5/16/2018

Insulin Update: New and Emerging

Joshua J. Neumiller, PharmD, CDE, FASCP Vice Chair & Associate Professor, Department of Pharmacotherapy Washington State University Spokane, WA

Disclosures to Participants

Conflicts of Interest and Financial Relationship Disclosures:

Presenter: Joshua J. Neumiller, PharmD, CDE, FASCP • ADA Editorial Board/Committee Membership: • Editor for the ADA journal Spectrum • Member of ADA Professional Practice Committee (PPC)

Learning Objectives This presentation will cover the following learning objectives: 1. Review the pharmacokinetic and clinical characteristics of currently available products; 2. Discuss considerations for use of newer, ultra‐long acting basal insulin products; and 3. Discuss the potential role of fixed‐dose insulin/GLP‐1 receptor products in the management of .

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ADA 2018: Summary of Glycemic Recommendations

Glycemic Targets: Standards of Medical Care in Diabetes ‐ 2018. Diabetes Care 2018; 41 (Suppl. 1): S55‐S64.

Determining an Appropriate A1C Target more A1C less Patient/Disease Features stringent 7% stringent Risk of /drug adverse effects low high Disease Duration newly diagnosed long-standing Life expectancy long short Important comorbidities absentFew/mild severe Established vascular complications absentFew/mild severe Patient attitude & expected highly motivated, adherent, excellent less motivated, nonadherent, poor treatment efforts self-care capabilities self-care capabilities Resources & support system readily available limited Glycemic Targets: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S55-S64

Antihyperglycemic Therapy in Adults with T2DM

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

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See page S77 in:

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

Antihyperglycemic Therapy in Adults with T2DM

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

Pharmacokinetic Profile of Currently Available Single Insulin Products

Rapid (aspart, lispro, glulisine, inhaled human insulin) Short (regular U‐100) Mixed short/intermediate (regular U‐500) Levels

Intermediate (NPH) Long (detemir) Long (U‐100 glargine) Ultra‐long (degludec) Insulin

Ultra‐long (glargine U‐300) Plasma

021418224 6 8 10 1216202426 28 30 32 34 36 Time (hr)

Hirsch IB. N Engl J Med. 2005; 352:174‐83. Flood TM. J Fam Pract. 2007; 56(suppl 1):S1‐S12. Becker RH et al. Diabetes Care. 2015; 38:637‐43.

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Insulin PK/PD Comparison Time to Onset Duration of Insulin Time to Peak Action (hr) of Action (hr) Action (hr) Lispro (U‐100* , U‐200) within 0.25 0.5‐1.5 4‐6 Aspart† within 0.25 0.5‐1.5 4‐6 Glulisine within 0.25 0.5‐24‐6 Insulin human (inhaled) within 0.25 1 3 Insulin human regular (U‐100) 0.5 3 8 Insulin human regular (U‐500) 0.25 4‐813‐24 *Follow‐on products Human insulin isophane (NPH) 2‐44‐10 12‐18 available Detemir 3‐46‐8 (though relatively flat) Up to 24 Glargine (U‐100)* 2‐4flat20‐24 † is Glargine (U‐300) 6flatup to 36 available in 2 Degludec (U‐100, U‐200) 1flat>42formulations; Fiasp Regular U‐100/NPH 70/30 within 0.5 3 12‐18 has a relatively fast Lispro mix 50/50 within 0.25 0.5‐1.5 Up to 24 onset of action Lispro mix 75/25 within 0.25 0.5‐1.5 18‐24 Aspart mix 70/30 within 0.25 1.5‐2.5 Up to 24 Degludec/aspart mix 70/30 within 0.25 1‐2.5 >24 Patient‐specific onset, peak, and duration may vary from times listed in table. Peak and duration are dose‐dependent with shorter durations of action seen for smaller doses and longer durations of action with larger doses. Hirsch IB. N Engl J Med. 2005; 352:174‐83; Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16‐38; Dansinger M. Types of insulin. June 21, 2016. www.webmd.com/diabetes/guide/diabetes‐types‐insulin (accessed 2016 Sep 29); Bennett JA. Insulin chart. July 17, 2015. www.dlife.com/diabetes/insulin/about_insulin/insulin‐chart (accessed 2016 Sep 29); Individual product prescribing information.

Basal Insulin Initiation in T2DM: • Start with 10 units/day or 0.1‐ 0.2 units/kg/day • Adjust 10‐15% or 2‐4 units once or twice weekly to reach FBG target • Assess and adjust for hypoglycemia

American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment: Approaches to glycemic treatment. Diabetes Care Standards2017; 40 (S uppl.of Medical 1): S64-S74 Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

U‐300 : Determining Starting Dose (and Dose Conversion) in T2DM

Prior Treatment: Start with: Once‐daily basal insulin 1:1 conversion* Twice‐daily NPH 80% of total daily NPH dose No current basal insulin 0.2 units/kg

• Only available in pens • Just dial the prescribed dose ‐ no “conversion” needed

U‐300 Insulin Glargine Prescribing Information. Available at: http://products.sanofi.us/toujeo/toujeo.pdf

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Insulin Glargine U100 vs U300 in T2DM Meta‐Analysis of 3 Phase 3 Studies

8.4 Any Time of Day, 24 h 10 Annual Rate Ratio U300/U100, Glargine U100 d b 8.2 8 15.22/17.73=0.86 Glargine U300 (95% CI, 0.77–0.97)

% 6 8.0 Events 4 7.8 Glargine U100 A1c, 2 Glargine U300 Cumulative 7.6 Mean 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 7.4 ‐1.02% 7.2 LSM Difference, 0.00%c Nocturnal, 00:00‐05:59 h 2.0 (95% CI, ‐0.08–0.07) ‐1.02% d Annual Rate Ratio U300/U100, a 7.0 1.5 2.10/3.06=0.69 Baseline Week 12 Month 6 (95% CI, 0.57–0.84)

Events 1.0

•Weight gain 0.5 Glargine U100

Cumulative Glargine U300 –Glargine U100, +0.79 kg Mean 0 –Glargine U300, +0.51 kg 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 –LSM Difference, ‐0.28 kgb Weeks of Treatment aP<0.001; bP<0.05; cP=NS; dConfirmed hypoglycemia (≤70 mg/dL) or severe hypoglycemia. N=1247 patients treated with glargine U300 and 1249 treated with glargine U100 in 3 phase 3 EDITION studies. Ritzel R, et al. Diabetes Obes Metab. 2015;17(9):859‐867.

Flexible vs Fixed Dosing U‐300 Glargine: Sub‐Studies of Phase III Trials

6-Month Treatment Period 6-Month Extension Period (main study) (main study) U-300 once daily U-300 once daily every 24 ± 3 h every 24 h sub-study U-300 once daily every 24 h

6 months (randomization, sub-study) 9 months (end of sub-study)

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

Riddle MC, Bolli GB, Home PD, et al. Diabetes Technol Ther 2016;18(4):252-257.

Insulin Degludec: Determining a Starting Dose in T2DM

Prior Treatment: Start with: Long or Intermediate‐ Same unit dose as the acting insulin current total daily dose No current basal insulin 10 units once daily

• Only available in pens • 100 units/mL or 200 units/mL • Just dial the prescribed dose; no “conversion” needed

Insulin degludec prescribing information. Available at: http://www.novo‐pi.com/tresiba.pdf

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BEGIN Type 2 ‐ Hypoglycemia Lower rates of hypoglycemia: overall and nocturnal

(A)Overall confirmed hypoglycemic episodes. (B) Nocturnal confirmed hypoglycemic episodes. (C) Diurnal Confirmed hypoglycemic episodes. (D) Cumulative # of hypoglycemic episodes per participant during 24 h

Garber A et al. Lancet. 2012;379(9825):1498–1507.

Flexible vs Fixed Dosing of Insulin Degludec

Meneghini L, et al. Diabetes Care 2013;36:858‐864.

Ultra‐Long Acting Insulin Comparison

Product Availability Dosing Range (per injection) U‐300 insulin SoloStar® prefilled pens 1‐80 units glargine (450 units/pen) (1 unit increments) Max SoloStar® prefilled pens 2‐160 units (900 units/pen) (2 unit increments) Insulin degludec U‐100 FlexTouch® pen 1‐80 units (300 units/pen) (1 unit increments) U‐200 FlexTouch® pen 2‐160 units (600 units/pen) (2 unit increments)

U‐300 Insulin Glargine Prescribing Information. Available at: http://products.sanofi.us/toujeo/toujeo.pdf Insulin degludec prescribing information. Available at: http://www.novo‐pi.com/tresiba.pdf

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Insulin Stacking vs. Therapeutic Accumulation

• “Insulin stacking” is the excessive accumulation of insulin within the circulation • Typically occurs with the administration of rapid‐acting insulin to correct hyperglycemia • Described as: • “…the practice of providing correctional doses of insulin before a prior dose of prandial insulin (or the peak action of neutral protamine Hagedorn, [NPH]) has had its full effect.”1 • “…previously infused insulin still has an effect on future values.”2

1Hirsch IB. N Engl J Med. 2005; 352:174‐83. 2Bequette BW. J Diabetes Sci Technol. 2009; 3:1005‐13.

Potential for Insulin Stacking with Rapid‐acting Insulin

Heise T, Meneghini LF. Endocr Pract. 2014; 20:75‐83.

Insulin Stacking vs. Therapeutic Accumulation

• Therapeutic, or steady‐state accumulation is a normal part of the PK process • Enables long‐acting insulin to reach a stable, steady‐state condition • Important to dose the basal insulin in appropriate amounts and titrate at appropriate time intervals to allow for steady‐state accumulation and avoid “overshooting” the target fasting blood glucose

Heise T, Meneghini LF. Endocr Pract. 2014; 20:75‐83.

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Therapeutic Accumulation with Once Daily Administration of Long‐acting Insulin: Impact of a Missed Dose

12.5‐hr half‐life 25‐hr half‐life

200

180 160 140 120 100 Concentration Maximum)

80

(% 60 40

Serum 20 0 1011 12 13 14 15 16 17 18 19 20 1011 12 13 14 15 16 17 18 19 20 Treatment Days Treatment Days

Heise T, Meneghini LF. Endocr Pract. 2014; 20:75‐83.

U‐200 • Available in 3mL prefilled pen • 600 units per vial (versus 300 units/vial for U‐100 lispro pens) • Can administer 1‐60 units/injection

Insulin lispro Prescribing Information. Available at: http://uspl.lilly.com/humalog/humalog.html#pi

Pharmacokinetic Profiles of Currently Available Insulin Products

Rapid‐acting (insulins aspart, lispro, glulisine; insulin human [inhaled]) U‐100 Regular U‐500 levels Intermediate‐acting (NPH insulin) Long‐acting () Ultralong‐acting insulin

Long‐acting (insulin glargine) (insulin degludec U100, U200) Ultralong‐acting (insulin glargine U300) Plasma

024 6 8 10 12162024 14182226 28 30 32 34 36 Time (h)

Hirsch IB. N Engl J Med. 2005; 352:174‐83. Flood TM. J Fam Pract. 2007; 56(suppl 1):S1‐S12. Becker RH et al. Diabetes Care. 2015; 38:637‐43.

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U‐500 Regular Insulin

• Concentrated human insulin • 20‐mL vials • U‐500 insulin syringes now available • 3‐mL pen (1,500 units/pen) now available • Reduced hexamer formation leads to faster dissociation and absorption • Time to peak: 30 minutes • Half‐life: ~4 hours • Indication • Patients requiring > 200 units of insulin/day

Lamos EM, et al. Ther Clin Risk Manag. 2016; 12:389‐400.

Steps for Initiating U‐500 Insulin

• Total daily dose determination

1 month prior: A1c >8% 1 month prior: A1c ≤8% & OR Within 1 week prior: BG ≥183 Within 1 week prior: BG <183 mg/dL mg/dL TDD: 100% of U‐100 dose TDD: 80% of U‐100 dose

• Dose proportion determination

Before Breakfast Before Lunch Before Dinner BID regimen 60% 0% 40% TID regimen 40% 30% 30%

Hood RC, et al. Endocr Pract. 2015; 21:782‐93.

U‐500 Insulin Titration: BID Regimen

Insulin Dose to Blood Glucose Value Reviewed Blood Glucose Action Adjust Value (mg/dL) Prebreakfast Median predinner OR median ≤70 ↓10% prelunch Median predinner 71‐130 No change 131‐180 ↑5% 181‐220 ↑10% >220 ↑15% Predinner Median prebreakfast, median ≤70 ↓10% bedtime, OR 3 AM value Median prebreakfast 71‐130 No change 131‐180 ↑5% 181‐220 ↑10% >220 ↑15%

Hood RC et al. Endocr Pract. 2015; 21:782‐93.

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U‐500 Insulin Titration: TID Regimen Insulin Dose to Adjust Blood Glucose Value Reviewed Blood Glucose Value Action (mg/dL) Prebreakfast Median prelunch ≤70 ↓10% 71‐130 No change 131‐180 ↑5% 181‐220 ↑10% >220 ↑15% Prelunch Median predinner ≤70 ↓10% 71‐130 No change 131‐180 ↑5% 181‐220 ↑10% >220 ↑15% Predinner Median prebreakfast, median bedtime, OR 3 ≤70 ↓10% AM value Median prebreakfast 71‐130 No change 131‐180 ↑5% 181‐220 ↑10% >220 ↑15%

Hood RC et al. Endocr Pract. 2015; 21:782‐93.

Who may Benefit from Concentrated Insulins?

• Patients not receiving a full 24 hours of fasting coverage with their current basal insulin product

• Patients with hectic/erratic schedules

• Patients who require large daily doses of insulin

• Patients experiencing nocturnal hypoglycemia with their current basal insulin (?)

Once FBG optimized –target PPG excursions: • Add 1 rapid‐acting insulin injection to largest meal, or • Add GLP‐1 RA, or • Change to premixed insulin twice daily

American Diabetes Association Standards of Medical Care in Diabetes. Pharmacologic Approaches to Glycemic Treatment: Approaches to glycemic treatment. Diabetes Care Standards2017; 40 (S uppl.of Medical 1): S64-S74 Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

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GLP‐1RA vs. Bolus Insulin in Patients with T2DM and Optimized Basal Insulin Insulin lispro 0.0 1.0 BID (%) (mmol/L) 0.5

‐0.5 0.0 a A1C ‐1.0 FPG ‐0.5 a a a a Δ Δ a a a ‐1.5 ‐1.0 0 2 4 6 8 12 18 24 30 0 2 4 6 8 12 18 24 30 Weeks since randomization Weeks since randomization (kg) 11 3 (mmol/L)

2 9 1 weight 0 7 ‐1 b b b b b glucose ‐2 b b b

5 Body ‐3 Pre Post Pre Post Pre Post 3AM Δ 0 2 4 6 8 12 18 24 30

Blood Breakfast Lunch Dinner Weeks since randomization ap < 0.01 for exenatide BID vs. insulin lispro bp < 0.001 for exenatide BID vs. insulin lispro

Exenatide caused more gastrointestinal issues (47% vs. 13%) but fewer non‐nocturnal episodes of hypoglycemia (15% vs. 34%) compared with insulin lispro

Diamant M, et al. Diabetes Care. 2014;37(10):2763‐2773.

GLP‐1 RAs + Basal Insulin vs Basal‐Bolus Insulin: A Meta‐analysis

Weighted Mean ∆A1c Difference (95% CI) Weight, % Diamant et al (2014) ‐0.03 (‐0.17 to 0.11) 32.25 Rosenstock et al (2014) ‐0.16 (‐0.33 to 0.01) 22.50 Shao et al (2014) ‐0.11 (‐0.23 to 0.01) 45.25 Overall (I2=0.0%, P=0.470) ‐0.10 (‐0.17 to ‐0.02) 100.00 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 Hypoglycemia Risk Relative Risk (95% CI) Weight, % Diamant et al (2014) 0.70 (0.55 to 0.90) 50.42 Rosenstock et al (2014) 0.65 (0.50 to 0.83) 49.21 Shao et al (2014) 0.14 (0.01 to 2.65) 0.37 Overall (I2=0.0%, P=0.526) 0.67 (0.56 to 0.80) 100.00 0.008 1 4.9 Weighted Mean ∆Body Weight Difference (95% CI) Weight, % Diamant et al (2014) ‐4.60 (‐5.33 to ‐3.87) 33.66 Rosenstock et al (2014) ‐1.50 (‐2.06 to ‐0.94) 33.81 Shao et al (2014) ‐11.07 (‐12.59 to ‐9.55) 32.53 Overall (I2=98.7%, P<0.0001) ‐5.66 (‐9.80 to ‐1.51) 100.00 -10 -6 -2 0 2 6 10 Favors GLP-1 RA + Basal Insulin Favors Basal-Bolus Insulin

Eng C, et al. Lancet. 2014;384(9961):2228‐2234.

Fixed‐Combination Basal + GLP‐1 Injectables

• Insulin glargine/ • Insulin degludec/

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Insulin Glargine/Lixisenatide Fixed‐Dose Combination • Fixed‐dose combination product • Insulin glargine U‐100 • Lixisenatide (short‐acting GLP‐1RA) –33 mcg/mL • Initiation: • For patients on < 30 units basal insulin: • 15 units insulin glargine U‐100 (5 mcg lixisenatide) • For patients on 30 ‐ 60 units basal insulin: • 30 units insulin glargine U‐100 (10 mcg lixisenatide) • Administration: within 1 hour before the first meal of the day • Titration: 2 ‐ 4 units (insulin glargine U‐100 component) once weekly on the basis of FPG • Max dose: 60 units insulin glargine U‐100/20 mcg lixisenatide • Pen device delivers 15‐60 units of insulin glargine Insulin glargine/lixisenatide Prescribing Information. Available at: http://products.sanofi.us/Soliqua100‐33/Soliqua100‐33.pdf

Insulin Degludec/Liraglutide Fixed‐Dose Combination • Fixed‐dose combination product • Insulin degludec U100 • Liraglutide (once‐daily GLP‐1RA) –3.6 mg/mL • Initiation: • 16 units insulin degludec (0.58 mg liraglutide) once daily • Administration: same time once daily (with or without food) • Titration: • Titrate by 2 units (insulin degludec) every 3 ‐ 4 days on the basis of FPG (or hypoglycemia) • Max dose: 50 units insulin degludec/1.8 mg liraglutide • Pen device delivers 10‐50 units of insulin degludec

Insulin degludec/liraglutide Prescribing Information. Available at: http://www.novo‐pi.com/xultophy10036.pdf

Thank you!

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