
Risk of thyroid tumors (shown in animal models)*
Adverse Effects
Nausea, vomiting, diarrhea, decreased appetite, weight loss, pancreatitis
Monitoring
FBG, A1C, SCr, BUN
Interactions
Agents that induce hypoglycemia
GLP-1 agonists may reduce rate of absorption of orally administered drugs
Clinical pearls
- Low hypoglycemia risk
- Injectable
- Avoid in patients with gastroparesis
May need to reduce dose of insulin and/or secretagogues
- Pregnancy category C
- All available as SC pens
% ↓ in A1C
* Contraindications and black box warning not reported for exenatide IR

11. Stability Once Opened at Room Temperature or Refrigerated (days)
GLP-1 RA Stability
GLP-1 RA
Stability Once Opened at Room Temperature or Refrigerated (days)
Byetta® (Exenatide IR) 30
Bydureon® (Exenatide ER) 28
Victoza® (Liraglutide)
Tanzeum® (Albiglutide)
Trulicity® (Dulaglutide) 14

12. Question 1
GLP-1 receptor agonists lower blood glucose by the following mechanism:
Increase glucose-dependent insulin & amylin secretion, decrease glucagon, decrease gastric emptying, and increase satiety
Activate PPAR- γ which leads to enhanced glucose and lipid metabolism and increased sodium reabsorption in the renal tubules. They also work to increase insulin sensitivity by improving target cell response to insulin
Increase muscle sensitivity to insulin, decrease hepatic glucose output, decrease LDL by increasing fatty acid oxidation, and decrease insulin resistance
Act via specific membrane-bound receptors on the liver, skeletal muscle, and adipose tissue to regulate metabolism of proteins, carbohydrates, and fats

13. Insulin
MOA
Insulin is endogenously produced in the beta islet cells of the pancreas and allows glucose to enter cells to be used as energy
Dosing
Initiate basal (long-acting) insulin at 0.2 units/kg at bedtime and increase by 2 units every 2-3 days until FBG levels are at goal
Adverse Effects
Weight gain, injection site reactions, lipoatrophy, lipohypertrophy, hypoglycemia
Monitoring
FBG, A1C
Interactions
Any agents which promote hypoglycemia
Clinical pearls
- Most effective method to lower A1C
% ↓ in A1C

14. Insulin: Duration of Action

15. Titrating Insulin
American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. 2016; 32(S1): S1-S112.

16. Titrating Insulin
Basal insulin (usually with metformin +/- other non-insulin agent
For hypoglycemia: determine & address cause; ↓ dose by 4 units or 10-20%
Adjust: 10-15% or 2-4 units 1-2x weekly to reach FBG target
Start: 10 units/day or units/day
If not controlled after FBG target is reached (or if dose > 0.5 units/kg/day), treat PPG excursions with mealtime insulin & consider initial GLP-1 RA trial
American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. 2016; 32(S1): S1-S112.

17. Titrating Insulin (continued…)
Add 1 rapid insulin injection before largest meal
Start: 4 units, 0.1 units/kg, or 10% basal dose, consider ↓ basal by same amount
Adjust: ↑ dose by 1-2 units or 10-15% 1-2x weekly until SMBG target reached
For hypoglycemia: determine and address cause; ↓ corresponding dose by 2-4 units or 10-20%
If not controlled, consider basal-bolus & add > 2 rapid insulin injections before meals
American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. 2016; 32(S1): S1-S112.

18. Titrating Insulin (continued…)
OR Change to premixed insulin twice daily
Start: divide current basal dose into 2/3 AM, 1/3 PM or 1/2 AM, 1/2 PM
Adjust: ↑ dose by 1-2 units or 10-15% 1-2x weekly until SMBG target reached
For hypoglycemia: determine and address cause; ↓ corresponding dose by 2-4 units or 10-20%
If not controlled, consider basal-bolus & add > 2 rapid insulin injections before meals
American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. 2016; 32(S1): S1-S112.

19. Titrating Insulin: Basal-bolus
Start: 4 units, 0.1 units/kg, or 10% basal dose/meal. If A1C < 8%, consider ↓ basal by same amount
Adjust: ↑ dose by 1-2 units or 10-15% 1-2x weekly until SMBG target reached
For hypoglycemia: determine and address cause; ↓ corresponding dose by 2-4 units or 10-20%
American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. 2016; 32(S1): S1-S112.

20. Insulin Formulation Onset of Action Peak Effect Duration Rapid-acting
- Lispro (Humalog® U-100, U-200)
- Aspart (Novolog®)
- Glulisine (Apidra®)
- Human (Afrezza® - inhaled)*
15-30 mins
hours
3-5 hours
Short-acting (regular insulin)
- Humulin R® (U-100, U-500)
- Novolin R®
0.5 – 1 hour
2-4 hours
4-8 hours
Intermediate-acting (NPH insulin)
- Humulin N®
- Novolin N®
1-3 hours
4-10 hours
10-18 hours
Long-acting
- Glargine (Lantus® U-100, Toujeo® U-300)
- Detemir (Levemir®)
- Degludec (Tresiba® U-100, U-200)
2-3 hours
1 hour
None
> 24 hours
< 24 hours
> 42 hours

21. Insulin: Mixed Formulations
Onset of Action
Peak Effect
Duration
Pre-mixed insulins
Humulin® 70/30 (70% NPH + 30% regular)
Novolin® 70/30 (70% NPH + 30% regular)
Humalog® Mix 75/25 (75% lispro protamine + 25% lispro)
Humalog® Mix 50/50 (50% lispro protamine + 50% lispro)
Novolog® Mix 70/30 (70% aspart protamine + 30% aspart)
0.5-1 hour
10-15 mins
2-10 hours
1-3 hours
10-18 hours
10-16 hours
When mixing NPH and regular insulin, draw up clear insulin first and roll NPH vial to mix prior to drawing up
American Diabetes Association (ADA) prefers basal-bolus dosing

22. Stability Once Opened at Room Temperature or Refrigerated (days)
Insulin Stability
Vial Formulation
Stability Once Opened at Room Temperature or Refrigerated (days)
Rapid-acting insulin
Humalog® (Lispro) 28
Novolog® (Aspart)
Apidra® (Glulisine)
Short-acting insulin
Humulin R® (Regular)
Novolin R® (Regular) 42
Intermediate-acting insulin
Humulin N® (NPH)
Novolin N® (NPH)
Long-acting insulin
Lantus® (Glargine)
Levemir® (Detemir)

23. Stability Once Opened at Room Temp or Refrigerated (days)
Insulin Stability
Pen Formulation
Stability Once Opened at Room Temp or Refrigerated (days)
Rapid-acting insulin
Humalog® KwikPen (Lispro) 28
Novolog® FlexPen (Aspart)
Apidra® SoloStar (Glulisine)
Short-acting insulin
Humulin R® U-500 KwikPen (Regular)
Intermediate-acting insulin
Humulin N® KwikPen (NPH) 14
Novolin N® FlexPen (NPH)
Long-acting insulin
Lantus® SoloStar, Toujeo® SoloStar (Glargine)
Levemir® FlexPen (Detemir) 42
Tresiba® FlexTouch (Degludec) 56

24. Stability Once Opened at Room Temp or Refrigerated (days)
Insulin Stability
Pre-Mixed Insulin
Stability Once Opened at Room Temp or Refrigerated (days)
Vials
Humulin® 70/30 8
Novolin® 70/30 42
Humalog® 75/25 28
Humalog® 50/50
Novolog® 70/30
Pens
Humalog® Mix 50/50 KwikPen 10
Humalog® Mix 75/25 KwikPen
Humulin® 70/30 KwikPen

25. Insulin Degludec (Tresiba ®)
FDA approved Sept. 2015
Duration: > 42 hours (dosed once daily)
Steady state achieved after 3-4 days of therapy
Half life ~ 25 hours
Caution when patients are sick

26. Meneghini et al 2013: Begin® Flex
Trial design: 26-week, randomized, open-label, parallel-group, treat-to-target trial in patients with type 2 diabetes
Primary outcome: non-inferiority of flexible insulin degludec dosing (8-40 hour intervals between doses) compared to glargine

27. Meneghini et al 2013: Begin® Flex

28. Meneghini et al 2013: Begin® Flex

29. Meneghini et al 2013: Begin® Flex
Flexible insulin degludec dosing was non-inferior to fixed dose glargine after 26 weeks
No statistically significant differences in rates of hypoglycemia
Dosing intervals 8-40 hours did not compromise glycemic control or safety

30. Insulin Degludec (Tresiba®)

31. Humulin® R U-500 5x as concentrated as Humulin® R U-100
Slightly delayed onset and longer duration of action
Prescribed in units of insulin
Instructions for administration vary by syringe used
U-100 syringe, divide prescribed dose by 5
Tuberculin syringe, divide prescribed dose by 500
Risk of overdose if used incorrectly

32. Question 2
True or False: If Humulin R U-500 is administered using a tuberculin syringe, the dose (in units) must be divided by 500 to correspond to the markings on the syringe.

33. Other Concentrated Insulins
Agents:
U-300 glargine (Toujeo)
U-200 degludec (Tresiba)
U-200 lispro (Humalog)
Prescribed in units of insulin
Must calculate what marking patient will draw up to using syringe
Allow smaller volume administration

34. Administering Insulin Using a Pen

35. Preparing the Insulin Pen

36. Priming the Insulin Pen

37. Selecting the Insulin Dose

38. Administering the Insulin Dose

39. Preparing the Pen for Future Use

40. Preparing the Pen for Future Use

41. Needles
Needles should NOT be re-used!

42. Insulin Syringes Always use the smallest syringe necessary
3/10 mL - < 30 units
½ mL – 31 to 50 units
1 mL – 51 to 100 units

43. Insulin Administration
Wash hands & dry well
Inspect insulin vial
Roll vial between hands if cloudy (pre-mixed, intermediate, or long-acting)
NEVER SHAKE!
Swab vial and injection site
Remove cap near plunger and needle cap
Draw up air into the syringe
Insert needle into vial and inject air

44. Insulin Administration
Invert vial and draw up insulin
Avoid critical areas
Check for bubbles, tap to expel
Remove needle from vial

45. Pinch an inch of fat (> 2 inches from navel)
Insert needle at a 90º angle (45º for very thin)
Depress plunger
Hold for 5 seconds
Withdraw needle
Dispose in sharps container
Rotate injection sites!

46. Glucagon Emergency Kit

47. Glucagon Emergency Kit (continued…)

48. Question 3
Which of the following medications has been associated with a decrease in appetite and weight loss?
Lantus
Exenatide
Symlin
Humalog

49. Adherence Barriers to Injectable Agents
Cost
Unwilling to inject
Fear of hypoglycemia
Forgetfulness
Low health literacy

50. Future Therapies / Drugs in the Pipeline
Lixisenatide (type 2 DM)
Currently approved in Europe and awaiting FDA approval
Lixisenatide / insulin glargine (type 2 DM)
Semaglutide (types 1 & 2 DM)
Once weekly
Ertugliflozin (type 2 DM)
Sotagliflozin (type 1 DM)
Insulin peglispro (types 1 & 2 DM)
Linagliptin / pioglitazone (type 2 DM)

51. Summary Amylin analog GLP-1 RAs Insulin products
Insulin pen administration
Insulin syringe administration
Glucagon administration

52. Thank you!

53. References
Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc. Accessed 18, March 2016.
Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically. Accessed 18, March 2016.
American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care. 2016; 32(S1): S1-S112.
Meneghini L, Atkin SL, Gough SC, et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care. 2013;36(4):
Tresiba® [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; 2015.
Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care. 2012;35(12):
Heller S, Buse J, Fisher M, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012; 379(9825):
Gough SC, Bhargava A, Jain R, et al. Low-volume insulin degludec 200 units/ml once daily improves glycemic control similarly to insulin glargine with a low risk of hypoglycemia in insulin-naive patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN LOW VOLUME trial. Diabetes Care. 2013;36(9):
Humulin R® U-500 [package insert]. Indianapolis, Indiana: Eli Lilly and Company;2016.
Comparison of Insulins and Injectable Diabetes Meds. Pharmacist’s Letter/Prescribers Letter. Stockton, CA. March
2010;26:1-10.