New Analog Insulins … Are They Worth It ??

Helen L. Baron, MD Director of Diabetes Services – Eisenhower Medical Center Eisenhower Endocrinology Rancho Mirage, CA Disclosures

Employer: • Eisenhower Medical Associates Director of Diabetes Services – Eisenhower Medical Center Clinical Endocrinologist

Financial Interests: • Consultant – AstraZeneca, Bayer, Janssen, Novo Nordisk, Sanofi • Speakers Bureau – AstraZeneca, Novo Nordisk, Sanofi Presentation Overview

• Describe the unique characteristics of novel insulin products that have recently entered the market: • Basal insulins: Basaglar®, Toujeo®, Tresiba® • Bolus insulins: Humalog® U-200, Fiasp® • Inhaled insulin: Afrezza® (insulin human) Inhalation Powder • Insulin devices: Humulin-R® U-500 Kwikpen® and U-500 syringe • Combination insulins: Ryzodeg®, Soliqua®, Xultophy® • Discussion regarding the potential benefits that may be obtained from utilization of these novel insulin products.

Goals of analog design. hypos, hypoglycemia.

Eberhard Standl, and David R. Owen Dia Care 2016;39:S172-S179

Hirsch IB, et al. Available at: http://diabetesmanager.pbworks.com/w/page/17680318/The%20Management%20of%20Type%201%20Diabetes%20. Accessed 11/28/2016. Opportunities to Improve Insulin

More Faster onset Longer duration Less variability concentrated

Less Improved More convenient hypoglycemia administration Lower cost /fewer injections and weight gain safety Insulin Update

Investor.lilly.com

drugs.re-publish.com

Xultophy10036pro.com

Soliqua100-33.com

Humalog.com

Healthline.com EMPR.com New(er) Insulin Products

• Basal (long-acting) • Tresiba® (insulin degludec U-100 & U-200) • Toujeo® (insulin glargine U-300) • Basaglar® (insulin glargine U-100) • Bolus (rapid; mealtime) • Humalog® U-200 (insulin lispro U-200) • Fiasp® (insulin aspart U-100) • Other • Humulin R® U-500 Kwikpen® and syringe • Afrezza® (insulin human) Inhalation Powder • Combination Products • Soliqua® (insulin glargine U-100 / lixisenatide) • Xultophy® (insulin degludec U-100 / liraglutide) • Ryzodeg® (insulin degludec U-100 / insulin aspart U-100) Basal Insulins Currently Available

Insulin Follow-on Insulin Insulin Insulin NPH Insulin Glargine Insulin Glargine Detemir Degludec U-100 Glargine U-300 Human; Analog; long- Analog; long- Analog; long- Analog; long- Analog; long- Insulin type intermediate- acting acting acting acting acting acting Onset 2-4 hours 1.3 hours 1.3 hours 6 hours 1 hour No No Peak 4-10 hours pronounced Relatively flat pronounced Flat Flat peak peak Effective Up to 24 Up to 24 Up to 24 10-16 hours ≤36 hours ≤42 hours duration hours hours hours Half-life Unknown* 14 hours 5-7 hours ~23 hours ~25 hours Time to Unknown 2 days 2 days 4 days 2-3 days steady-state

Porcellati F, et al. Diabetes Care. 2007;30(10):2447-2452. Lucidi P, et al. Diabetes Care. 2011;34(6):1312-1314. Niswender K. Clin Diabetes. 2009;27:60-68. Novolin N [package insert]. Indianapolis, IN: Eli Lilly & Co.; January 2017. Lantus [package insert] Bridgewater, NJ: sanofi-aventis US LLC; August 2015. Basaglar [package insert]. Indianapolis, IN: Eli Lilly & Co.; April 2017. Levemir [package insert]. Princeton, NJ: Novo Nordisk US; February 2015. Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; October 2015. Becker RH, et al. Diabetes Care. 2015;38:637-643. Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; December 2016. Heise T, et al. Diabetes Obes Metab. 2012;14(10):944-950. Tresiba® (insulin degludec)

• “Ultra-long” 42+ hour duration of action • Available in 100 units/mL or 200 units/mL • No PK difference between U-100 and U-200 • Versus Levemir® or Lantus®: • Similar A1C reduction • ↓ within-day and within-subject variability

• ↓ hypoglycemia and ↓nocturnal hypoglycemia https://www.dovepress.com/cr_data/article_fulltext/s59000/59566/img/fig2.jpg

Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874 Johnson et al. J Diabet Sci Tech 2016; DOI: 10.1177/1932296816680830. Woo VC,. Clinical Therapeutics 2017; ePub ahead of print. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Stailey M, et al. Consult Pharm 2017;32:42-46. http://online.lexi.com. Accessed 11/27/2016. Heller, et al. Diabet. Med. 2016;33:478-487. Insulin Degludec: BEGIN Program

Philis-Tsimikas. J Fam Pract. 2016;65(10 Suppl):S14-S22. Insulin Degludec vs Insulin Glargine U-100: Glycemic Efficacy

HbA1c (%) Fasting Plasma Glucose (mg/dL) 8.5 180 52-week 52-week 170 52-week 52-week Core Trial Extension Phase Core Trial Extension Phase 8 160 150

7.5 140 130

HbA1c (%) HbA1c 120 7 110 100 6.5 90 0 15 30 45 60 75 90

Fasting Plasma Glucose (mg/dL)Glucose Plasma Fasting 0 15 30 45 60 75 90 Time (weeks) Time (weeks) Insulin Degludec Insulin Glargine U-100 N=725

Rodbard HW, et al. Diabet Med. 2013;30:1298-1304. Insulin Degludec vs Insulin Glargine U-100: Other Outcomes

3 2.7 kg 2.5 2.4 kg

1.5

1 0.63 units/kg 0.63 units/kg 0.5

0 Weight Gain (kg) Total Daily Insulin Dose (units/kg) Insulin Degludec Insulin Glargine U-100 N=1023

Rodbard HW, et al. Diabet Med. 2013;30:1298-1304. Insulin Degludec vs Insulin Glargine U-100 Cumulative hypoglycemic events (confirmed <56 mg/dL)

2.0 18% lower Glargine U-100 1.6 with degludec Anytime P=0.11 events/patient 1.2 0.8 Degludec

0.4

12 24 36 48 Weeks of treatment

0.40 Glargine U-100 36% lower 0.32 Nocturnal with degludec events/patient 0.40 P=0.04 0.60 Degludec

0.80 1023 insulin-naïve Weeks of treatment patients with T2DM 12 24 36 48

Zinman B, et al. Diabetes Care. 2012;35:2464-2471. Cardiovascular Safety of Insulin Degludec: DEVOTE Study

• 7637 people with T2DM at high • At baseline CV risk were randomized to – Age (mean): 65.0 y standard care plus – HbA1c (mean): 8.4% – Insulin degludec or – Duration of T2DM (mean): 16.4 y – Insulin glargine U-100 – 85.2% established CVD or moderate – Target: FPG 71 to 90 mg/dL CKD • – 83.9% receiving insulin Follow-up ~2 years • 54.8% basal-bolus

Marso SP, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615692. Cardiovascular Safety of Insulin Degludec: DEVOTE Study (cont)

Outcome Hazard 95% CI Ratio Primary composite1 0.91 0.78-1.06 Degludec non-Inferior to glargine for major CV events Expanded composite2 0.92 0.80-1.05 All-cause death 0.91 0.76-1.11 Non-CV death 0.84 0.60-1.16 CV death 0.96 0.76-1.21 Nonfatal MI 0.85 0.68-1.06 Nonfatal stroke 0.90 0.65-1.23 UA → hospitalization 0.95 0.68-1.31 Severe hypoglycemia 0.60 0.48-0.76 Nocturnal severe hypoglycemia 0.47 0.31-0.73

1CV death, nonfatal MI, nonfatal stroke 2CV death, nonfatal MI, nonfatal stroke, unstable angina leading to hospitalization

Marso SP, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615692. Flexible Dosing with Degludec

• 26-wk randomized, open- Change from baseline* to 26 Degludec Glargine label, treat-to-target trial weeks (N=687) Flexible Fixed

• Glargine once daily at same HbA1c (%) -1.28 -1.07 -1.26 time each day FPG (mg/dL) -58 -54 -50 • Degludec once daily – Fixed: same time each day Confirmed or severe 3.6 3.6 3.5 – Flexible: schedule to hypoglycemia create 8-40 hour dosing (events/patient-year) intervals Confirmed or severe 0.6 0.6 0.8 nocturnal hypoglycemia (events/patient-year) *HbA1c 8.4-8.5% at baseline

Meneghini L, et al. Diabetes Care. 2013;36:858-864. Tresiba® (insulin degludec)

Insulin degludec “Flex” dosing

Insulin degludec can be administered anytime of the day as long as it is more at least 8 hours since previous dose and no more than 40 hours from last dose

Meneghini L, et al. Diabetes Care 2013;36:858-864. Tresiba® (insulin degludec)

• Degludec pen: https://cdn.diabetesdaily.com/wp • U-100 dialed in 1 unit increments up to 80 units max

• U-200 dialed in 2 unit increments up to 160 units max -

• Dose conversion: content/blogs.dir/21/files/2015/09/Screen • 1:1 dose conversion from Levemir®, Lantus®

• 1:1 dose conversion between deguldec U-100 and U-200

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Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed 11/27/2016. Toujeo® (insulin glargine U-300)

• Concentrated insulin glargine (300 units/mL) -

• Less volume administered

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• Forms smaller depot when injected

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• Smaller depot alters kinetics, prolongs duration

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Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874 Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available Stailey M, et al. Consult Pharm 2017;32:42-46. at: http://online.lexi.com. Accessed 11/27/2016. Johnson et al. J Diabet Sci Tech 2016; DOI: 10.1177/1932296816680830. Owens DR. Expert Opin Drug Metab Toxicol 2016;12(8):977-987. Toujeo Prescribing Information Toujeo® (insulin glargine U-300)

• 30+ hour duration of action

• Versus Lantus®: • Similar A1C reduction • ↓ within-day and within-subject variability • ↓ hypoglycemia and nocturnal hypoglycemia

• Slightly less weight gain (0.2-0.7 kg) https://www.medicines.org.uk/emc/images/spc~30586~2~127837.GIF

Anderson JE. J Fam Pract. 2016;65(10 Suppl):S23-S28. Insulin Glargine U-300 vs U-100: Glycemic Efficacy*

HbA1c Fasting Plasma Glucose 8.4 170 Glargine U-300 8.2 160 Glargine U-100 8 150

7.8 140

7.6 130 HbA1c (%) HbA1c 7.4 120

7.2 110

7 (mg/dL) Glucose Plasma Fasting 100 0 W12 M6 0 W12 M6 Time Time * Meta-Analysis of EDITION 1, 2, 3; N=2496

Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):859-867 Insulin Glargine U-300 vs U-100: Other Outcomes*

Weight Change (kg) Insulin Dose (units/kg/day) 0.8 1 0.9 0.6 0.8 0.7 0.4 0.6 0.5 0.2 0.4

Weight Change (kg) Change Weight 0.3

0 (units/kg/day)Dose Insulin 0.2 Glargine U-300 Glargine U-100 0.1 -0.2 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time (weeks) Time (weeks) * Meta-Analysis of EDITION 1, 2, 3; N=2496

Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):859-867 Insulin Glargine U-300 vs U-100: Hypoglycemia

Cumulative mean number of nocturnal severe or confirmed (≤70 mg/dL) events/participant

48% lower Glargine U-100 with U-300 P=0.001

Patients with Difference T2DM using Glargine U-300 mostly basal insulin + oral agent(s) up to 12 wk (N=811)

Yki-Jarvinen H, et al. Diabetes Care. 2014;37:3235-3243. Cardiovascular Safety of Insulin Glargine U-100*: ORIGIN Study

Composite of MI, Stroke, CV Death Composite of Revascularization or Heart Failure Hospitalization

*12,537 people with increased CV risk plus impaired fasting glucose, impaired glucose tolerance, or T2DM were randomized to insulin glargine U-100 vs standard care. Mean follow-up was 6.2 years.

ORIGIN Investigators. N Engl J Med. 2012;367():319-328. Flexible Dosing with Glargine U-300

• Sub-study of pooled data from Change from baseline to Flexible Fixed EDITION 1 and 2 (N=194) 3 months • Glargine U-300 once daily for Daily basal insulin dose (units/kg) 0.03 0.03 3 months HbA1c* (%) 0.05 0.00 – Fixed: same time each day FPG (mg/dL) 6.6 3.9 – Flexible: same time each day ± 3h Confirmed or severe hypoglycemia 10.44 14.81 (events/patient-year) *HbA1c 7.30% at baseline Confirmed or severe nocturnal 2.30 1.95 64% of fixed-dose and 15% of flexible-dose hypoglycemia (events/patient-year) participants reported all intervals within 23- 25h range

Riddle MC, et al. Diabetes Technol Ther. 2016;18(4):252-257. Toujeo® (insulin glargine U-300)

• Toujeo® pen: • 450 units per pen • Adjust in 1 unit increments up to max dose per injection only 80 units • Dose conversion: • From Lantus® or Levemir® to Toujeo®: 1:1 dose conversion • From BID NPH to Toujeo®: 20% dose reduction • From Toujeo® to Lantus® or Levemir®: 20% dose reduction

https://www.toujeopro.com Toujeo Prescribing Information Hypoglycemia with Degludec and Glargine U-300 vs Glargine U-100

Meta-analyses of phase 3 clinical studies in T2DM Degludec1 Glargine U-3002 # Studies 5 3 # Participants 3372 2496 Definition of confirmed hypoglycemia <56 mg/dL and severe ≤70 mg/dL or severe

Anytime events 0.83 (0.74-0.94) 0.86 (0.77-0.97) [Rate ratio vs glargine U-100 (95% CI)]

Nocturnal events 0.68 (0.57-0.82) 0.69 (0.57-0.84) [Rate ratio vs glargine U-100 (95% CI)] With both insulins, ~15% fewer overall and ~30% fewer nocturnal events vs glargine U-100

1. Ratner RE, et al. Diabetes Obes Metab. 2013;15(2):175-184. 2. Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):859-867. Basaglar® (insulin glargine U-100)

• First “follow-on” insulin • Lantus® patent recently expired • Biologic drugs: different FDA regulations, no “generics” • Basaglar®: “highly similar” to Lantus® • Compared with Lantus®: • ≈ Equivalent PK/PD • Non-inferior efficacy and safety

• Clinical trials too small/short to identify rare safety events https://www.basaglar.com/hcp/about-basaglar

Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874. Rosenstock J, et al. Diabetes Obes Metab 2015;17(8):734-741. Pardos CL, et al. Med Clin (Barc) 2016;147(7):297-299. Basaglar® [package insert]. Indianapolis, IN. Eli Lilly and Co.; 2016. Grant JS, et al. Home Healthc Now 2016;34(6):336-337. Blevins TC, et al. Diabetes Obes Metab 2015;17(8):726-733. Linnebjerg H, et al. Diabetes Care 2015;38(12):2226-33. Efficacy and Safety of Follow-on Glargine U-100 (Basaglar®) vs Glargine U-100 (Lantus®) in Insulin-naïve Patients with T2DM1 22.9 21.6 25 EPY Insulin Follow-on EPY Endpoint Hypoglycemia2 Glargine Insulin 20 (N=455) U-100 Glargine U-100 15

7.6 HbA1c (%), change 10 6.7 -1.54 -1.48 EPY from baseline EPY 5 Insulin dose n=2 n=2 0.44 0.42 (units/kg-day) 0 Overall Nocturnal Severe Weight gain (kg) 2.2 2.0 hypoglycemia hypoglycemia Insulin Glargine U-100 Follow-on Insulin Glargine U-100 1Mean age = 58 years; duration of diabetes = 11 2 years; Baseline: HbA1c = 8.4% to 8.5%, weight = 89-91 Overall (plasma glucose ≤70 mg/dL or sign or symptom kg, BMI = 32 kg/m2 of hypoglycemia) and nocturnal hypoglycemia (between bedtime and waking) are expressed as events/patient-year (EPY). Severe hypoglycemia Rosenstock J, et al. Diabetes Obes Metab. 2015;17:734-741. (requiring assistance, baseline to month 6) is number of patients. Basaglar® (insulin glargine U-100)

• Equivalent dosing to Lantus® • Pen contains 300 units • Adjust dose in 1 unit increments; max 80 units per injection • Dose conversion: • If switching from Lantus®, Levemir® or Tresiba®: no dose adjustment • If switching from NPH or Toujeo®: 20% dose reduction

https://cdn.diabetesdaily.com/wp-content/blogs.dir/21/files/2016/09/kwikpen-DES.jpg

Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874. Blevins TC, et al. Diabetes Obes Metab 2015;17(8):726-733. Grant JS, et al. Home Healthc Now 2016;34(6):336-337. Basaglar® [package insert]. Indianapolis, IN. Eli Lilly and Co.; 2016. Rosenstock J, et al. Diabetes Obes Metab 2015;17(8):734-741. Current and Emerging Prandial Insulins

Prandial

Analogs Human insulins (short- Analogs (ultra-rapid- acting) (rapid-acting) acting)

Regular human insulin Technosphere Lispro Aspart Glulisine (RHI) inhaled insulin

Faster-acting U-100 RHI U-100 lispro aspart

U-500 RHI U-200 lispro

Follow-on lispro a Not currently approved by the US FDA. Ultra-rapid lisproa

US Food and Drug Administration. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Humalog U-200® (insulin lispro U-200)

• First concentrated ultra-rapid insulin • PK/PD equivalent to Humalog U-100 • Pen: • Contains twice as much insulin • Dosed in 1 unit increments • Single dose still capped at 60 units • 1:1 dose conversion with other bolus insulins

Johnson et al. J Diabet Sci Tech 2016; DOI: 10.1177/1932296816680830. Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874. Eli Lilly and Co. Prescribing Humalog U 200 to Patients. Available at: http://www.humalog.com/humalog-u200-hcp.aspx. Accessed 11/27/2016. U-200 Lispro*

Pharmacokinetics Pharmacodynamics

80 LISPRO 0.2 U/kg (n = 10) 250 LISPRO 0.2 U/kg (n = 10) RHI (n = 10); 70 RHI (n = 10); mean dose, 15.4 U 200 mean dose, 15.4 U 60

50 150 40 30 100 20 50

Serum Free Insulin Free Serum 10

Concentration, mU/L Concentration, Blood Glucose, mg/dL Glucose, Blood 0 0 0 60 120 180 240 300 360 420 480 0 60 120 180 240 300 360 420 480 Time, min Time, min

Potentially offers the advantage of a smaller injection volume for patients with high prandial insulin requirements *PK/PD data generated from a study of 10 patients with T1DM.

Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; January 2017. Insulin Lispro U-200

• Same dose as U-100, but half the volume • Hypokalemia- monitor at-risk persons • Fluid retention/Heart failure with concomitant TZD • Most common adverse events – Hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash

Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; January 2017. Newer Aspart (Fiasp®) – ONSET studies

Similar A1c reduction with better 1-hr PPG reduction with newer aspart compared to aspart Prandial insulin timing with meals

Minutes Prescribing information Technosphere Inhaled Human Insulin

• Technosphere insulin is a dry powder pulmonary formulation of insulin synthesized using Technosphere technology, for the treatment of Type 1 and Type 2 diabetes. • It consists of insulin loaded onto fumaryl diketopiperazine (FDKP) microparticles, and exhibits rapid absorption with high bioavailability, approximating the 1st phase insulin spike seen at the beginning of a meal (short acting insulin). • Limitations of use – Not for diabetic ketoacidosis, persons who smoke • Contraindicated in chronic lung disease – Assess lung function prior to and during treatment • Hypokalemia – Monitor at-risk persons • Fluid retention/Heart failure with concomitant TZD • Most common adverse events – Hypoglycemia, cough, throat pain/irritation

Afrezza [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; January 2016 Inhaled Technosphere Insulin in T2DM

5.0 Inhaled TI (48 units) SC RHI (24 units) 4.0

3.0

2.0 mg/kg/min

1.0 Glucose Infusion Rate, Infusion Glucose

0.0 0 60 120 180 240 300 360 420 480 540 Time, min

• Duration of action for inhaled insulin is much shorter than for RHI1 • Almost complete PPG suppression has been observed in a double-blind, placebo- controlled trial in insulin-naive patients with T2DM using OADs2

1. Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212. 2. Rosenstock J, et al. Diabetes Care. 2015; 38(12):2274-2281. Regular Human Insulin U-500

• Limitations of use – Use in adults/children requiring >200 units insulin/day – Safety/efficacy in combination with other insulins has not been determined • If using vial/syringe, use only U-500 syringe • Hypokalemia- monitor at-risk persons • Fluid retention/Heart failure with concomitant TZD • Most common adverse events – Hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash

Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly and Company; March 2017. Humulin-R® U-500 Kwikpen®

• U-500 insulin now available in a pen! • Same drug, less risk of confusion • Pen contains 1500 units of insulin • Dosed in 5 unit increments up to max 300 units per injection • Crucial to ensure patient understanding of dose prior to switching

https://diatribe.org/sites/default/files/images/kwikpen.png

Johnson et al. J Diabet Sci Tech 2016; DOI: 10.1177/1932296816680830. Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874. Humulin-R U-500 Prescribing Information U-500 Insulin Syringe

U-500 insulin syringe also now available!

https://www.drugs.com/pro/humulin-r-u-500.html

http://www.humulin.com/delivery-options.aspx

Humulin-R U-500 Prescribing Information Combination Products

• Two new basal insulin/GLP-1 combo pens • Soliqua® [LixiLan (insulin glargine and lixisenatide)] • Xultophy® [IDegLira (insulin degludec and liraglutide)]

• Insulin / GLP-1 combinations: • Vs. Basal insulin: ↑ efficacy, ↓ weight gain, ↓ hypoglycemia, ↓ post-meal BG • Vs. GLP-1: ↑ efficacy, ↓ GI adverse effects

http://www.pharmasay.com/wp-content/uploads/2016/12/Soliqua-glargine-lixisenatide.jpg https://www.xultophy10036pro.com/content/dam/novonordisk/xultophy10036pro/Now_Approved_Images/xultophy-pen.png

Greig SL, et al. Drugs 2015;75:1523-1534. Rosenstock J, et al. Diabetes Care 2016;39:2026-2035. Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874. Aroda VA, et al. Diabetes Care 2016;39:1972-1980. Rosenstock J, et al. Diabetes Care 2016;39:1579-1586. Combination Products

• Soliqua® (insulin glargine and lixisenatide): • Dosed once daily without regard to food • Each dosing increment contains 1 unit of glargine and 0.33 mg of lixisenatide • Recommended starting doses: • Taking <30 units basal insulin or currently treated with lixisenatide: 15 units glargine / 5 mcg lixisenatide • Taking 30-60 units basal insulin: 30 units / 10 mcg • Max dose: 60 units / 20 mcg

Soliqua® Prescribing information Combination Products

• Xultophy® (insulin degludec and liraglutide) • Dosed once daily without regard to food • Each dosing increment contains 1 unit of degludec and 0.036 mg of liraglutide • Recommended starting dose: 16 units degludec / 0.58 mg liraglutide • Max dose: 50 units / 1.8 mg

Xultophy Prescribing Information Combination Products

• Basal insulin / bolus insulin combo pen • Ryzodeg® (insulin degludec / insulin aspart 70/30) • FDA approved but expected market arrival unknown • First pre-mixed insulin containing ≥24-hour basal insulin Atkin S, et al. Ther Adv Chronic Dis 2015;6(6):375-388. • Available in pen containing 70% degludec and 30% aspart • Dosed once or twice daily • Comparisons:

• Vs. basal insulin: Same number of injections, ↑ A1c lowering

• Vs. Novolog® Mix 70/30: similar efficacy, ↓ hypoglycemia

Atkin S, et al. Ther Adv Chronic Dis 2015;6(6):375-388.

Ryzodeg Prescribing Information Atkin S, et al. Ther Adv Chronic Dis 2015;6(6):375-388. Segal AR, et al. Endocrinol Metab Clin N Am 2016;45:845-874. Franek E, et al. Diabet. Med. 2016;33:497-505. Summary Table 1 – New Insulin Products

Product Concentration Volume/pen Units/pen Max single dose Stability at room Dosing increment Duration Minimum titration temp frequency

BASAL INSULIN

INSULIN GLARGINE Basaglar® 100 units/mL 3 mL/pen 300 units/pen 80 units 4 weeks 1 unit/click ~24 hours 3-4 days Toujeo® 300 units/mL 1.5 mL/pen 450 units/pen 80 units 6 weeks 1 unit/click ~30 hours 3-4 days

INSULIN DEGLUDEC Tresiba® U-100 100 units/mL 3 mL/pen 300 units/pen 80 units 8 weeks 1 unit/click 42 hours 3-4 days Tresiba® U-200 200 units/mL 3 mL/pen 600 units/pen 160 units 8 weeks 2 units/click 42 hours 3-4 days

BOLUS INSULIN

INSULIN LISPRO Humalog® U-200 200 units/mL 3 mL/pen 600 units/pen 60 units 4 weeks 1 unit/click ≤5 hours Individualize per KwikPen® patient

OTHER INSULIN

REGULAR INSULIN Humulin®R U-500 500 units/mL 3 mL/pen 1500 units/pen 300 units 4 weeks 5 units/click ~13-24 hours Individualize per KwikPen® patient

Johnson et al. J Diabet Sci Tech 2016; DOI: 10.1177/1932296816680830. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed March 2017. Basaglar, Toujeo, Tresiba, Humalog, and Humulin R U-500 Prescribing Information Summary Table 2 – Dose Conversions

DOSE CONVERSIONS TO NEW INSULIN PRODUCTS Product Concentration From glargine U-100 From detemir U-100 From twice daily NPH From other rapid For U-500 convert from acting total daily insulin dose

BASAL INSULIN

INSULIN GLARGINE Basaglar® 100 units/mL 1:1 1:1 80% of NPH dose n/a n/a Toujeo® 300 units/mL 1:1 1:1 80% of NPH dose n/a n/a *often requires higher dose *often requires higher dose *often requires higher dose

INSULIN DEGLUDEC Tresiba® 100 units/mL 1:1 1:1 1:1 n/a n/a Tresiba® 200 units/mL 1:1 1:1 1:1 n/a n/a

BOLUS INSULIN

INSULIN LISPRO Humalog® U-200 200 units/mL n/a n/a n/a 1:1 n/a KwikPen®

OTHER INSULIN

REGULAR INSULIN Humulin®R U-500 500 units/mL n/a n/a n/a n/a A1C <8: 80% of U-100 dose KwikPen® A1C >8: 100% of U-100 dose

Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed March 2017 Basaglar, Toujeo, Tresiba, Humalog, and Humulin R U-500 Prescribing Information Summary Table 3 – Key Considerations

KEY CONSIDERATIONS Product Improved Safety Less hypoglycemia Less nocturnal Less weight gain Flexible dosing Lower cost More concentrated hypoglycemia

BASAL INSULIN

INSULIN GLARGINE Basaglar® ✓

Toujeo® ✓ ✓ ✓ ? ✓

INSULIN DEGLUDEC Tresiba® U-100 ✓ ✓ ✓ Tresiba® U-200 ✓ ✓ ✓ ✓

BOLUS INSULIN

INSULIN LISPRO Humalog® U-200 KwikPen® ✓

OTHER INSULIN

REGULAR INSULIN Humulin®R U-500 KwikPen® ✓ ✓

Johnson et al. J Diabet Sci Tech 2016 Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed March 2017 Summary Table 4 - Combination Insulin Products

Product Drug components Daily dose range Stability at Starting dose Maximum dose Dosing titration Pens/box (amount/mL) room temp

BASAL INSULIN + GLUCAGON LIKE PEPTIDE-1 (GLP-1) AGONIST

INSULIN GLARGINE + LIXISENATIDE Soliqua® Insulin glargine 15 to 60 units insulin 2 weeks Basal insulin <30 units/day: 60 units daily Titrate by 2-4 units 5 pens/box 100/33 (100 units/mL) 15 units subQ daily (60 units & 20 mcg) every week (3 mL/pen) Pen dials 1 unit/click Lixisenatide Basal insulin ≥ 30 units/day: (33 mcg/mL) 30 units subQ daily

INSULIN DEGLUDEC + LIRAGLUTIDE Xultophy® Insulin degludec 10 to 50 units insulin 3 weeks Starting dose: 50 units daily Titrate by 2 units 5 pens/box 100/3.6 (100 units/mL) 16 units subQ daily (50 units & 1.8 mg) every 3-4 days (3 mL/pen) Pen dials 1 unit/click Liraglutide (3.6 mg/mL)

BASAL INSULIN + BOLUS INSULIN

INSULIN DEGLUDEC + INSULIN ASPART Ryzodeg® Insulin degludec No max dose 4 weeks Insulin naïve: 10 units daily No maximum dose Titrate up or down 5 pens/box 70/30 (70 units/mL) every 3-4 days (3 mL/pen) Pen dials 1 unit/click Basal only regimen: start at previous basal Max 80 units per Insulin aspart dose with a main meal single injection (30 units/mL) Basal + mealtime boluses: start at previous basal dose with a main meal

Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed March 2017 Xultophy Prescribing Information Soliqua Prescribing Information. Ryzodeg Prescribing Information Dr. Peter Singer’s 3 Laws of Medicine:

Ability Affinity Availability Basal Insulin

Drug name Insulin type Lowest GoodRx price Quantity Humulin N intermediate-acting human $99.38 (1) 10 ml vial, 100 units/ml

Novolin N intermediate-acting human $26.79 (1) 10 ml vial, 100 units/ml

Levemir long-acting analog $465.98 (5) 3 ml pens, 100 units/ml

Lantus long-acting analog $286.27 (5) 3 ml pens, 100 units/ml

Basaglar long-acting analog $248.59 (5) 3 ml pens, 100 units/ml

Toujeo highly concentrated long- $308.16 (3) 1.5 ml pens, 300 units/ml acting analog

Tresiba ultra long-acting analog $612.41 (3) 3 ml pens, 200 units/ml Bolus Insulin

Drug name Insulin type Lowest GoodRx price Quantity Humulin R short-acting human $99.38 (1) 10 ml vial, 100 units/ml

Novolin R short-acting human $28.38 (1) 10 ml vial, 100 units/ml

Humalog rapid-acting analog $177.87 (1) 10 ml vial, 100 units/ml

Novolog rapid-acting analog $561.65 (5) 3 ml pens, 100 units/ml

Afrezza rapid-acting analog $337.21 90 cartridges, 4 units each (inhaled)

Apidra rapid-acting analog $206.62 (1) 10 ml vial, 100 units/ml

Fiasp rapid-acting analog $585.97 (1) 10 ml vial, 100 units/ml Co-Formulations of Basal Insulin / GLP1-RAs

Drug name Medication type Lowest GoodRx price Quantity Soliqua 100/33 long-acting insulin analog $636.13 (2) 3 ml pens, 20 mcg + Adlyxin (for type 2 only)

Xultophy long-acting insulin analog $1,037.88 (5) 3 ml pens, 100 units/ml + Victoza (for type 2 only) Drug Discount Programs

Product Program details

BASAL INSULIN

INSULIN GLARGINE

Basaglar® Discount cards are available • Can reduce copay to as little as $5/month with a maximum savings of $150/monthly prescription ; valid for 24 fills (each fill is a 30-day supply) Toujeo® Discount cards are available • Can reduce copay to as little as $10/month; valid for up to 12 months • Maximum savings of $500/pack (commercial insurance) or $200/pack (no commercial insurance); valid for up to three packs/prescription

INSULIN DEGLUDEC Tresiba® Discount cards are available • Can reduce copay to as little as $15/month with a maximum of $500/monthly prescription; valid for up to 24 months

BOLUS INSULIN

INSULIN LISPRO

Humalog® U-200 KwikPen® Discount cards are available • Can reduce copay to as little as $25/month with a maximum savings of $100/monthly prescription; valid for 24 prescriptions

OTHER INSULIN

REGULAR INSULIN Humulin®R U-500 KwikPen® Discount cards are available • Can reduce copay to as little as $25/month; valid for 12 fills (maximum of 7 KwikPen packs/prescription fill)

www.basaglar.com; www.toujeo.com; www.tresiba.com; www.humulin.com; www.humalog.com Advantages of Basal Analogs Over Human NPH Insulin

• Longer-acting (up to 24 hours or more) • Supports once-daily administration for most patients • Less day to day variability • Flatter time action profile with less peak in activity • Lower risk of nocturnal and overall hypoglycemia • Less weight gain (insulin detemir / U300 Insulin Glargine) Advantages of Rapid-Acting Analogs Over RHI

• More rapid onset of action • Facilitates more convenient mealtime administration • Offers potential for better postprandial glucose control • More rapid return to basal insulin levels • Potentially less hypoglycemia • Greater predictability Opportunities to Improve Insulin

More concentrated Faster onset Longer duration Less variable PK Toujeo, Tresiba, Afrezza, Fiasp Toujeo, Tresiba Toujeo, Tresiba Humalog U-200

More convenient / Less hypoglycemia Improve fewer injections and weight gain administration safety Lower cost Toujeo, Tresiba, Toujeo, Tresiba, U-500 Kwikpen and Basaglar Ryzodeg, Xultophy, Xultophy, Soliqua Syringe Soliqua, Afrezza Conclusion

• Many new insulin formulations: • New insulin concentrations offer alternatives to improve tolerability, adherence, and safety • Improve on several concerns of previous insulins • Hypoglycemia / Nocturnal hypoglycemia • Less glycemic variability • Weight gain • Convenience / fewer injections • “Follow-on” insulins and increased competition may reduce costs • All health care professionals need to be aware of the safety risks than can occur due to prescribing and dispensing of concentrated insulins • Patient education is imperative • Cost may limit use  Cost of therapy needs to be discussed and readdressed at each visit Thank you for your kind attention!

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