Injectable Medications for Treatment of Diabetes GETTING TO

Injectable Medications for Treatment of Diabetes GETTING TO THE POINT Stephanie Lewis, Pharm. D PGY-1 Resident University of New England – Hannaford Pharmacy – Martin’s Point Health Care SLewis 17@une. edu

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

Injectable Products

® 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, A 1 C 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 A 1 C

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 2016. Diabetes Care. 2016; 32(S 1): S 1 -S 112. http: //www. azpicentral. com/symlinpen_120_piu_medguide_814003 -01. pdf

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) ↑ glucose-dependent insulin & amylin secretion, ↓ glucagon, ↓ gastric emptying, ↑ satiety https: //beyondthedish. wordpress. com/2014/05/20/anti-diabetes-drug-acts -with-stem-cells-to-repair-heart-after-heart-attack/

http: //www. medscape. com/viewarticle/835947

GLP-1 RAs: Dosing Drug Initial Titrate Exenatide IR (Byetta®) 5 mcg BID within 60 mins of a meal (> 6 H between doses) ↑ to 10 mcg after 1 month Exenatide ER (Bydureon®) 2 mg once weekly N/A Liraglutide (Victoza®) Albiglutide (Tanzeum®) Dulaglutide (Trulicity®) 0. 6 mg once daily Max 2 mg once weekly Dose Adjustments Renal impairment: Cr. Cl 30 -50 m. L/min: use caution; Cr. Cl < 30 m. L/min not recommended Hepatic impairment: not studied 1. 2 mg once 1. 8 mg daily per once daily week Renal & hepatic impairment: use caution – limited experience 30 mg once weekly ↑ to 50 mg once weekly 50 mg if inadequate once daily response Renal impairment: use caution when initiating or escalating doses Hepatic impairment: not studied, unlikely required 0. 75 mg once weekly ↑ to 1. 5 mg once weekly once if inadequate weekly response Renal impairment: use caution when initiating or escalating doses Hepatic impairment: use with caution

GLP-1 RAs: Dosing Switching from exenatide IR to ER Begin ER 1 day after d/c IR; may have ↑ BG levels for ~ 2 wks Missed Dose Information Exenatide IR (Byetta®) Exenatide ER (Bydureon®) Liraglutide (Victoza®) 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 Albiglutide (Tanzeum®) Dulaglutide (Trulicity®) If > 3 days skip missed dose and resume at next regularly scheduled weekly dose

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, A 1 C, 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 - 1 -1. 5 % ↓ in A 1 C * Contraindications and black box warning not reported for exenatide IR

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

Question 1 GLP-1 receptor agonists lower blood glucose by the following mechanism: a. b. c. d. 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

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, A 1 C Interactions Any agents which promote hypoglycemia Clinical pearls - Most effective method to lower A 1 C - 1. 5 -3. 5 % ↓ in A 1 C

Insulin: Duration of Action

Titrating Insulin American Diabetes Association Standards of Medical Care in Diabetes 2016. Diabetes Care. 2016; 32(S 1): S 1 -S 112.

Titrating Insulin Basal insulin (usually with metformin +/- other noninsulin agent Start: 10 units/day or 0. 1 -0. 2 units/day Adjust: 10 -15% or 2 -4 units 1 -2 x weekly to reach FBG target For hypoglycemia: determine & address cause; ↓ dose by 4 units or 10 -20% 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 2016. Diabetes Care. 2016; 32(S 1): S 1 -S 112.

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 -2 x 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 2016. Diabetes Care. 2016; 32(S 1): S 1 -S 112. If not controlled, consider basal-bolus & add > 2 rapid insulin injections before meals

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 -2 x 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 2016. Diabetes Care. 2016; 32(S 1): S 1 -S 112. If not controlled, consider basal-bolus & add > 2 rapid insulin injections before meals

Titrating Insulin: Basal-bolus Start: 4 units, 0. 1 units/kg, or 10% basal dose/meal. If A 1 C < 8%, consider ↓ basal by same amount Adjust: ↑ dose by 1 -2 units or 10 -15% 1 -2 x 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 2016. Diabetes Care. 2016; 32(S 1): S 1 -S 112.

Insulin Onset of Action Peak Effect Duration Rapid-acting - Lispro (Humalog® U-100, U-200) - Aspart (Novolog®) - Glulisine (Apidra®) - Human (Afrezza® - inhaled)* 15 -30 mins 0. 5 -1. 5 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 Formulation > 24 hours < 24 hours > 42 hours

Insulin: Mixed Formulations Formulation Onset of Action Peak Effect Pre-mixed insulins Humulin® 70/30 (70% NPH + 30% regular) 0. 5 -1 hour 2 -10 hours Novolin® 70/30 (70% NPH + 30% regular) 0. 5 -1 hour 2 -10 hours Humalog® Mix 75/25 (75% lispro protamine + 25% lispro) 10 -15 mins 1 -3 hours Humalog® Mix 50/50 (50% lispro protamine + 50% lispro) 10 -15 mins 1 -3 hours Novolog® Mix 70/30 (70% aspart protamine + 30% aspart) 10 -15 mins 1 -3 hours Duration 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 basalbolus dosing

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

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

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

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

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

Meneghini et al 2013: Begin® Flex

Meneghini et al 2013: Begin® Flex

Meneghini et al 2013: Begin® Flexible insulin degludec dosing was noninferior 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

® Insulin Degludec (Tresiba )

Humulin® R U-500 5 x 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 http: //www. medscape. com/viewarticle/857811

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.

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

Administering Insulin Using a Pen http: //pi. lilly. com/us/humalog-kwikpen-um. pdf

Preparing the Insulin Pen http: //pi. lilly. com/us/humalog-kwikpen-um. pdf

Priming the Insulin Pen http: //pi. lilly. com/us/humalog-kwikpen-um. pdf

Selecting the Insulin Dose http: //pi. lilly. com/us/humalog-kwikpen-um. pdf

Administering the Insulin Dose http: //pi. lilly. com/us/humalog-kwikpen-um. pdf

Preparing the Pen for Future Use http: //pi. lilly. com/us/humalog-kwikpen-um. pdf

Preparing the Pen for Future Use http: //pi. lilly. com/us/humalog-kwikpen-um. pdf

Needles should NOT be re-used!

Insulin Syringes Always use the smallest syringe necessary 3/10 m. L - < 30 units ½ m. L – 31 to 50 units 1 m. L – 51 to 100 units http: //www. bd. com/us/diabetes/page. aspx? cat=7001&id=7252

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 https: //www. bd. com/resource. aspx? IDX=3260

Insulin Administration Invert vial and draw up insulin Avoid critical areas Check for bubbles, tap to expel Remove needle from vial https: //www. bd. com/resource. aspx? IDX=3260

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! https: //www. bd. com/resource. aspx? IDX=3260 http: //www. drugs. com/cg/giving-an-insulin-injection. html

Glucagon Emergency Kit http: //www. lillyglucagon. com/important-safety-information

Glucagon Emergency Kit (continued…) http: //www. lillyglucagon. com/important-safety-information

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

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

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)

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

Thank you! http: //co 9 to 25. org/

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 2016. Diabetes Care. 2016; 32(S 1): S 1 S 112. 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): 858 -64. 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): 246471. Heller S, Buse J, Fisher M, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basalbolus 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): 1489 -97. 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): 2536 -42. 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.