Basal Insulin Therapy in the Treatment of Insulin Resistant Type 2 Diabetes: the Role of the Pharmacist in Ensuring Their Safe and Effective Use in Patients

Basal Insulin Therapy in the Treatment of Insulin Resistant Type 2 Diabetes: The Role of the Pharmacist in Ensuring Their Safe and Effective Use in Patients

Susan Cornell, BS, Pharm.D., CDE, FAPhA, FAADE Midwestern University Chicago College of Pharmacy Objectives

1. Describe the reasons for the use of high concentration insulin formulations in the treatment of type 2 diabetes

2. Discuss the clinical, pharmacokinetic and pharmacodynamic profiles for current and emerging basal insulins

3. Implement strategies for safely converting between U-100 and concentrated insulin formulations using different syringes and pen devices in patients with type 2 diabetes

4. Review currently available insulin pens and syringes used for the administration of insulin

5. Explain and apply strategies to overcome the barriers to insulin-mediated glucose control Disclosures

• Susan Cornell, Pharm.D., CDE, FAPhA, FAADE has no real or potential conflicts of interest to report. How to Receive Credit

• You must complete an online evaluation in order to receive credit for this program. The link to the evaluation will be emailed to you after the program. • If you did not pre-register for this program, please complete a Request for Credit form at the registration desk today and include your email address. Pre-Activity Questions 1-4 Pre-test Question #1

Which of the following does NOT represent a reason for using high concentration insulin formulations in the treatment of type 2 diabetes? 1. Volume of insulin dose is physically too large for a single SC administration 2. Patient cannot manipulate vials and syringes 3. Multiple injections are required to deliver a single insulin dose 4. Discomfort 5. Unpredictable insulin absorption Pre-test Question #2

A 55 year old female, high school teacher with Type 2 diabetes is referred to you for dosing of U500 insulin. Her current meds are NPH 100 units twice daily, lispro 10-30 units with meals plus correction, and metformin 1000mg daily. Her A1C is 7.1% and Scr is 1.1. How would you instruct the patient to draw up 110 units of U500 insulin?

1) Using a U100 syringe, draw to the 50 units marking 2) Using a U100 syringe, draw to the 25 units marking 3) Using a tuberculin syringe, draw 0.2 mL

4) Using a tuberculin syringe, draw 0.4 mL Pre-test Question #3

Which of the following is NOT a strategy to overcome the barriers to insulin therapy? 1. Avoid using insulin as a “threat” and discuss it as an option early 2. Dose NPH insulin twice daily to minimize hypoglycemia 3. Use insulin pens and regimens that offer maximum flexibility 4. Give a “limited” trial of insulin Pre-test Question #4

Which of the following statements is INCORRECT regarding the new basal insulin U300 glargine? 1. It is associated with less nocturnal hypoglycemia 2. It has a flatter PK profile and a duration of action ≤36 hrs 3. It is only available in a pen with 1.5 mL of U300 glargine 4. Current pen allows for a max of 240 units of insulin per shot 5. Patients switching from twice daily NPH to U300 glargine should start with 80% of total daily NPH dosage The Diabetes Epidemic Diabetes in the United States

• 29.1 million people (9.3% of the population) have diabetes • 8.1 million are undiagnosed • CDC estimates that 1 in 3 adult Americans will have diabetes by 2050

• Type 2 Diabetes (T2DM)

– Associated with obesity, older age, decreased physical activity, and race/ethnicity

– Incidence in children and adolescents is increasing • Estimated total costs in 2012: $245 billion

http://www.cdc.gov/media/pressrel/2010/r101022.html. Accessed February 5, 2015. CDC. National Diabetes Statistics Report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf. Accessed April 15, 2015. Type 2 Diabetes

• Characterized by chronic hyperglycemia • Associated with microvascular and macrovascular complications • Generally arises from a combination of insulin resistance and β-cell dysfunction

Scheen AJ. Acta Clin Belg. 2003;58(6):335-41. ? By the time a person is diagnosed with type 2 diabetes, approximately how much β-cell function has been lost?

1. <10% 2. 10–30% 3. 30–50% 4. 50–80% 5. 100% Progressive Deterioration in β-Cell Function Over Time

100

Monotherapy 75 Combination Therapy 50 Insulin Intensive or in Combination (%, HOMA) HOMA) (%, 25 Beta-Cell Function Beta-CellFunction

0 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 Years from Diagnosis

HOMA = homeostasis model assessment. Based on data of UKPDS 16. Diabetes. 1995;4(11):1249-1258. Pathophysiologic Defects in Type 2 Diabetes: The Ominous Octet Decreased Incretin Effect

Impaired Islet β-cell Increased Insulin Lipolysis Secretion

Increased Islet α-cell Increased Glucagon Hyperglycemia Glucose Secretion Reabsorption

Decreased Increased Glucose HGP Uptake

Neurotransmitter Dysfunction DeFronzo RA. Diabetes. 2009;58(4):773-795. Insulin Resistance ~90% of People with Type 2 Diabetes are Overweight or Obese

World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity. Insulin Resistance

• Major defect in individuals with type 2 diabetes • Reduced biological response to insulin • Closely associated with obesity • Associated with cardiovascular risk • Type 1 diabetes patients can be insulin resistant as well…

1. American Diabetes Association. Diabetes Care. 1998; 21:310-314. 2. Beck-Nielsen H, Groop LC. J Clin Invest 1994; 94:1714-1721. 3. Bloomgarden ZT. Clin Ther 1998; 20:216-231. 4. Boden G. Diabetes 1997; 46:3-10. More than 80% of Patients Progressing to Type 2 Diabetes are Insulin Resistant

Insulin sensitive; low insulin secretion (16%) Insulin sensitive; good insulin secretion (1%)

Insulin resistant; Insulin resistant; good insulin secretion 83% low insulin secretion (29%) (54%)

Haffner SM, et al. Circulation. 2000;101:975-980. Insulin Resistance Reduces Response to Circulating Insulin

Insulin resistance IR

Adipose Liver Muscle tissue

↑ Glucose output ↓ Glucose uptake ↓ Glucose uptake

↑ Insulin/medication requirements needed to maintain Hyperglycemia glycemic control Treatment Options for Type 2 Diabetes 12 Pharmacotherapy Options

Insulin Oral Medications • Bolus insulin • α-glucosidase inhibitors (AGI) – Insulin lispro (Humalog) • Biguanides – Insulin aspart (NovoLog) • Bile acid sequestrants (BAS) – Insulin glulisine (Apidra) • Dipeptidyl peptidase-4 (DPP-4) – Insulin human inhaled (Afrezza) inhibitors (gliptins) – Regular human insulin • Dopamine agonists • (Humulin R) • Glitinides • (Novolin R) • Sulfonylureas • Basal insulin • Sodium glucose co-transporter-2 inhibitors – Insulin NPH • (Humulin N) • Thiazolidinediones (TZDs or glitazones) • (Novolin N) Non-insulin injectable agents – Insulin detemir (Levemir) • Glucagon-like peptide-1 (GLP-1) – Insulin glargine U-100 (Lantus) agonists – Insulin glargine U-300 (Toujeo) • Amylinomimetics

Cornell S, et al. Postgrad Med. 2012;124(4):84-94. http://www.pdr.net/search-results?q=afrezza. Accessed January 30, 2015. http://www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015. Glucose-Lowering Comparison

Route of Targets Insulin Target Glucose: A1C Reduction Monotherapy Administration Resistance FPG or PPG (%) Sulfonylurea Oral No Both 1.5–2.0 Metformin Oral Yes FPG 1.5 Glitazones Oral Yes Both 1.0–1.5 Meglitinides Oral No PPG 0.5–2.0 AGIs Oral No PPG 0.5–1.0 DDP-4 inhibitors Oral No PPG 0.5–0.7 Bile acid sequestrant Oral No PPG 0.4 Dopamine agonists Oral No PPG 0.4 SGLT-2 inhibitors Oral ↓ glucose toxicity FPG 0.7–1.1 Short-acting – PPG GLP-1 agonists Injectable No 0.8–1.5 Long-acting – Both Amylin analogs Injectable No PPG 0.6 Basal – FPG ↓ as much as Insulin Injectable ↓ glucose toxicity Bolus – PPG needed

FPG = fasting plasma glucose; PPG = postprandial glucose. Unger J, et al. Postgrad Med. 2010;122(3):145-157. Cornell S, et al. Postgrad Med. 2012;124(4):84-94. Basal Insulin Therapy: Concept and Physiology UKPDS: Progressive Deterioration in Glycemic Control Over Time

HbA1C Level 9

7 Conventional

Median A1C(%) Median Intensive

6 0 0 3 6 9 12 15 Time from Randomization (y)

UKPDS Group. Lancet. 1998;352:837-853. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25. Currently Available Insulins

Insulin Type Onset Peak, h Duration of Action, h Rapid-acting analogs Insulin lispro, aspart, glulisine 15 min 0.5–1.5 3–5 Insulin human inhaled 12–15 min ~1.0 2.5–3.0 Short-acting Regular human (U-100) 30–60 min 2–4 5–8 Regular human (U-500) 30–60 min 4–8 14–15 Intermediate-acting Human NPH insulin 1–3 h 6–12 12–24 Long-acting (basal) Insulin glargine 2–4 h No pronounced 20–24 Insulin detemir 1–3 h peak 18–20 Ultralong-acting (basal) Insulin glargine U-300 6 h No pronounced peak ≤36

Walia M and Molitch M. JAMA. 2014;311:2315-2325. Accessed March 24, 2014. http://www.pdr.net/full- prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015. http://www.pdr.net/full- prescribing-information/afrezza?druglabelid=3540. Accessed April 5, 2015. Thinking Like a Pancreas

More for “waking up” No food Meals Less overnight

8 AM 12 NOON 3 PM 6 PM 9 PM 3 AM 7 AM

Time PK Profile of Currently Available Inhaled insulin Insulins Aspart, Lispro, Glulisine Regular Intermediate (NPH insulin) Long (Insulin detemir) Long (Insulin glargine) Ultralong (U300 glargine) Plasma Insulin Levels PlasmaInsulin

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (hours) PK = pharmacokinetic; NPH = neutral protamine Hagedorn. Adapted from Hirsh IB. NEJM. 2005;352:174-183. Flood TM. J Fam Pract. 2007;56(suppl 1):S1-S12. Becker RH, et al. Diabetes Care. 2014;pii:DC_140006. http://www.pdr.net/full-prescribing-information/ afrezza?druglabelid=3540. Accessed April 5, 2015. Insulin Regimens Used in T2DM • Basal only – 1 injection – Added to oral agents • Basal plus – 2 injections or 1 injection + 1 inhalation – Adding one rapid-acting analog sequentially starting with largest meal • Basal bolus – 4 injections or 1 injection + 3 inhalations – Rapid-acting analog before each meal • Pre-mixed – 2 injections

American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S41-S48. The Basal-Bolus Concept • Basal insulin – 50% of daily needs – Controls nighttime and between meal glucose

• At a nearly constant level • Bolus insulin – 50% of daily needs – Controls mealtime glucose – 10–20 % of total daily insulin requirement at each meal • Correction dose (sensitivity factor) – Correct hyperglycemia reactively

Sisson EM, et al. Pharmacotherapy for glucose management. Diabetes Desk Reference. American Association of Diabetes Educators. 2014;491-540. Insulin Therapy in Patients with Insulin Resistance • Insulin, insulin, and yet more insulin! – Causes weight gain and fluid retention – Increased risk of hypoglycemia – Expensive at high volumes (especially the pens) – Multiple injections per day often needed • Pumps not practical with high volume insulin usage High Doses of Insulin • Concerns: – Hypoglycemia – Medication errors in dosing – Absorption issues • Problems: – Over-basalization – Failure to treat the physiological defects

• Insulin resistance

• Decrease satiety Concentrated Insulin Why Concentrated Insulin? • When daily insulin requirements are in excess of 200 units/day, the volume of U-100 injected insulin becomes a challenge:

– Physically too large for a single SC administration

– Multiple injections are required to deliver a single dose – Increased injections may lead to adherence issues and poor glycemic control

– Discomfort – Unpredictable absorption (rate-limiting step in insulin activity)

Cochran E. Diabetes Spectrum. 2009;22(2):116-122. Kelly JL. Am J Health-Syst Pharm. 2010;67(suppl 8):S9-S16. Patients Who May Require Concentrated Insulin • Patients with insulin resistance – Patients with inherited insulin receptor abnormalities or presence of autoantibodies to insulin receptor

– Diabetes patients with insulin antibodies – Type 2 diabetes patients – Overweight/obese Type 1 diabetes patients • Other patients

– Obstetrics patients – Patients receiving high-dose glucocorticoid therapy

Cochran E. Diabetes Spectrum. 2009;22(2):116-122. Kelly JL. Am J Health-Syst Pharm. 2010;67(suppl 8):S9-S16. Currently Available Concentrated Insulins

Regular human insulin U-500 (Humulin R U-500)

Insulin glargine U-300 (Toujeo)

1. http://www.pdr.net/drug-summary/humulin-r-u-500?druglabelid=293. Accessed March 28, 2015. 2. http:// www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015. U-500 Regular Human Insulin

• U-500 is highly concentrated and contains five times as much insulin in 1 mL as standard U-100 insulin

• U-500 vial

– U-500 : contains 20 mL

– U-100: contains 10 mL • U-500 vial

– Marked with a band of diagonal brown stripes to distinguish it from the U-100 vial, which has no stripes

– “U-500” is also highlighted in red on the label http://www.pdr.net/drug-summary/humulin-r-u-500?druglabelid=293. Accessed March 28, 2015. U-100 Insulin vs U-500 Insulin • Both have onset of action of 30 minutes • U-500 insulin exhibits a delayed and lower peak effect relative to U-100 • U-500 insulin typically has a longer duration of action compared to U-100 (up to 24 hours following a single dose) • Clinical experience has shown that U-500 insulin frequently has time action characteristics reflecting both prandial and basal activity

de la Peña A, et al. Diabetes Care. 2011;34(12):2496-501. PK and PD Profiles for U-500 vs U-100 Human Insulin

/L) /L) 1400 1400 1200 50-Unit Dose 1200 100-Unit Dose pmol 1000 1000 Human 800 800 Regular 600 600 U-500 Insulin 400 400 Human Regular MeanSerum IRI 200 200 U-100 Insulin 0 0 Concentration ( Concentration 1000 1000 50-Unit Dose 100-Unit Dose 800 800

600 600

400 400

200 200 Rate (mg/min) Glucose Infusion Infusion Glucose 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time (hours) Time (hours) IRI = immunoreactive insulin. de la Peña A, et al. Diabetes Care. 2011;34:2496-2501. Safety Concerns with Concentrated Insulin Medication Errors Associated with U-500 Insulin

• Some health care professionals may not be aware of U-500 insulin, increasing the chance of dispensing errors – From the shelf during dispensing – From the computer screen when prescribing – Communication errors during medication reconciliation • Dosing errors – No insulin syringe designed to measure U-500 insulin

• Due to increasing medication errors with U-500 insulin and the lack of a U-500 specific syringe, The Institute for Safe Medication Practices suggests “It’s time to rethink safe use of strengths above U-100” http://www.consumermedsafety.org/insulin-safety-center/item/499. Accessed March 28, 2015. http:// www.ismp.org/newsletters/acutecare/showarticle.aspx?id=62. Accessed March 28, 2015. U-500 Insulin Dosing Conversion

U-500 Insulin Dose U-100 Syringe Volume for Tuberculin (Actual units) (Unit markings) Syringe (mL) 25 5 0.05 50 10 0.10 75 15 0.15 100 20 0.20 125 25 0.25 150 30 0.30 175 35 0.35 200 40 .040 225 45 0.45 250 50 050 275 55 0.55 300 60 0.60 325 65 0.65 350 70 0.70 375 75 0.75 400 80 0.80 425 85 0.85 450 90 0.90 475 95 0.95 500 100 1.00

*The following dosing formulas may also be used: dose (actual units) x 0.2 = unit markings in a U-100 insulin syringe, dose (actual units) x 0.002 = volume (mL) in a tuberculin syringe. Food and Drug Administration. Humulin R-U-500 (concentrated) Insulin Human Injection. Drugs@FDA .gov. New and Emerging Basal Insulins Quest for Better Insulin Products

1. Efficacy – Reductions in A1C – Reductions in FBG and PPG 2. Convenience – Pen dosing – Flexible dosing (any time of day) – Different concentrations – Ability to mix with other insulin and non-insulin agents 3. Safety – Low incidence of hypoglycemia – Low incidence of nocturnal hypoglycemia – Less individual variability – Less weight gain Newly Approved U-300 Insulin Glargine • U-300 insulin glargine offers a smaller depot surface area leading to a reduced rate of absorption • Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency • Half-life is ~23 hours • Steady state in 4 days • Duration of action ≤36 hours • Associated with less hypoglycemia especially nocturnal hypoglycemia • FDA approved February 25, 2015

Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19. Steinstraesser A, et al. Diabetes Obes Metab. 2014 Feb 26. [Epub ahead of print]. http://www.australianprescriber.com/magazine/19/3/76/8. Accessed March 11, 2014. PK and PD of U-300 Insulin Glargine vs U-100 Insulin Glargine 25

] 20 -1 15

INS 10

[ µ U/mL 5 LLOQ 0

] 3 -1 -1 Gla-100 0.4 U/kg Gla-300 0.4 U/kg-1 2 /min N = 30 -1

GIR 1

[mg/kg 0 0 6 12 18 24 30 36 Time (h) U-300 glargine displays a more even and prolonged PK/PD profile compared with U-100 glargine, offering blood glucose control beyond 24 hours LLOQ = lower limit of quantification; GIR = glucose infusion rate; PK = pharmacokinetic; PD = pharmacodynamic. Becker RH, et al. Diabetes Care. 2014;pii:DC_140006. U-300 Glargine vs U-100 Glargine in T2DM: Meta-Analysis of Phase III Trials EDITION 1, 2, & 3

Baseline to Month 6 Glar U-300 Glar U-100 RR (95% CI) (N=1247) (N=1249) A1C (%), LS mean –1.02 –1.02 NS Weight (kg), LS mean 0.49 0.75 P = 0.058 Any hypo in 24 hr* 67.8 73.8 0.92 (0.87–0.96) Any nocturnal hypo* 31.7 41.3 0.77 (0.69–0.85) Confirmed BG <54 mg/dl 26.9 33.3 0.81 (0.72–0.90) or severe hypo*

Confirmed nocturnal BG 9.7 13.2 0.73 (0.59–0.91) <54 mg/dl or severe hypo*

*% people ≥1 event. LS = least squares; RR = relative risk; BG = blood glucose; CI = confidence interval. Ritzel RA, et al. Presentation 963, 50th EASD Annual Meeting, September 15-19, 2014, Vienna, Austria. Flexible vs Fixed Dosing U-300 Glargine: Sub-Studies of Phase III Trials 6-Month Treatment Period 6-Month Extension Period (main study) (main study)

U-300 once daily U-300 once daily every 24 ± 3 h every 24 h sub-study U-300 once daily every 24 h

6 months (randomization, sub-study) 9 months (end of sub-study) Edition 1 Sub-Study Edition 2 Sub-Study 100 N = 109 N = 89 • No difference in A1C between flexible- vs Flexible dosing 80 fixed-dosing Fixed dosing 60 • No difference in 40 severe or nocturnal hypoglycemia within 20 Injections (%) Injections Percentage of each sub-study 0 24 ± <1 h 24 ± 1-3 h 24 ± >3 h 24 ± <1 h 24 ± 1-3 h 24 ± >3 h

Ritzel R, et al. Presentation 919-P 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. http://ada.scientificposters.com/epsAbstractADA.cfm?id=6. Accessed August 15, 2014. U-300 Insulin Glargine

• Only available in pens

– 300 U/mL, 1.5 mL

– Max dose per shot is 80 units with current pen – New pen in development will allow a max dose of 240 units

– Just dial the prescribed dose; no conversion needed like U-500 • U-300 glargine pen is white and green with the concentration highlighted in orange to distinguish it from U-100 glargine

1. http://www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015. 2. http://www.pdr.net/drug-summary/lantus?druglabelid=520. Accessed March 26, 2015. U-300 Insulin Glargine Dosing

• Insulin-Naive Patients:

– Type 1 Diabetes – Start with 1/3 to 1/2 of the total daily insulin dose calculated by using 0.2-0.4 U/kg/day; give the remainder of the total daily insulin dose as a short-acting insulin and divide between each daily meal

– Type 2 Diabetes – Start with 0.2 U/kg/day • Type 1 or Type 2 Diabetes:

– Changing from once daily long-acting or intermediate-acting insulin:

• Initial dose can be the same as the once daily long-acting dose; for patients controlled on U-100 insulin glargine, expect that a higher daily dose of U-300 glargine will be needed to maintain the same level of glycemic control

– Changing from twice daily NPH insulin:

• Initial dose is 80% of the total daily NPH dosage http://www.pdr.net/drug-summary/toujeo?druglabelid=3688. Accessed March 28, 2015. Insulin Degludec*

• Duration of action >42 hours • Half-life ~25 hours – Detectable for at least 5 days • Steady state in 2–3 days • FDA denied approval in 2013, research continues – Approved in EU

*Not FDA approved. Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19. Basal Insulin Degludec Flat, stable profile of both 100 unit/mL and 200 unit/mL formulations Mean 24-Hour GIR Profile of the Two Insulin Degludec Formulations at Steady State

5 IDeg 100 U/mL 0.8 U/kg Half-life at Mean IDeg 100 U/mL 0.6 U/kg Steady State Half-life 4 IDeg 100 U/mL 0.4 U/kg IDeg 200 U/mL (hours) IDeg 200 U/mL 0.6 U/kg 0.6 U/kg 26.2 h 3

2 n = 21 n = 37 1 n = 16 n = 22

Glucose Infusion Rate Infusion Glucose 0 Day 6 Day 7

GIR = glucose infusion rate. Heise T, et al. ADA. 2012, Oral 349 Abstract (Trial: NN1250-1987). Nosek L, et al. IDF 2011: P-1452; Diabetologia. 2011;54(suppl. 1):S429 (1055-P); Diabetes. 2011;60(suppl. 1A):LB14. Pharmacodynamic Variability with Insulin Degludec vs Insulin Glargine 1200 1100

180 Insulin degludec 160 Insulin glargine 140 120 100 80 of Variation (%) Variation of 60 Individual Coefficient Coefficient Individual 40 20 0 1 4 7 10 13 16 19 22 25 27 Subjects listed in increasing order of individual coefficient of variation

Heise T, et al. Diabetes Obes Metab. 2012;14(9):859-864. 53 U-200 Insulin Degludec: Safety and Efficacy 26-week Open-label, Randomized Study of 457 Patients with Type 2 Diabetes

8.5 IDeg 200 Units/mL OD (n=228) 8.3 IGlar OD (n=229) 8.1 7.9 7.7 7.5 7.3

HBA1c(%) 7.1 Treatment 6.9 difference: noninferior 6.7 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks)

No difference in hypoglycemia between the two treatment groups

Gough SC, et al. Diabetes Care. 2013;36(9):2536-42. PEGylated Insulin Lispro*

• Polyethylene glycol polymer covalently attached to lispro • Half-life 2–3 days • Steady state in 7–10 days • Duration of action >36 hours • Phase II–III clinical trials

*Not FDA-approved. Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19. Accessed March 11, 2014. Sinha VP, et al. Diabetes Obesity Metab. 2014;16(4):344-350. https://www.clinicaltrials.gov/ct2/results?term=LY2605541&Search=Search. PEGylated Insulin Lispro (LY2605541) Pharmacodynamics Glucose clamp study in 32 patients, 8 per study arm Pegylated Insulin Lispro

5 0.33 U/kg 0.67 U/kg 0.5 U/kg 1.0 U/kg 4

Mean GIR (mg/min/kg) (mg/min/kg) MeanGIR 0 0 4 8 12 16 20 24 Time (hours)

GIR = glucose infusion rate. Heise T, et al. Diabetes. 2012;61(suppl 1):A256 [abstract 1000-P]. PEGylated Insulin Lispro (LY2605541) vs Glargine U-100 in T1DM Treatment Period 1 Treatment Period 2 (Crossover) 8.0 LY2605541 Treatment at 8 weeks 7.8 • Significantly lowered A1C vs 7.6 p < 0.001 glargine 7.4 7.2 • Significantly reduced weight A1c(%) (1.2 kg) 7.0 6.8 • Increased overall hypos 0 (p = 0.04) but less nocturnal 88 hypos (p = 0.01) 87 86 • Lowered prandial insulin dose 85 84 • Significantly increased liver 83 enzymes 82 Weight (kg) Weight 81 p < 0.0001 Glargine 80 0 LY2605541 0 4 8 12 16 Week Rosenstock J, et al. Diabetes Care. 2013;36(3):522-528. Is there an alternative to concentrated insulin for patients on high doses of insulin? Combination Basal Insulin and GLP-1 RAs

Basal Bolus Add Prandial Insulin before Each Meal Basal plus Basal Plus GLP-1 RAs Add Prandial Insulin at Main Meal

Basal Add Basal Insulin and Titrate

Lifestyle Changes plus Metformin (± other agents) Barriers to Insulin-Mediated Glucose Control Significant Delay in Insulin Initiation

8.9% SOLVE: Baseline A1C Distribution 18 at Insulin Initiation 16

Patients(%) 6

0 5 6 7 8 9 10 11 12 13 14 15 16 A1C (%)

Data from Khunti K, et al. SOLVE Study Group. Diabetes. 2011;60(Suppl 1):A306. The reason for delay in starting insulin in diabetes management is: a. Provider reluctance (clinical inertia) b. Patient reluctance c. Lack of time d. Fear of hypoglycemia e. All of the above Key Barriers to Insulin Therapy Patient Barriers Provider Barriers • Patient reluctance • Clinical inertia • Sense of failure • Lack of insulin training, time, and/or support • Loss of independence • Fear of hypoglycemia • Belief that insulin is ineffective • Weight gain • Fear of injections • Fear of hypoglycemia • Weight gain

Adapted from Funnell MM. Clinical Diabetes. 2007;25(1):36-38. Polonsky WH, et al. Curr Med Res Opin. 2011;27(6):1169-1174. Overcoming the Barriers to Insulin Therapy

• Avoid using insulin as a “threat,” but a solution and discuss it as an option early

• Use insulin pens and regimens that offer maximum flexibility

• Give a “limited” trial of insulin • Tell patient injection is less painful than finger stick and give an injection in the office

• Teach patient to recognize and treat hypoglycemia, and use basal analog insulins to minimize hypoglycemia risk

• Meet with dietitian before initiation of insulin

1. Kruger D, et al. Diabetes Educ. 2010;36(suppl 3):44S-72S. 2. Funnell MM. Clinical Diabetes. 2007;25(1): 36-38. 3. Derr RL, et al. Diabetes Spectrum. 2007; 20(3):177-185. Insulin Administration Insulin Titration and Education

• First, do no harm – Halt the hypoglycemia • Fix the fastings • Pare the postprandials Patient Education

• Equipment and supplies patients need to effectively manage their insulin therapy at home – Insulin – Syringes or pen needles – Blood glucose meter and strips – Lancets and lancing device – Glucagon emergency kit – Contact information of diabetes care provider(s) Expiration of Products

Products/Device Refrigerated Unrefrigerated Once Used (opened) Vials Insulin lispro Expiration Insulin aspart 28 days 28 days Date Insulin glulisine Insulin glargine Vials Expiration Insulin human N 31 days 31 days Date Insulin human R Pens Insulin lispro Do not refrigerate Insulin aspart Expiration 28 days (lispro, glargine) – 28 days, Insulin glulisine Date (aspart) – 14 days Insulin glargine U-100 Insulin glargine U-300 Vials and pens Expiration 42 days 42 days Insulin detemir Date (pens should not be refrigerated) Inhaled: Insulin human — Expiration Date 15 days for device http://www.pdr.net/browse-by-drug-name. Accessed March 28, 2015. Basal Insulin Delivery Options

Insulin Concentration Vial Pen

NPH U-100 X X

Glargine U-100 X X

Glargine U-300 X

Detemir U-100 X X

Regular Human U-500 X

Food and Drug Administration. Drugs@FDA FDA Approved Drug Products. http://www.accessdata.fda.gov Vial and Syringe

• Some patients still use vials and syringes – Wipe the rubber stopper (on vial) with alcohol swab – Put equivalent amount of air into the vial before drawing up the insulin (based on insulin dose) • When mixing insulin: – Clear before cloudy – Pre-drawn N + R = stable for 30 days refrigerated Needles and Syringes

12.7 mm 8 mm 5 mm Outer protective cap (1/2") (5/16") (3/16") Peel foil

Inner protective cap

Needle (cannula)

Needle hub Insulin Pens Patient Cases Case 1

• 67-year-old male, retired engineer – BMI 45 – A1c = 8.5% – SrCr = 1.2 • Medications: – Glargine (pen) 80 units twice per day – Aspart (pen) 30–60 units per meal + correction – Lisinopril 10 mg daily – Atorvastatin 10mg daily • Total daily dose (TDD) insulin: ~300 units per day • Largest meal is supper and snacks at night ? Case #1 – Question #1 • The physician recently became aware of concentrated insulin and would like to switch the patient to U-500. For a total daily dose of 300 units to be given twice daily, how would you instruct the patient to draw up 150 units of U-500 insulin? 1) Using a U-100 syringe, draw to the 60 units marking 2) Using a U-100 syringe, draw to the 30 units marking 3) Using a tuberculin syringe, draw 0.2 mL 4) Using a tuberculin syringe, draw 0.4 mL Case 1 Continued

• First assess patient current insulin injection technique

– If technique is appropriate then….. • Start U-500 insulin:

– 300 units divided into two doses = 150 units twice daily

– 150 units of U-500 insulin is equal to 30 units on a U-100 syringe

– 30 units x 5 (5 times concentration) = 150 units of actual insulin

– If using tuberculin syringe, 150 units = 0.3 mL • U-300 insulin glargine is not a substitute for U-500 insulin because the current U-300 pen delivers only up to 80 units per injection Case 2

• 56 year old female, high school principal – BMI 32 – A1c = 8.9% – SrCr = 1.1 • Patient did report occasional episodes nocturnal hypoglycemia – ~ 3–5 per month • Medications: – NPH (pen) 63 units twice per day • Morning (7 AM) and 2 hours before bed (9 PM) – Metformin 1000 mg daily – Sitagliptin 100 mg daily – Lisinopril 10 mg daily – Simvastatin 20 mg daily • Total daily dose (TDD) insulin: ~126 units per day • Patient does not want to start bolus insulin due to erratic meal and work schedules ? Case #2 – Question #1

• The physician wants to switch the patient to U-300 insulin glargine. What would be your recommendation for switching from 63 units twice daily (126 units/day) NPH to U-300 insulin glargine? 1) Using a U-100 syringe, draw to 21 units marking (63 units) and inject twice daily 2) Using a U-100 syringe, draw to 49 units marking (126 units) and inject once daily 3) Using the U-300 pen, dial to 126 units and inject once daily 4) Using the U-300 pen, dial to 51 units and inject twice daily Case 2

• Switching to U-300 insulin glargine

– Determine starting dose:

Prior treatment Start with Once daily long-acting or 1:1 intermediate acting insulin Twice-daily NPH 80% total daily basal dose No current basal insulin 0.2 U/kg/day

• 126 units x 0.80 = 100.8 units U-300 glargine

– 101 units/2 = 51 units given twice daily; current U-300 pen has max dose of 80 units per injection

• To minimize hypoglycemia risk, titrate the dose no more frequently than every 3–4 days Summary

• Type 2 diabetes is a growing epidemic with an ever- growing number of patients requiring high doses of insulin to maintain glycemic control • Insulin resistance is a MAJOR problem among patients with type 2 diabetes, and combination therapy is often needed to improve insulin sensitivity • A basal-bolus insulin regimen is best to mimic natural insulin physiology but requires frequent BG monitoring and provider/patient education • Concentrated insulin is ideal for patients with insulin doses >200 U/day due to the large volume associated with U-100 insulin Summary Continued

• U-500 regular human insulin is associated with a high incidence of dosing errors due to the lack of a U-500 specific insulin syringe • Newly approved U-300 insulin glargine is available in a pen, avoiding the need for conversion using U-100 or tuberculin syringes needed with U-500 insulin • Insulin in T2DM is often delayed, but in order to optimize glycemic control, it is important that clinicians recognize and address the barriers to insulin therapy • U-300 insulin glargine and emerging basal insulins have improved PK/PD profiles compared to current insulins – Flatter time–action profiles with less variability – Less hypoglycemia, particularly nocturnal hypoglycemia Post-Activity Questions 1-4 Post-test Question #1

1) Using a U100 syringe, draw to the 50 units marking 2) Using a U100 syringe, draw to the 25 units marking 3) Using a tuberculin syringe, draw 0.2 mL

4) Using a tuberculin syringe, draw 0.4 mL Post-test Question #3

Which of the following statements is INCORRECT regarding the new basal insulin U300 glargine? 1. It is associated with less nocturnal hypoglycemia 2. It has a flatter PK profile and a duration of action ≤36 hrs 3. It is only available in a pen with 1.5 mL of U300 glargine 4. Current pen allows for a max of 240 units of insulin per shot 5. Patients switching from twice daily NPH to U300 glargine should start with 80% of total daily NPH dosage Backup Slides ? In what year was insulin made available to treat humans?

1) 1898 2) 1922 3) 1937 4) 1948 5) 1956 BANTING (1891–1941) First Commercial & BEST (1899–1978) Insulin Milestones in Insulin Development

Synthetic human Insulin lispro approved insulin developed (1965) in U.S. (1996) Insulin discovered (1921) Insulin detemir Recombinant human approved in U.S. insulin developed (2005) NPH insulin (1979) developed (1946) Inhaled insulin (2006) 2014 Degludec (2013)

1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2013 2014

In development: Lente (zinc) insulins Insulin pen Degludec U-200 developed (1952) developed (1981) Glargine U-300 Insulin Pegylated Lispro glulisine Biosimilars Insulin pump Protamine and protamine (2004) developed (1978?) zinc insulins developed (1936) Insulin aspart and insulin glargine First human treatment approved in U.S. with bovine insulin (1922) (2000)

1. Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Blackwell Science: Malden, MA; 2003:1.1-1.22; 2. Drugs@ FDA; http://diabetes.webmd.com/news/20071018/pfizer-quits-inhaled-insulin- exubera. First Time Preparation • Check the pen

– Make sure liquid is clear, colorless, particle-free (N insulin and mixed insulin will be cloudy)

– Wipe the rubber stopper with alcohol • Attach the needle • Prime the needle

– Dial 2 to 3 units, hold up and depress the button

• Repeat the process until a drop of insulin appears at the tip of the needle • Dial up the dose Insulin Injection • Inject straight into the skin – Depress the button to release insulin into SC tissue • Hold for 5 to 10 seconds before removing the needle from skin Inject “straight in” • Remove needle and dispose flush with skin into sharps container • Always have the patient demonstrate their technique – At first education of the device – At first follow-up visit – At frequent intervals thereafter Improper Insulin Injection Technique • The patient did not tip and roll insulin suspension pen injector to ensure proper mixing • The patient put a needle on the pen, dialed to 10 units, pushed the needle into the injection pad, and then proceeded to dial back to zero • The patient omitted the 2-unit air shot prior to each dose • The patient injected his insulin into the orange (as he was taught) and then ate the orange Insulin Resistance: Patient Risk Factors • Medical conditions associated with risk: – History of gestational diabetes (GDM) – Lipodystrophy and other inherited disorders – Fatty liver disease – Metabolic syndrome (obesity, HTN, mixed hyperlipidemia) – Polycystic ovarian syndrome (PCOS) • Physical exam/historical markers associated with risk: – Obesity – Increased waist-to-hip ratio (visceral adiposity) – Certain ethnic groups have increased risk – Acanthosis nigricans

Andrews L. Overcoming the frustration of severe insulin resistance. American Diabetes Association, 2014 professional Educator Conference.