1

SafeandEffectiveUseofNewandEmergingInsulinTherapy

Zachary Freedman, MD, FACE

Rochester Regional Health

11/6/2016

Disclosures

Speaker’s Bureau (Honoraria):Lilly, Sanofi, Novo‐Nordisk, Merck, Takeda, AstraZeneca

Stocks, Advisory Committee, Review Panel, Royalty: None

LearningObjectives

• Evaluate the role of insulin within the AACE and ADA guidelines for the treatment of T1 and T2DM.

• Differentiate the pharmacokinetic and pharmacodynamic actions of available and emerging basal insulins.

• Discuss strategies for overcoming common barriers to optimal glucose control with basal insulin therapy.

• Using patient specific information, make recommendations regarding insulin initiation, dose adjustments and monitoring.

Review Use of Insulin in Type 2 DiabetesWhy?  When?  Type of Insulin?

Barriers to Use of InsulinPatientsProvidersSolutions

Why new insulins?Discuss PK, PD, 

New insulinsGlargineU300, Degludec, 

Biosimilars

Role of U500 insulin

Emerging Bolus InsulinsFast Acting Aspart

Outline

Insulin(µU/mL)

Glucose(mg/dL)

Physiologic Insulin Secretion: 24-Hour Profile

150

100

50

07 8 9 10 11 12 1 2 3 4 5 6 7 8 9

A.M. P.M.

Basal Glucose

Time of Day

50

25

0 Basal Insulin

Breakfast Lunch Dinner

7Weyer C, et al. J Clin Invest. 1999;104:787-794.

NGTNGT

NGT

Non-progressors

NGT

IGT

DIA

Progressors

Insulin SensitivityM-low (mg/kg EMBS per minute)

Insulin Response(U/mL)

0 54321

0

100

200

300

400

500

Changes in Insulin Secretion and Action: Staying on the Curve

8

2

• First-phase of glucose-induced insulin release is reduced or missing

• Second-phase of insulin secretion is reduced or inadequate (high or low)

• Changes of oscillatory secretion of insulin (brief, irregular pulses with small amplitudes)

• Reversible low response of glucose-induced insulin release due to gluco- and/or lipotoxicity

• Increase of proinsulin release

What is wrong with the ß-cells in Type 2 diabetes?

Time (minutes)

1st-Phase 2nd-Phase

i.v. Glucose

People with diabetes

Healthy subjects

-5-10 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 10095

Insulin secretory pattern in healthy individuals and people with diabetes

Time (minutes)

Insulin secretion

Years from diagnosis

0

-cellfunction (%)

80

0

60

40

20

2 4 6 0

Insulinsensitivity

0

40

20

2 4 6

60

Patients with diet failure2–4 years after diagnosisPatients with diet failure5–7 years after diagnosisPatients with diet failure8–10 years after diagnosis

Progression of Type 2 diabetes relates to declining ß-cell function rather than insulin resistance Natural History of Type 2 Diabetes

Insulin ResistanceHepatic Glucose Production

Endogenous Insulin

Postprandial Blood Glucose

Fasting Blood Glucose

Typical Diagnosis of Diabetes

Microvascular ComplicationsMacrovascular Complications

Severity of Diabetes

Impaired Glucose Tolerance Frank Diabetes

Years to DecadesTime

CARL67 yo retired chef, active lifestyle, an epicurean 15 yr Type 2 DM:  BMI=35, BP 132/80  HbA1C=8.9, Cr=1.3 (eGFR=40), LDL=80, FBS=210Hypertension, HypercholesterolemiaRx with metformin 500 mg BID, Glyburide 5 mg BID, atorvastatin 40 mg/d, lisinopril 10 mg QDRecent complaints of fatigue, groin itching, urinary frequency, thirst

What is his next best treatment?1)  Gastric bypass2)  SGLT2i3)  Pioglitazone4)  Basal insulin

3

CARL67 yo retired chef, active lifestyle, an epicurean 15 yr Type 2 DM:  BMI=35, BP 132/80  HbA1C=8.9, Cr=1.3 (eGFR=40), LDL=80, FBS=210Hypertension, HypercholesterolemiaRx with metformin 500 mg BID, Glyburide 5 mg BID, atorvastatin 40 mg/d, lisinopril 10 mg QDRecent complaints of fatigue, groin itching, urinary frequency, thirst

What is his next best treatment?1)  Gastric bypass2)  SGLT2i3)  Pioglitazone4)  Basal insulin

TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE

Over time,most patients will need

insulinto control glucose

6-7

MIMICKING NATURE WITH INSULIN THERAPY

Over time,

most patients will need

both basal and mealtime insulin

to control glucose

Barriers to Insulin Use: Patient Issues

Barriers Solutions

Fear of injections Syringes, pens, and needles vastly improved

Fear of hypoglycemia Low rate of severe hypoglycemiain type 2 diabetes

Fear of weight gain Glucose control is more importantthan mild-to-moderate weight gain

4

Concerns Responses

Insulin equates to Diabetes is a progressive “worse diabetes” disease: early intervention critical

Inconvenience New delivery systems (pens,pumps) and insulins increase flexibility

Is insulin therapy No evidence in clinical trials of atherogenic? exogenously administered

insulin (UKPDS, DCCT, DIGAMI)

Barriers to Insulin Use: Patients and Providers

Barriers to Insulin TherapyCommon Concerns

Insulin therapy might cause

• Worsening Insulin Resistance

• More Cardiovascular Risk

• Weight Gain

• Hypoglycemia

• Side Effects (Ads, friends, Internet)

23

Correlation Between Weight Gain and Treatment

Type 1 patients in DCCT, baseline to year 1

The Diabetes Control and Complications Trial Research Group (DCCT). Diabetes Care. 1988;11:567-573; UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

∆ in wt (lb)

0 3 6 9 12

Type 2 patients in UKPDS Years

15

5

10

20

0

Conventional groupIntensive group

∆ in wt (lb)

2.5

5.0

7.5

10.0

0.0

Intensive groupConventional group

15p<0.0001

24

Fear of Hypoglycemia: The Closer to Target, the Higher the Risk

Severe hypoglycemic

events per 100 patient

years

120

60

05.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 10.0 10.59.5

A1c (%)

The Diabetes Control and Complications Trial Research Group (DCCT). Diabetes. 1996;45:1289-1298.

BARRIERS TO INSULIN THERAPY

Reassurance About Common Concerns

Insulin Therapy in Type 2 DM

• Improves Insulin Sensitivity by Reducing Glucotoxicity

• Probably Reduces Cardiovascular Risk

• Causes Modest Weight Gain

• Rarely Causes Severe Hypoglycemia

• The patient wants to have insulin therapy

• Greater flexibility in lifestyle

• Insulin replacement is more physiological

• The individual treatment goal has not been achieved with non-pharmacological intervention and other agents within 3–6 months

• Reduction of complicated and complex oral/injectable polypharmacy

• Relative/absolute contraindications for OAD/injectables

• Side effects with OAD/injectables

Philosophy for earlier insulin treatment (1)

5

• The traditional insulinotropic agents, such as glibenclamide and glimepiride, result in delayed and sustained insulin release and are, therefore, effective mainly in controlling fasting and postabsorptive glycaemia, while being poorly adapted for controlling postprandial hyperglycaemia

• Meglitinides are more effective in controlling postprandial glycaemia

• Glp1 agonists, DPP4i, and SGLT2i useful but often insufficient to control hyperglycemia, especially late in disease progression

• Short-acting insulins and rapid-acting insulin analogues can replace, at least in part, first-phase insulin release

• Long-acting insulins (Degludec, Glargine 300, Glargine, Detemir, NPH) are able to control postabsorptive and, especially, fasting hyperglycaemia

Philosophy for earlier insulin treatment (2)MIMICKING NATURE WITH INSULIN THERAPY

The Basal/Bolus Insulin Concept

• Basal Insulin— Suppresses glucose production between meals and overnight

— Nearly constant levels

— 50% of daily needs

• Bolus Insulin (Mealtime or Prandial)— Limits hyperglycemia after meals

— Immediate rise and sharp peak at 1 hour

— 10% to 20% of total daily insulin requirement at each meal

• Ideally, for insulin replacement therapy, each component should come from a different insulin with a specific profile

BasalInsulins

30

Ideal basal insulin

Time

Glucose infusion rate (GIR)

Target insulin range

Consistent Blood Glucose Response

Which is the better insulin profile?

Mean insulin action profileIndividual insulin action profile

Basal insulin with varying daily profiles

Time

Glucose infusion rate (GIR)

hypoglycemicevent

hyperglycemia

This is a graphical representation.

A B

31

Correlation Between Variability in Blood Glucose Response and Incidence of Hypoglycemia

BG = blood glucose; FBG = fasting blood glucose; CV = coefficient of variation

Heller S et al. Diabetologia. 2004;47(s1):A303.

0

10

20

30

40

50

60

70

80

90

0 20 40 60 80

Within-patient variability (CV) of fasting blood glucose (%)

Hypoglycemia(episodes/person/year)

32

CV = coefficient of variation;*Significant differences in the CV of FPG (p<0.001)

Muggeo M et al. Diabetes Care. 2000;23:45-50.

Variability of FPG and cardiovascular mortality10-year survival

Variability in Blood Glucose Is anIndependent Risk Factor for Mortality

Group 1 (8.5%)

Group 2 (14.8%)Group 3 (27.7%)

1.0

0.7

0.6

0.5

00 2 4 6 8 10

Time (years)

0.8

0.9

Survival probability

Mean CV of FPG *

6

33

● Once-daily dosing● Low intra-patient variability/high consistency

of time-action profile● Low risk of hypoglycemia● Little or no weight gain● Easy to teach, easy to learn

Optimal Starter Insulin Properties Molly33yo female with Type 2 DM for 8 years

Hyperlipidemia, Hypertension, Sedentary lifestyleWt 156 lbs (BMI=28)  BP=120/76RX: glargine 40 u at supper; pre meal lispro insulin 10‐12 units; liraglutide 1.8 mg/d;  metformin 750 mg BIDMost recent HbA1C=6.2 range of 5.9‐6.4 in past 2 years; LDL=87; Cr=0.6

At office visit complains of nightmares, often awakes with damp night shirtPre bk glucoses range from 85‐175; pre lunch, dinner, bedtime 96‐166

Best option for change in her treatment regimen:1) Reduce liraglutide to 1.2 mg/d2) D/C glargine and replace with 40 units glargine 300 or degludec insulin3) Stop metformin4) Reduce pre meal insulin to 8 units5) Add a SGLT2i

Glargine 300

7

8

© 2012 Sanofi US

GLA-2814

• Insulin degludec (IDEG) is a new-generation, long-acting basal insulin developed by Novo Nordisk. It is an investigational product.

• Upon SQ injection, IDEG has been shown to self-associate to form large, soluble multi-hexamers at physiologic pH, which, with the gradual release of zinc ions, results in the slow release of IDEG monomers, which bind to plasma albumin. This leads to a delayed absorption into the circulation and prolonged action profile

• Novo Nordisk filed for FDA approval at the end September 2011

Overview of Insulin Degludec

FDA, Food and Drug Administration; IDEG, insulin degludec; SC, subcutaneous.1. Kurtzhals P et al. Paper presented at: 71st Scientific Sessions of the American Diabetes Association; June 2011; San Diego, CA. Abstract 42-LB, and at: 46th Annual Meeting of the European Association for the Study of Diabetes; September 2010; Stockholm, Sweden. Abstract 1049. 2. Diabetic Hypoglycemia Editorial Team. Diabetic Hypoglycemia 2011;4(2):17-21. 3. De Rycke A and Mathieu C. Eur J Endocrinol 2011;7(2):84-87. Picture from Owens DR. Diabetes Technol Ther. 2011;13(Suppl 1);S5-S14.

47

TAMRC # - s-a to add

© 2012 Sanofi US

Insulin Degludec: Pharmacodynamics• Degludec is almost identical to human insulin

– Last amino acid deleted from B-chain– Addition of glutamyl link from LysB29 to a hexadecandioic

fatty acid

• Prolonged duration of action and flat plasma profile– Terminal half-life of > 25 hours and activity > 40 hours– Reduced variability in plasma concentration and activity– Flat steady-state plasma profile with once-daily injection

• Albumin binding– Degludec forms multihexamer insulin chains in SC depots– Accumulation slows release of insulin monomers, which are

retained longer in circulation by attachment to albumin

SC = subcutaneous.Jonassen I et al. Diabetes. 2010;59:A11.

9

Recent Trial Highlights – BEGIN Type 2

Type 2 DM

insulin degludec vs. glargine

Study Trial design & Treatment arms

Trial population Results

BEGIN Basal-Bolus Type 2 4

• 52 weeks, randomized, controlled, open-label, treat-to-target, multinational, non-inferiority trial

• 1006 patients with type 2 DM

• Diabetes duration for > 6 months, any insulin use for at least 3 months, HbA1c of 7.0 –10.0%, and BMI of 40.0 kg/m2

or less, with or without oral antidiabetic drugs

• 744 patients to degludec

• 248 patients to glargine

• Excluded: glp-1 agonist or rosiglitazone use within previous 3 months

• HbA1c fall at year 1• 1.1 % degludec• 1.2 % glargine• Treatment difference:

0.08% [95% CI -0.05 to 0.21], confirming non-inferiority

70

40

Hb

A1

c(m

mo

l/mo

l)

65

0

35

50

55

60

75

45

Treatment difference: non-inferior

Basal–bolus in T2D:HbA1c and FPG over time BEGIN® BB T2D IDeg OD + IAsp (n=744)

IGlar OD + IAsp (n=248)

Mean±SEM; FAS; LOCF; IAsp, insulin aspart Comparisons: estimates adjusted for multiple covariatesGarber et al. Lancet 2012;379:1498–507

Treatment difference: –0.29 mmol/L (ns)

Time (weeks) Time (weeks)

0.0 0.026 26

BEGIN® BB T2D Basal–bolus in T2D: confirmed hypoglycaemia

IDeg OD + IAsp (n=753)IGlar OD + IAsp (n=251)

Severe hypoglycaemia: IDeg, 0.06 events/PYE; IGlar, 0.05 events/PYESAS; LOCF; Comparisons: estimates adjusted for multiple covariatesGarber et al. Lancet 2012;379:1498–507

18% lower rate with

IDeg, p=0.0359

Time (weeks)

IDeg: 11.09 events/PYEIGlar: 13.63 events/PYE

Basal–bolus in T2D: confirmed nocturnal hypoglycaemiaBEGIN® BB T2D IDeg OD + IAsp (n=753)

IGlar OD + IAsp (n=251)

SAS; LOCFComparisons: estimates adjusted for multiple covariatesGarber et al. Lancet 2012; 379:1498–507

25% lower rate with IDeg, p=0.0399

Time (weeks)

IDeg: 1.39 events/PYEIGlar: 1.84 events/PYE

10

Based on the long duration of action and flat profile insulin degludec can be administered

at any time of the day

© 2012 Sanofi US

GLA-2814

Hypoglycemia

Hypoglycemia: Summary of Data Comparing IDEG With IGLAR

• Three phase 2 studies have similar hypoglycemia rates1-3

• Exception is post hoc analysis of Zinman et al.3

• Inconsistent results for Phase 3 studies in Type I and Type II DM4,5,6

• Meta-analysis demonstrates significantly lower rates of both overall and nocturnal hypoglycemia than IGlar at similar levels of A1C6

• Severe hypoglycemic events very low in all studies of IDEG vs IGLAR

IDEG, insulin degludec; IGLAR, insulin glargine.1. Birkeland KI et al. Diabetes Care. 2011;34(3):661-665. 2. Heise T et al. Diabetes Care. 2011;34(3):669-674. 3. Zinman B et al. Lancet. 2011;377(9769):924-931.4. Atkin SL et al. Paper presented at: 47th Annual EASD Meeting; September 2011; Lisbon, Portugal. Abstract 112. 5. Meneghini L et al. Paper presented at: 46th Annual EASD; September 2010; Stockholm, Sweden. Abstract 973. 6. Ratner RE et al. [ADA abstract]. Diabetes. 2012;61(suppl 1):A387-P.

T1DM+T2DM

Biosimilars

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WhatAreBiosimilars?• Biosimilars

– Are biological products that are highly similar to a reference product, notwithstanding minor differences in clinically inactive components, with no clinically meaningful differences in safety, efficacy, and purity1,2

– Are not generics; they are similar but not the same3

– Provide valuable options that create choice for prescribers and patients4

• Biosimilar manufacturing quality matters– Manufacturing processes that may influence quality and/or

immunogenicity of biological products include protein production, purification, formulation, and storage and handling5

1. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/WC500167838.pdf3. Declerck PJ. GaBI J 2012;1:13-64. Wilkins AR et al. J Diabetes Sci Technol 2014;8:23-55. Sharma B. Biotechnol Adv 2007;25:325-31

Biosimilars:Introduction

• Biologic drugs– Offer new treatment options for rare or life-threatening diseases1

– Are more expensive than small molecule chemical drugs2

– Sales may exceed $167 billion by 20151

• Impending patent expiration set the stage for new biosimilar drug development3

– Biosimilars may reduce treatment costs (by 10%-35%)4-6 and increase patient access7

– 2015 global market penetration expected to be $2.0-2.5 billion2

– Understanding the concept of “biosimilarity” is essential for clinicians and patients

1. Sekhon BS and Saluja V. Biosimilars 2011;1:1-112. Blackstone EA and Fuhr JP Jr. Biotechnol Healthc 2012;9:24-73. Mellstedt H et al. Ann Oncol 2008;19:411-94. http://ec.europa.eu/DocsRoom/documents/7651/attachments/1/tran

slations/en/renditions/pdf5. http://www.rand.org/pubs/perspectives/PE127

6. Blackstone EA and Fuhr JP Jr. Am Health Drug Benefits 2013;6:469-78

7. DeVries JH et al. Diabetes Obes Metab 2015;17:445-51

DemonstratingBiosimilarity:HowSimilarIsSimilar?

• When compared to the reference product, a biosimilar medicine must comply with regulatory guidelines and demonstrate1,2

– In vitro & in vivo nonclinical characteristics similar to the reference product

– Similar PK and PD within predefined regulatory acceptance limits

– No clinically meaningful difference in efficacy (eg, based on noninferiority studies)

– No clinically meaningful differences in safety profile, including drug-related AEs and immunogenicity

• Currently, a number of biosimilar products are available in the EU3,4; in the US, the first biosimilar, filgrastim-sndz was approved in March 20155

1. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291134.pdf2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500184161.pdf3. http://goo.gl/x8LP6Z4. Abasaglar® [Summary of Product Characteristics]5. http://www.biosimilarnews.com/fda-approves-first-biosimilar-zarxio-filgrastim-sndz-from-sandoz

InsulinGlargine:Introduction

• Insulin glargine1,2

– Long-acting human insulin analog

– An important treatment option for patients requiring a basal insulin as part of their diabetes treatment plan

• In 2000, Lantus® insulin glargine (IGlar) gained FDA and EMA approval for once-daily subcutaneous administration for treatment of type 1 and type 2 diabetes mellitus (T1DM and T2DM)1

• In patients with T1DM or T2DM, IGlar, when compared to neutral protamine Hagedorn (NPH), was shown to1,2

– Provide similar glycemic control

– Have lower or similar rates of hypoglycemia

1. Blevins TC et al. Diabetes Obes Metab 2015;17:726-332. Rosenstock J et al. Diabetes Obes Metab 2015;17:734-41

LY2963016InsulinGlargine:Introduction• LY2963016 insulin glargine (LY IGlar)1,2

– Long-acting human insulin analog

– Identical amino acid sequence as IGlar

– Same pharmaceutical form and strength (concentration of active ingredient) as IGlar

• LY IGlar was the first biosimilar insulin approved for marketing authorization in the EU (2014)1,2

– LY Glar is not considered a biosimilar in the US as it was submitted for approval under a different regulatory pathway; it is a follow-on biologic

• In Phase 1 studies, LY IGlar and IGlar were shown to have similar PK and PD properties3-5

• In Phase 3 studies, LY IGlar provided equivalent efficacy and a similar safety profile as IGlar when used

– In combination with insulin lispro in patients with T1DM1

– In combination with OAMs in patients with T2DM2

1. Blevins TC et al. Diabetes Obes Metab 2015;17:726-332. Rosenstock J et al. Diabetes Obes Metab 2015;17:734-413. Linnebjerg H et al. Diabetes Care 2015;38:2226-334. Zhang X et al. Diabetes 2014;63(Suppl 1):A227. Abstract 890-P5. Heise T et al. Diabetes 2014;63(Suppl 1):A228. Abstract 891-P

HasLYIGlarMetBiosimilarity Criteria?

Head‐to‐head clinical trials to detect relevant differences in efficacy or drug‐related safety6,7

No clinically meaningful differences in immunogenicity6,7

Similarity demonstrated in clinical trials designed to assess PK and PD against standard acceptance limits3‐5

Similarity demonstrated in preclinical in vitro and in vivo PD and toxicology studies1,2

1. Owens RA et al. Diabetes2015;64(Suppl 1):A265. Abstract 1033-P

2. Byrd RA et al. The Toxicologist 2014;138:1650

3. Linnebjerg H et al. Diabetes Care 2015;38:2226-33

4. Zhang X et al. Diabetes2014;63(Suppl 1):A227. Abstract 890-P

5. Heise T et al. Diabetes2014;63(Suppl 1):A228. Abstract 891-P

6. Blevins TC et al. Diabetes Obes Metab 2015;17:726-33

7. Rosenstock J et al. Diabetes Obes Metab 2015;17:734-41

12

SafetyandTolerability

• No notable differences were observed in AE profiles of LY IGlar and IGlar in healthy subjects, and no safety concerns were noted in the clinical laboratory evaluations, vital signs, or ECG data, in any of the 3 studies

Linnebjerg H et al. Diabetes Care 2015;38:2226-33

U500 Regular Human Insulin

Comparison of Pharmacokinetics of U-500 and U-100 Human Regular Insulin1

1. de la Peña et al. Diabetes Care 2011;34(12):2496-501.

Comparison of Pharmacodynamics of U-500 and U-100 Human Regular Insulin1

1. de la Peña et al. Diabetes Care 2011;34(12):2496-501.

U-500 Human Regular Insulin:Clinical Pharmacology1

1. U-500 Regular Insulin prescribing information, 2013.

Clinical experience has shown that U-500 human regular insulin frequently has time action characteristics reflecting both prandial and basal activity

U-500 human regular insulin has an onset within 30 minutes and has a relatively long duration of action (up to 24 hours following a single dose) compared with other regular insulins; this effect has been attributed to the high concentration of the preparation

U-500 human regular insulin is not modified by any agent that might prolong its action

U-500 = 500 units/mL, U-100 = 100 units/mL

Potential Candidates for U-500 Human Regular Insulin Therapy1-3

1. Cochran et al. Diabetes Care 2005;28(5):1240-4.2. Lane et al. Endocr Pract 2009;15(1):71-9.3. Segal et al. Am J Health Syst Pharm 2010;67(18):1526-35.

Patients with the following medical conditions may be considered for U-500 human regular insulin therapy • Type 2 diabetes with obesity and/or severe insulin resistance

• Type 2 diabetes with insulin requirements >200 units per day Postoperative or post-transplant state

High-dose glucocorticoid therapy

Severe systemic infection

• Gestational diabetes mellitus with severe insulin resistance

• Genetic defects of insulin action Type A insulin resistance syndromes

Lipodystrophic diabetes

• Rare forms of immune-mediated diabetes such as anti-insulin receptor antibodies (type B insulin resistance syndrome)

U-500 = 500 units/mL

13

Nonsyndromic Severe Insulin Resistance

1. Lane et al. Endocr Pract 2009;15(1):71-9.2. Cochran and Gorden. Insulin 2008;3(4):211-83. Cochran et al. Diabetes Care 2005;28(5):1240-4.

Some patients with type 2 diabetes, by virtue of their weight and/or severe insulin resistance, may require insulin doses exceeding 200 units/day1-3

• Many patients with type 2 diabetes who have severe insulin resistance (>2units/kg/day insulin requirement1 will require “high-dose insulin” [>200 units/day])

• Some patients with type 2 diabetes will require high-dose insulin solely on the basis of their high body weight

(eg, the 140 kg patient requiring exogenous insulin at 1.5 units/kg/day = 210 units/day)

Occasionally, patients with type 1 diabetes may require >200 units/day2,3

U-500 Regular Insulin: Dosage and Administration

1. U-500 Regular Insulin prescribing information, 2013.2. Lane et al. Endocr Pract 2009;15(1):71-9.3. Segal et al. Am J Health Syst Pharm 2010;67(18):1526-35.

U-500 regular insulin takes effect within 30 minutes, therefore, it should be followed by a meal within 30 minutes of administration1-3

U-500 regular insulin should only be administered SC1,3

Most patients will require 2 or 3 injections daily1-3

U-500 = 500 units/mL, U-100 = 100 units/mL, OADs: oral antidiabetics, SC: subcutaneously

Algorithm for U-500 Regular Insulin Dosing1,a (1 of 2)

U-500 = 500 units/mL, U-100 = 100 units/mL, TDI: total daily insulin, CSII: continuous subcutaneous insulin infusion, U-500R: U-500 regular human insulin, TDD: total daily dose (of insulin), A1C: glycated hemoglobinaSimplified algorithm for conversion from previous TDD of U-100 insulins to U-500 regular insulin bWhen switching to U-500 regular insulin, the TDD may be reduced by 10%-20% for initial A1C ≤8%; increasing the dose by 10% to 20% for initial A1C ≥10% may be consideredcU-500 regular boluses are recommended 30 minutes before a meal; dosage may be titrated according to frequent self-monitored blood glucosedMay initially use fixed ratios or distribute boluses according to the proportion of carbohydrates with meal or carbohydrate-counting according to patient preference and physician judgment

1. Cochran et al. Diabetes Educ 2014;40(2):153-65.

TDI Dose(units/day)b

Injection Frequency/Delivery Methodc

Dosage Distribution(% of TDD)d

150 - 300

2 injections/day (before breakfast and evening meal)

3 injections/day (before meals)

CSII (1 “pump unit” = 0.01 mL; 0.01 mL of U-500R insulin = 5

actual units)

60/40 or 50/50

40/30/30 or 33.3/33.3/33.3

3 mealtime boluses (50% TDD) with basal rate (50% TDD)

Algorithm for U-500 Regular Insulin Dosing1,a (2 of 2)

U-500 = 500 units/mL, U-100 = 100 units/mL, TDI: total daily insulin, CSII: continuous subcutaneous insulin infusion, U-500R: U-500 regular human insulin, TDD: total daily dose (of insulin) , A1C: glycated hemoglobinaSimplified algorithm for conversion from previous TDD of U-100 insulins to U-500 regular insulinbWhen switching to U-500 regular insulin, the TDD may be reduced by 10%-20% for initial A1C ≤8%; increasing the dose by 10% to 20% for initial A1C ≥10% may be consideredcU-500 regular boluses are recommended 30 minutes before a meal; dosage may be titrated according to frequent self-monitored blood glucosedMay initially use fixed ratios or distribute boluses according to the proportion of carbohydrates with meal or carbohydrate-counting according to patient preference and physician judgmenteNot to inject more than 2 mL at any one injection site

1. Cochran et al. Diabetes Educ 2014;40(2):153-65.

TDI Dose(units/day)b

Injection Frequency/Delivery Methodc

Dosage Distribution(% of TDD)d

300 - 600

3 injections/day

4 injections/day (before meals and bedtime)

CSII (1 “pump unit” = 0.01 mL; 0.01 mL of U-500R insulin = 5 actual units)

40/30/30 or 33.3/33.3/33.3

30/30/30/10

3 mealtime boluses (50% TDD) with basal rate (50% TDD)

>600 4 injections/daye 30/30/30/10

14

FastActingInsulinAspart

15

1. Glargine300insulinascomparedtoglargineinsulin…

1. Reduces post meal glucoses

2. Has a shorter duration of action

3. Has 3x the amount of insulin in a given volume of insulin

4. Increases nocturnal hypoglycemia

2. Degludecinsulinbenefitsinclude…

1. 12 hrs duration

2. Availability in vials and pens

3. Ability to reduce post meal glucose

4. 25 hr half life-twice that of glargine insulin

3. Themostsignificantreasonfortheprogression(higherglucoses)ofType2DMis:

1. Increase in insulin resistance

2. Decline in Beta cell function

3. Increase alpha cell secretion of glucagon

4. Increase in catecholamine secretion from nerves/adrenal gland

4. Biosimilarinsulinsare:

1. Generic insulins

2. May have meaningful differences in purity, safety and efficacy from reference insulin

3. Similar to a reference product with minor differences in clinically inactive components

4. Different PK and PD from reference product

5. U500regularhumaninsulin’sprinciplerole is:

1. Patients developing rash/hives using aspart, lispro or regular human insulin

2. Patients with a BMI > 40

3. Patients requiring over 200 units daily to control hyperglycemia

4. Patients moving away from basal/bolus insulin to pump delivered insulin