Treatment of Insulin Resistant Type 2 Diabetes: The Role of the - - PowerPoint PPT Presentation

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:

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.

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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

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.

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

Type 2 Diabetes

• Characterized by chronic hyperglycemia
• Associated with microvascular and

macrovascular complications

• Generally arises from a combination
• f 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%

?

HOMA = homeostasis model assessment.

Based on data of UKPDS 16. Diabetes. 1995;4(11):1249-1258.

Progressive Deterioration in β-Cell Function Over Time

Beta-Cell Function (%, HOMA)

Insulin

Intensive or in Combination

25 100 75 50

• 12 -10
• 6
• 2

2 6 10 14

Years from Diagnosis

• 8
• 4

4 8 12 Combination Therapy Monotherapy

Pathophysiologic Defects in Type 2 Diabetes: The Ominous Octet

Decreased Incretin Effect Neurotransmitter Dysfunction

Islet β-cell

Impaired Insulin Secretion Decreased Glucose Uptake

Islet α-cell

Increased Glucagon Secretion Increased Lipolysis Increased Glucose Reabsorption Increased HGP DeFronzo RA. Diabetes. 2009;58(4):773-795.

Hyperglycemia

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

Haffner SM, et al. Circulation. 2000;101:975-980.

83%

Insulin resistant; low insulin secretion (54%) Insulin resistant; good insulin secretion (29%) Insulin sensitive; good insulin secretion (1%) Insulin sensitive; low insulin secretion (16%)

Insulin Resistance Reduces Response to Circulating Insulin

Insulin resistance

↑ Glucose output ↓ Glucose uptake ↓ Glucose uptake

Hyperglycemia

Liver Muscle Adipose tissue

↑ Insulin/medication requirements needed to maintain glycemic control

IR

Treatment Options for Type 2 Diabetes

12 Pharmacotherapy Options

Insulin

• Bolus insulin

– Insulin lispro (Humalog) – Insulin aspart (NovoLog) – Insulin glulisine (Apidra) – Insulin human inhaled (Afrezza) – Regular human insulin

• (Humulin R)
• (Novolin R)
• Basal insulin

– Insulin NPH

• (Humulin N)
• (Novolin N)

– Insulin detemir (Levemir) – Insulin glargine U-100 (Lantus) – Insulin glargine U-300 (Toujeo)

Oral Medications

• α-glucosidase inhibitors (AGI)
• Biguanides
• Bile acid sequestrants (BAS)
• Dipeptidyl peptidase-4 (DPP-4)

inhibitors (gliptins)

• Dopamine agonists
• Glitinides
• Sulfonylureas
• Sodium glucose co-transporter-2

inhibitors

• Thiazolidinediones (TZDs or glitazones)

Non-insulin injectable agents

• Glucagon-like peptide-1 (GLP-1)

agonists

• 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

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. Monotherapy Route of Administration Targets Insulin Resistance Target Glucose: FPG or PPG A1C Reduction (%) 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 GLP-1 agonists Injectable No Short-acting – PPG Long-acting – Both 0.8–1.5 Amylin analogs Injectable No PPG 0.6 Insulin Injectable ↓ glucose toxicity Basal – FPG Bolus – PPG ↓ as much as needed

Basal Insulin Therapy: Concept and Physiology

UKPDS: Progressive Deterioration in Glycemic Control Over Time

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

HbA1C Level

Intensive Conventional

Time from Randomization (y) Median A1C (%)

9 8 7 6 3 9 6 15 12

Currently Available Insulins

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

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

No food Meals Less overnight More for “waking up”

Time

PK Profile of Currently Available Insulins

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.

12 16 20 24 8 4

Plasma Insulin Levels

2 14 18 22 10 6

Intermediate (NPH insulin) Long (Insulin detemir) Long (Insulin glargine) Time (hours)

26 28 30 32 34 36

Ultralong (U300 glargine) Aspart, Lispro, Glulisine Regular Inhaled insulin

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.

IRI = immunoreactive insulin.

de la Peña A, et al. Diabetes Care. 2011;34:2496-2501.

PK and PD Profiles for U-500 vs U-100 Human Insulin

1000 800

Glucose Infusion Rate (mg/min) Time (hours)

200 600 400

50-Unit Dose

1400 1200

Mean Serum IRI Concentration (pmol/L)

200 800 400

50-Unit Dose

Human Regular U-500 Insulin Human Regular U-100 Insulin

1000 800

Time (hours)

200 600 400

100-Unit Dose

1400 1000 200 600 400

100-Unit Dose

1000 600 1200 800 16 24 4 20 12 8 16 24 4 20 12 8

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

*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.

U-500 Insulin Dose (Actual units) U-100 Syringe (Unit markings) Volume for Tuberculin 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

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.

LLOQ

PK and PD of U-300 Insulin Glargine vs U-100 Insulin Glargine

LLOQ = lower limit of quantification; GIR = glucose infusion rate; PK = pharmacokinetic; PD = pharmacodynamic.

Becker RH, et al. Diabetes Care. 2014;pii:DC_140006.

GIR [mg/kg-1/min-1]

3 1

Time (h)

2 36 Gla-100 0.4 U/kg-1 Gla-300 0.4 U/kg-1 24 18 12 6 30

INS [µU/mL-1]

25 5 15 20 10 N = 30

U-300 glargine displays a more even and prolonged PK/PD profile compared with U-100 glargine, offering blood glucose control beyond 24 hours

U-300 Glargine vs U-100 Glargine in T2DM:

Meta-Analysis of Phase III Trials EDITION 1, 2, & 3

Baseline to Month 6 RR (95% CI) Glar U-300 (N=1247) Glar U-100 (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

• r severe hypo*

26.9 33.3 0.81 (0.72–0.90) Confirmed nocturnal BG <54 mg/dl or severe hypo* 9.7 13.2 0.73 (0.59–0.91)

*% 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

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.

• No difference in A1C

between flexible- vs fixed-dosing

• No difference in

severe or nocturnal hypoglycemia within each sub-study Edition 1 Sub-Study

N = 109

Percentage of Injections (%)

20 100 24 ± <1 h 80 60 40 24 ± 1-3 h 24 ± >3 h 24 ± <1 h 24 ± 1-3 h 24 ± >3 h

Edition 2 Sub-Study

N = 89 Flexible dosing Fixed dosing

6 months (randomization, sub-study) U-300 once daily every 24 ± 3 h U-300 once daily every 24 h 9 months (end of sub-study) sub-study 6-Month Treatment Period (main study) 6-Month Extension Period (main study) U-300 once daily every 24 h

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

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.

Glucose Infusion Rate

2

Day 6 Day 7

4 1 3 5 IDeg 100 U/mL 0.4 U/kg IDeg 100 U/mL 0.8 U/kg IDeg 100 U/mL 0.6 U/kg IDeg 200 U/mL 0.6 U/kg

Mean 24-Hour GIR Profile of the Two Insulin Degludec Formulations at Steady State

Half-life at Steady State IDeg 200 U/mL 0.6 U/kg Mean Half-life (hours) 26.2 h n = 21 n = 37 n = 16 n = 22

Pharmacodynamic Variability with Insulin Degludec vs Insulin Glargine

53 ¡

Subjects listed in increasing order of individual coefficient of variation

1 4 7 10 13 16 19 22 25 27 20 40 60 80 100 120 140 160 180 1200 1100

Individual Coefficient

• f Variation (%)

Heise T, et al. Diabetes Obes Metab. 2012;14(9):859-864. Insulin degludec Insulin glargine

U-200 Insulin Degludec: Safety and Efficacy

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

26-week Open-label, Randomized Study of 457 Patients with Type 2 Diabetes

HBA1c (%)

7.5 0.0 26

Time (weeks)

22 18 6 2 12 6.9 8.1 8.5 IDeg 200 Units/mL OD (n=228) IGlar OD (n=229) 8.3 7.7 7.9 7.1 7.3 6.7 20 16 10 14 8 4 24 Treatment difference: noninferior

No difference in hypoglycemia between the two treatment groups

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

GIR = glucose infusion rate.

Heise T, et al. Diabetes. 2012;61(suppl 1):A256 [abstract 1000-P].

Glucose clamp study in 32 patients, 8 per study arm

Mean GIR (mg/min/kg)

2 4 1 3 5 0.33 U/kg 0.5 U/kg 0.67 U/kg 1.0 U/kg

Pegylated Insulin Lispro

24

Time (hours)

20 16 8 4 12

7.4 7.6 7.0 7.8 7.2 8.0

A1c (%)

6.8 88 83

Weight (kg)

4

Week

12 8 80 16 85 87 82 86 81 84

p < 0.001 p < 0.0001

PEGylated Insulin Lispro (LY2605541) vs Glargine U-100 in T1DM

LY2605541 Treatment at 8 weeks

• Significantly lowered A1C vs

glargine

• Significantly reduced weight

(1.2 kg)

• Increased overall hypos

(p = 0.04) but less nocturnal hypos (p = 0.01)

• Lowered prandial insulin dose
• Significantly increased liver

enzymes

Rosenstock J, et al. Diabetes Care. 2013;36(3):522-528. LY2605541 Glargine Treatment Period 1 Treatment Period 2 (Crossover)

Is there an alternative to concentrated insulin for patients

• n high doses of insulin?

Combination Basal Insulin and GLP-1 RAs

Lifestyle Changes plus Metformin

(± other agents)

Basal

Add Basal Insulin and Titrate

Basal Plus

Add Prandial Insulin at Main Meal

Basal plus GLP-1 RAs Basal Bolus

Add Prandial Insulin before Each Meal

Barriers to Insulin-Mediated Glucose Control

Significant Delay in Insulin Initiation

Data from Khunti K, et al. SOLVE Study Group. Diabetes. 2011;60(Suppl 1):A306.

A1C (%) Patients (%)

6 9 12 15 2 4 6 10 18 8 16 14 12 5 8 11 14 7 10 13 16 8.9%

SOLVE: Baseline A1C Distribution at Insulin Initiation

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

• Patient reluctance
• Sense of failure
• Loss of independence
• Belief that insulin is

ineffective

• Fear of injections
• Fear of hypoglycemia
• Weight gain

Provider Barriers

• Clinical inertia
• Lack of insulin training,

time, and/or support

• 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 Insulin aspart Insulin glulisine Insulin glargine Expiration Date 28 days 28 days Vials Insulin human N Insulin human R Expiration Date 31 days 31 days Pens Insulin lispro Insulin aspart Insulin glulisine Insulin glargine U-100 Insulin glargine U-300 Expiration Date 28 days Do not refrigerate (lispro, glargine) – 28 days, (aspart) – 14 days Vials and pens Insulin detemir Expiration Date 42 days 42 days (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

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

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

• nce 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:

• 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

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

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

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

Post-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

Post-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

Post-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

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) & BEST (1899–1978) First Commercial Insulin

Milestones in Insulin Development

• 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.

1920 1930 1940 1960 1970 1980 2000 2010 1990 1950

Insulin discovered (1921) First human treatment with bovine insulin (1922) Protamine and protamine zinc insulins developed (1936) NPH insulin developed (1946) Lente (zinc) insulins developed (1952) Synthetic human insulin developed (1965) Recombinant human insulin developed (1979) Insulin pump developed (1978?) Insulin pen developed (1981) Insulin lispro approved in U.S. (1996) Insulin aspart and insulin glargine approved in U.S. (2000) Insulin glulisine (2004) Insulin detemir approved in U.S. (2005) Inhaled insulin (2006) 2014

2013

Degludec (2013) In development: Degludec U-200 Glargine U-300 Pegylated Lispro Biosimilars

2014

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 in” flush with skin

• 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

• Remove needle and dispose

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.