5/16/2018. Insulin Update: New and Emerging Insulins. Disclosures to Participants. Learning Objectives

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1 Insulin Update: New and Emerging Insulins 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 Memership: Editor for the ADA journal Diaetes Spectrum Memer of ADA Professional Practice Committee (PPC) Learning Ojectives This presentation will cover the following learning ojectives: 1. Review the pharmacokinetic and clinical characteristics of currently availale insulin products; 2. Discuss considerations for use of newer, ultra long acting asal insulin products; and 3. Discuss the potential role of fixed dose insulin/glp 1 receptor agonist products in the management of type 2 diaetes. 1

2 ADA 218: Summary of Glycemic Recommendations Glycemic Targets: Standards of Medical Care in Diaetes 218. Diaetes Care 218; 41 (Suppl. 1): S55 S64. Determining an Appropriate A1C Target Patient/Disease Features Risk of hypoglycemia/drug adverse effects Disease Duration Life expectancy Important comoridities Estalished vascular complications more stringent low newly diagnosed long asent asent A1C 7% Few/mild Few/mild less stringent high long-standing short severe severe Patient attitude & expected treatment efforts Resources & support system highly motivated, adherent, excellent self-care capailities readily availale less motivated, nonadherent, poor self-care capailities limited Glycemic Targets: Standards of Medical Care in Diaetes Diaetes Care 218; 41 (Suppl. 1): S55-S64 Antihyperglycemic Therapy in Adults with T2DM Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diaetes Diaetes Care 218; 41 (Suppl. 1): S73-S85 2

3 See page S77 in: Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diaetes Diaetes Care 218; 41 (Suppl. 1): S73-S85 Antihyperglycemic Therapy in Adults with T2DM Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diaetes Diaetes Care 218; 41 (Suppl. 1): S73-S85 Pharmacokinetic Profile of Currently Availale Single Insulin Products Plasma Insulin Levels Rapid (aspart, lispro, glulisine, inhaled human insulin) Short (regular U 1) Mixed short/intermediate (regular U 5) Intermediate (NPH) Long (detemir) Long (U 1 glargine) Ultra long (glargine U 3) Ultra long (degludec) Time (hr) Hirsch IB. N Engl J Med. 25; 352: Flood TM. J Fam Pract. 27; 56(suppl 1):S1 S12. Becker RH et al. Diaetes Care. 215; 38:

4 Insulin PK/PD Comparison Insulin Time to Onset Duration of Time to Peak Action (hr) of Action (hr) Action (hr) Lispro (U 1*, U 2) within Aspart within Glulisine within Insulin human (inhaled) within Insulin human regular (U 1) Insulin human regular (U 5) Human insulin isophane (NPH) Detemir (though relatively flat) Up to 24 Glargine (U 1)* 2 4 flat 2 24 Glargine (U 3) 6 flat up to 36 Degludec (U 1, U 2) 1 flat >42 Regular U 1/NPH 7/3 within Lispro mix 5/5 within Up to 24 Lispro mix 75/25 within Aspart mix 7/3 within Up to 24 Degludec/aspart mix 7/3 within >24 Patient specific onset, peak, and duration may vary from times listed in tale. Peak and duration are dose dependent with shorter durations of action seen for smaller doses and longer durations of action with larger doses. *Follow on products availale Insulin aspart is availale in 2 formulations; Fiasp has a relatively fast onset of action Hirsch IB. N Engl J Med. 25; 352:174 83; Umpierrez GE et al. J Clin Endocrinol Meta. 212; 97:16 38; Dansinger M. Types of insulin. June 21, types insulin (accessed 216 Sep 29); Bennett JA. Insulin chart. July 17, chart (accessed 216 Sep 29); Individual product prescriing information. Basal Insulin Initiation in T2DM: Start with 1 units/day or.1.2 units/kg/day Adjust 1 15% or 2 4 units once or twice weekly to reach FBG target Assess and adjust for hypoglycemia American Diaetes Association Standards of Medical Care in Diaetes. Pharmacologic Approaches to Glycemic Treatment: Approaches to glycemic treatment. Diaetes Care Standards 217; 4 (Suppl. of Medical 1): S64-S74 Care in Diaetes Diaetes Care 218; 41 (Suppl. 1): S73-S85 U 3 Insulin Glargine: Determining Starting Dose (and Dose Conversion) in T2DM Prior Treatment: Start with: Once daily asal insulin 1:1 conversion* Twice daily NPH 8% of total daily NPH dose No current asal insulin.2 units/kg Only availale in pens Just dial the prescried dose no conversion needed U 3 Insulin Glargine Prescriing Information. Availale at: 4

5 Insulin Glargine U1 vs U3 in T2DM Meta Analysis of 3 Phase 3 Studies A1c, % 8.4 Any Time of Day, 24 h Glargine U1 1 Annual Rate Ratio U3/U1, /17.73=.86 Glargine U3 (95% CI,.77.97) Glargine U1 2 Glargine U % 7.2 Nocturnal, : 5:59 h LSM Difference,.% c (95% CI,.8.7) 1.2% 2. Annual Rate Ratio U3/U1, /3.6=.69 a (95% CI,.57.84) Baseline Week 12 Month 6 1. Weight gain Glargine U1, +.79 kg Glargine U3, +.51 kg LSM Difference,.28 kg Cumulative Mean Events d Cumulative Mean Events d a P<.1; P<.5; c P=NS; d Confirmed hypoglycemia ( 7 mg/dl) or severe hypoglycemia. N=1247 patients treated with glargine U3 and 1249 treated with glargine U1 in 3 phase 3 EDITION studies Weeks of Treatment Glargine U1 Glargine U Ritzel R, et al. Diaetes Oes Meta. 215;17(9): Flexile vs Fixed Dosing U 3 Glargine: Su Studies of Phase III Trials 6-Month Treatment Period (main study) U-3 once daily every 24 h 6-Month Extension Period (main study) U-3 once daily every 24 ± 3 h su-study U-3 once daily every 24 h 6 months (randomization, su-study) 9 months (end of su-study) Percentage of Injections (%) Edition 1 Su-Study Edition 2 Su-Study N = 19 N = 89 Flexile dosing Fixed dosing 24 ± <1 h 24 ± 1-3 h 24 ± >3 h 24 ± <1 h 24 ± 1-3 h 24 ± >3 h No difference in A1C etween flexile- vs fixed-dosing No difference in severe or nocturnal hypoglycemia within each su-study Riddle MC, Bolli GB, Home PD, et al. Diaetes Technol Ther 216;18(4): Insulin Degludec: Determining a Starting Dose in T2DM Prior Treatment: Long or Intermediateacting insulin No current asal insulin Start with: Same unit dose as the current total daily dose 1 units once daily Only availale in pens 1 units/ml or 2 units/ml Just dial the prescried dose; no conversion needed Insulin degludec prescriing information. Availale at: pi.com/tresia.pdf 5

6 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 Garer A et al. Lancet. 212;379(9825): Flexile vs Fixed Dosing of Insulin Degludec Meneghini L, et al. Diaetes Care 213;36: Ultra Long Acting Insulin Comparison Product Availaility Dosing Range (per injection) U 3 insulin glargine SoloStar prefilled pens (45 units/pen) 1 8 units (1 unit increments) Max SoloStar prefilled pens (9 units/pen) 2 16 units (2 unit increments) Insulin degludec U 1 FlexTouch pen (3 units/pen) 1 8 units (1 unit increments) U 2 FlexTouch pen (6 units/pen) 2 16 units (2 unit increments) U 3 Insulin Glargine Prescriing Information. Availale at: Insulin degludec prescriing information. Availale at: pi.com/tresia.pdf 6

7 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 Descried as: the practice of providing correctional doses of insulin efore 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 glucose values. 2 1 Hirsch IB. N Engl J Med. 25; 352: Bequette BW. J Diaetes Sci Technol. 29; 3: Potential for Insulin Stacking with Rapid acting Insulin Heise T, Meneghini LF. Endocr Pract. 214; 2: Insulin Stacking vs. Therapeutic Accumulation Therapeutic, or steady state accumulation is a normal part of the PK process Enales long acting insulin to reach a stale, steady state condition Important to dose the asal insulin in appropriate amounts and titrate at appropriate time intervals to allow for steady state accumulation and avoid overshooting the target fasting lood glucose Heise T, Meneghini LF. Endocr Pract. 214; 2:

8 Therapeutic Accumulation with Once Daily Administration of Long acting Insulin: Impact of a Missed Dose 12.5 hr half life 25 hr half life 2 Serum Concentration (% Maximum) Treatment Days Treatment Days Heise T, Meneghini LF. Endocr Pract. 214; 2: Availale in 3mL prefilled pen 6 units per vial (versus 3 units/vial for U 1 lispro pens) Can administer 1 6 units/injection U 2 Insulin Lispro Insulin lispro Prescriing Information. Availale at: Pharmacokinetic Profiles of Currently Availale Insulin Products Plasma insulin levels Rapid acting (insulins aspart, lispro, glulisine; insulin human [inhaled]) Regular insulin U 1 Regular U 5 Intermediate acting (NPH insulin) Long acting (insulin detemir) Long acting (insulin glargine) Ultralong acting (insulin degludec U1, U2) Ultralong acting (insulin glargine U3) Time (h) Hirsch IB. N Engl J Med. 25; 352: Flood TM. J Fam Pract. 27; 56(suppl 1):S1 S12. Becker RH et al. Diaetes Care. 215; 38:

9 U 5 Regular Insulin Concentrated human insulin 2 ml vials U 5 insulin syringes now availale 3 ml pen (1,5 units/pen) now availale Reduced hexamer formation leads to faster dissociation and asorption Time to peak: 3 minutes Half life: ~4 hours Indication Patients requiring > 2 units of insulin/day Lamos EM, et al. Ther Clin Risk Manag. 216; 12: Steps for Initiating U 5 Insulin Total daily dose determination 1 month prior: A1c >8% & Within 1 week prior: BG 183 mg/dl TDD: 1% of U 1 dose Dose proportion determination 1 month prior: A1c 8% OR Within 1 week prior: BG <183 mg/dl TDD: 8% of U 1 dose Before Breakfast Before Lunch Before Dinner BID regimen 6% % 4% TID regimen 4% 3% 3% Hood RC, et al. Endocr Pract. 215; 21: U 5 Insulin Titration: BID Regimen Insulin Dose to Adjust Prereakfast Predinner Blood Glucose Value Reviewed Median predinner OR median prelunch Blood Glucose Value (mg/dl) Action 7 1% Median predinner No change % % >22 15% Median prereakfast, median 7 1% edtime, OR 3 AM value Median prereakfast No change % % >22 15% Hood RC et al. Endocr Pract. 215; 21:

10 U 5 Insulin Titration: TID Regimen Insulin Dose to Adjust Blood Glucose Value Reviewed Blood Glucose Value Action (mg/dl) Prereakfast Median prelunch 7 1% No change % % >22 15% Prelunch Median predinner 7 1% No change % % >22 15% Predinner Median prereakfast, median edtime, OR 3 7 1% AM value Median prereakfast No change % % >22 15% Hood RC et al. Endocr Pract. 215; 21: Who may Benefit from Concentrated Insulins? Patients not receiving a full 24 hours of fasting coverage with their current asal insulin product Patients with hectic/erratic schedules Patients who require large daily doses of insulin Patients experiencing nocturnal hypoglycemia with their current asal 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 Diaetes Association Standards of Medical Care in Diaetes. Pharmacologic Approaches to Glycemic Treatment: Approaches to glycemic treatment. Diaetes Care Standards 217; 4 (Suppl. of Medical 1): S64-S74 Care in Diaetes Diaetes Care 218; 41 (Suppl. 1): S73-S85 1

11 GLP 1RA vs. Bolus Insulin in Patients with T2DM and Optimized Basal Insulin ΔA1C (%) Blood glucose (mmol/l) Weeks since randomization 3 Pre Post Pre Post Pre Post 3AM Breakfast Lunch Dinner a p <.1 for exenatide BID vs. insulin lispro p <.1 for exenatide BID vs. insulin lispro ΔFPG (mmol/l) ΔBody weight (kg) a a a a Weeks since randomization a a a a Weeks since randomization 3 3 Insulin lispro Exenatide BID Exenatide caused more gastrointestinal issues (47% vs. 13%) ut fewer non nocturnal episodes of hypoglycemia (15% vs. 34%) compared with insulin lispro Diamant M, et al. Diaetes Care. 214;37(1): GLP 1 RAs + Basal Insulin vs Basal Bolus Insulin: A Meta analysis A1c Weighted Mean Difference (95% CI) Weight, % Diamant et al (214).3 (.17 to.11) Rosenstock et al (214).16 (.33 to.1) 22.5 Shao et al (214).11 (.23 to.1) Overall (I 2 =.%, P=.47).1 (.17 to.2) Hypoglycemia Risk Relative Risk (95% CI) Weight, % Diamant et al (214).7 (.55 to.9) 5.42 Rosenstock et al (214).65 (.5 to.83) Shao et al (214).14 (.1 to 2.65).37 Overall (I 2 =.%, P=.526).67 (.56 to.8) Body Weight Weighted Mean Difference (95% CI) Weight, % Diamant et al (214) 4.6 ( 5.33 to 3.87) Rosenstock et al (214) 1.5 ( 2.6 to.94) Shao et al (214) 11.7 ( to 9.55) Overall (I 2 =98.7%, P<.1) 5.66 ( 9.8 to 1.51) Favors GLP-1 RA + Basal Insulin Favors Basal-Bolus Insulin Eng C, et al. Lancet. 214;384(9961): Fixed Comination Basal + GLP 1 Injectales Insulin glargine/lixisenatide Insulin degludec/liraglutide 11

12 Insulin Glargine/Lixisenatide Fixed Dose Comination Fixed dose comination product Insulin glargine U 1 Lixisenatide (short acting GLP 1RA) 33 mcg/ml Initiation: For patients on < 3 units asal insulin: 15 units insulin glargine U 1 (5 mcg lixisenatide) For patients on 3 6 units asal insulin: 3 units insulin glargine U 1 (1 mcg lixisenatide) Administration: within 1 hour efore the first meal of the day Titration: 2 4 units (insulin glargine U 1 component) once weekly on the asis of FPG Max dose: 6 units insulin glargine U 1/2 mcg lixisenatide Pen device delivers 15 6 units of insulin glargine Insulin glargine/lixisenatide Prescriing Information. Availale at: 33/Soliqua1 33.pdf Insulin Degludec/Liraglutide Fixed Dose Comination Fixed dose comination product Insulin degludec U1 Liraglutide (once daily GLP 1RA) 3.6 mg/ml Initiation: 16 units insulin degludec (.58 mg liraglutide) once daily Administration: same time once daily (with or without food) Titration: Titrate y 2 units (insulin degludec) every 3 4 days on the asis of FPG (or hypoglycemia) Max dose: 5 units insulin degludec/1.8 mg liraglutide Pen device delivers 1 5 units of insulin degludec Insulin degludec/liraglutide Prescriing Information. Availale at: pi.com/xultophy136.pdf Thank you! 12