Catherine Bourg Rebitch, PharmD, BCACPClinical Associate Professor

Newly Approved Insulin Products

What’s New in the Medication

Pipeline

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Disclosure

The presenter has nothing to disclose concerning possible financial or personal relationships with any entities mentioned in

this presentation.

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Learning Objectives

Summarize the place in therapy for insulin in a type 2 diabetes patient

Discuss characteristics of newly available insulin products

Prevent and address hypoglycemia in patients on insulin therapy

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Audience Poll

Do you use any of these products in your practice? Any preference from the group for a particular product?

• Toujeo® (insulin glargine U-300)• Tresiba® (insulin degludec U-100, U-200)• Xultophy® (degludec/liraglutide) or Soliqua® (glargine/lixisenatide)• Afrezza® (inhaled insulin)

PLACE IN THERAPY

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Insulin Therapy in T2DM

• Initial therapy vs. treatment intensification

• Avoidance of clinical inertia

• Addressing barriers: patient & system

• Importance of education

Russel-Jones D. et al. Identification of barriers to insulin therapy and

approaches to overcoming them. Diabetes Obes Metab. 2018;20:488–496.

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The Progression of Diabetes

The Diabetes Educator. Volume 36, Supplement 2, May/June 2010

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Guideline Recommendations

Pharmacologic Approaches to Glycemic Treatment: Standards of

Medical Care in Diabetes – 2019. Diabetes Care 2019;42(Suppl.

1):S90–S102 | https://doi.org/10.2337/dc19-S009

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Pharmacologic Approaches to Glycemic Treatment: Standards of

Medical Care in Diabetes – 2019. Diabetes Care 2019;42(Suppl.

1):S90–S102 | https://doi.org/10.2337/dc19-S009

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Insulin DosingInitiation Titration

Basal Bolus Basal Bolus

10 units subcutaneously per day OR

4 units or 10% basal dose [with largest meal, ADA]

ADA:“evidence-based titration”; ex. 2 units every 3 days

ADA:10-15% 1-2x weekly OR1-2 units 1-2x weekly

0.1-0.2 units/kg/day [ADA] OR

5 units or 10% of basal dose [with largest meal, AACE]

AACE:2 units every 2-3 days OR1 unit “” if FBG 110-139mg/dL10% ‘’’ if FBG 140-180mg/dL20% if FBG > 180mg/dL

AACE:10% or 1-2 units every 2-3 days [2hrPPBG > 140mg/dL]

0.1-0.3 units/kg/day[AACE]

50% of TDD in 3 divided doses [if starting basal/bolus, AACE]

NEW PRODUCTS

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New Formulations

• Potential benefits of concentrated insulin products

• Combination basal insulin + GLP-1 agonist products

• Inhaled insulin

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Agent Dosing How Supplied

Insulin glargine U-300 (Toujeo®)

• Insulin naive T2DM: 0.2 units/kg/day

• 1:1 dose conversion from Lantus®

• 450 units/1.5mL SoloStar® pen; max 80 units per single dose delivery

• 900 units/3mL pen; max 160 units per single dose delivery

Insulin glargine U-100(Basaglar®)

• 1:1 dose conversion from Lantus® • U-100 Kwikpen®, 5 x 3mL [300 unit] pens per box

Insulin degludec U-100 and U-200 (Tresiba®)

• Insulin naive T2DM: 10 units daily• 1:1 dose conversion from total

daily long or intermediate acting dose

• U-100 FlexTouch®: 300 units/3mL pen; max dose 80 units

• U-200 FlexTouch®: 600 units/3mL pen; max dose 160 units

Insulin lispro U-200 (Humalog®)

• 1:1 conversion from Humalog® • U-200 Kwikpen®; 2 x 3mL [600 unit] pens per box

Insulin aspart U-100 (Fiasp®)

• 1:1 conversion from Novolog® • U-100 FlexTouch® pen, U-100 suspension

Insulin human inhalation powder (Afrezza®)

• Insulin naïve: initiate with 4 unitsat each meal

• Conversion from injection

• Single-use plastic cartridges of 4, 8 and 12 units

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Agent Dosing/Titration How Supplied

Insulin degludec/liraglutide(Xultophy®)

• Initial: 16 units (16 units of insulin degludec and 0.58 mg of liraglutide)

• Titrate +/- 2 units every 3-4 days

Insulin degludec 100 units/mL + liraglutide 3.6 mg/mL

Insulin glargine/lixisenatide(Soliqua®)

Initial: Currently using < 30 units of basal insulin: 15 units (15 units insulin glargine/5 mcg lixisenatide)

Initial: Currently using 30-60 units of basal insulin: 30 units (30 units insulin glargine/10 mcg lixisenatide)

• Titrate +/- 2-4 units weekly

Insulin glargine 100 units/mL + lixisenatide 33 mcg/mL

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Type of Insulin Onset (Hours) Peak (Hours) Duration (Hours)

Appearance

Rapid Acting • Aspart• Lispro• Glulisine• Technosphere

[inhaled]

~15 min~15 min~15 min5-10 min

1-21-21-2

0.75-1

3-53-43-4~3

Clear

[inhaled insulin is powder]

Short Acting (Regular)

0.5-1 2-3 4-6*maximum 8

Clear

Intermediate Acting (NPH)

2-4 4-8 8-12*maximum 18

Cloudy

Long Acting• Detemir• Glargine U-100• Glargine U-300• Degludec

~2 hours [glargine U-100 may be up to 3

hours]

Negligible*[some PK/PD

variability]

14-2422-2424-3030-36

Clear

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Insulin Pharmacokinetics

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Toujeo® [insulin glargine U-300]

https://www.toujeopro.com/toujeo-insulin-

dosing-and-titration-calculator

• Smaller subcutaneous depot compared to U-100 glargine; prolonged/constant release of insulin into the bloodstream

• Consider total daily dose & dose increments per pen when adjusting

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Toujeo® [insulin glargine U-300]

EDITION Clinical Trial Program [4 trials]

Key Results• Noninferior glycemic control; slightly higher basal doses

required• Flexible daily dosing support• Reduced hypoglycemia compared to U-100 glargine

T1DM Insulin-naïve T2DM Insulin switch T2DM

Basal insulin switch + mealtime T2DM

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Tresiba® [insulin degludec U-100, U-200]

• Forms multi-hexamer chains and reversibly binds to albumin upon injection; allows for slower release into systemic circulation

• Consider total daily dose & dose increments per pen when adjusting

https://www.tresibapro.com/dosing-and-device/starting-adult-

patients.html

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Tresiba® [insulin degludec U-100, U-200]

BEGIN Clinical Trial Program [7 trials]• 2 trials evaluated degludec (U100 or U200) in T2DM patients

inadequately controlled on OADs compared to glargine U-100• 3 trials in T1DM, compared to glargine [prandial bolus- aspart]

Key Results• Noninferior glycemic control; slightly lower fasting BG with

degludec• Mean daily basal insulin doses similar • Reduced nocturnal hypoglycemia in T1DM

Lamos EM, Younk LM, Davis SN. Concentrated insulins: the

new basal insulins.

Therapeutics and Clinical Risk Management 2016:12 389–400

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Tresiba® [insulin degludec U-100, U-200]

DEVOTE Trial [vs. glargine U-100]• No increased risk of major adverse cardiovascular events

[noninferior]• Significantly less severe hypoglycemia events

SWITCH 2 Trial [vs. glargine U-100]• Noninferior with regard to glycemic control• Significantly less severe or blood glucose-confirmed

symptomatic hypoglycemia events

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BRIGHT Trial [first comparator data]

• Insulin naïve T2DM patients randomized 1:1 to glargine U-300 or degludec U-100 [n = 463]

• Noninferiority for glycemic control [change in A1c from baseline to week 24]

• Hypoglycemia rates comparable• *Exception: significantly lower during titration period for glargine U-

300

• “More similarities than differences?”

Rosenstock J, Cheng A, Ritzel R et al. Diabetes

Care 2018;41:2147-54.

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Combination products

• Consider pen formulations & priming

• Clinical utility• Likely most useful either as 1) initial injectable therapy, or 2) switch

from modest basal dose monotherapy

• Patient education

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Soliqua® [insulin glargine + lixisenatide]

Aroda VR, et. al. Diabetes Care. 2016;39:1972-1980.

Rosenstock J, et. al. Diabetes Care. 2016;39:2026-2035.

• LixiLan-O

– iGlarLixi compared to monocomponents

– A1c reduction: 0.8% lixi, 1.3% iGlar, 1.6% combo

– Weight change: -2.3kg lixi, +1.1kg iGlar, -0.3kg combo

• LixiLan-L

– iGlarLixi compared to iGlar

– A1c reduction: 0.6% iGlarvs. 1.2% combo

– Weight change: +0.7kg iGlar vs. -0.7kg combo

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Xultophy® [insulin degludec + liraglutide]

Harris and Nealy. Annals of Pharmacotherapy.

2018;52(I):69-77.

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Xultophy® [insulin degludec + liraglutide]

DUAL7 [iDegLira vs. iGlar + aspart]

Billings LK, et. al. Diabetes Care. 2018 (epub)

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Afrezza® [inhaled insulin]

https://www.afrezza.com/pdf/Afrezza-IFU-Mar-2017.pdf

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Afrezza® [inhaled insulin]

https://www.afrezza.com/pdf/Afrezza-IFU-Mar-2017.pdf

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Afrezza® [inhaled insulin]

• Studied in both T2DM and T1DM patients• T1DM comparator data [vs. injected insulin aspart]

• Noninferior [mean change in A1c]

• Lower incidence of hypoglycemia and weight gain

• Increased incidence of cough

• Earlier onset, shorter duration vs. insulin lispro

Rosenstock et al. Bade BW et al. Diabetes Care Volume 38, December

2ttps://hcp.afrezza.com/hcp/afrezza-action-profile/

MANAGEMENT OF ADVERSE EFFECTS

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Hypoglycemia

• Most significant side effect of insulin therapy

• Generally defined as blood glucose < 70mg/dL

• Wide variation in symptoms

• Hypoglycemia unawareness

• Importance of proper treatment

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Insulin “Stacking”

Heise T, Meneghini LF. Insulin Stacking versus Therapeutic

Accumulation: Understanding the Differences.

ENDOCRINE PRACTICE Vol 20 No. 1 January 2014

33Heise T, Meneghini LF. Insulin Stacking versus Therapeutic

Accumulation: Understanding the Differences.

ENDOCRINE PRACTICE Vol 20 No. 1 January 2014

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Insulin “Stacking”

• Long-acting insulin must “accumulate” to steady-state to assist with achieving minimal fluctuation in glucose levels

• This is different than acute over-accumulation of rapid-acting insulin when a corrective dose is administered before the previous dose has been eliminated

• Basal insulins with a half-life of >24 hours should not result in stacking, as long as dosing and adjustment is done appropriately

Heise T, Meneghini LF. Insulin Stacking versus Therapeutic

Accumulation: Understanding the Differences.

ENDOCRINE PRACTICE Vol 20 No. 1 January 2014

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Pearls

• Have your patient demonstrate use of vial/syringe/pen/inhaler• Priming, injection technique/site, timing

• Dosing considerations• More than one injection needed?

• Storage • Room temperature stability varies per product

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Summary

Insulin therapy should not be delayed when indicated for a patient with type 2 diabetes.

Concentrated insulin products may pose lower hypoglycemic risk and improve administration discomfort.

Combination basal insulin + GLP-1 agonist products may be considered as first-line injectable therapy for a patient with type 2 diabetes.

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Questions/Comments?