Objectives Compare and contrast currently available products. Navigating New s Diana Isaacs, PharmD, BCPS, BC-ADM, CDE Clinical Pharmacy Specialist Cleveland Clinic Diabetes Center Determine the factors that guide selection based on individualized patient characteristics. Disclosures Diana Isaacs has nothing to disclose. Diabetes: The Stats Cases of diabetes - 29.1 million people in the U.S. (9.3% population) New cases: 1.4 million Americans/year On : 28.7% http://www.diabetes.org/diabetes-basics/statistics/ Accessed April 9 th, 2017 27 th, 2016 Normal Release Individuals without diabetes bolus occurs in the first 10 minutes after eating Blood sugar 1910: Discovery of 1982: 1953: Humulin R, Lente Humulin N History of 1996: Rapid acting lispro 2000: Long acting analog; glargine 2005: detemir 2015: U-300 glargine U-100/ degludec lispro 2017: Fiasp in Canada: ultra rapid Basal Basal is released every 12 minutes Meal Meal Meal Blood sugar goes up after eating 1950: NPH 1976: 1st pump 1994: R U-500 Human 2000: aspart 2004: glulisine 2014: inhaled 2016: GLP-1 combos, biosimilar glargine http://www.diabetes.org/research-and-practice/student-resources/history-of-diabetes.htmlc 1
5/23/17 ADA Treatment Algorithm So Much Regular Novolin R, Humulin R Neutral protamine hagedorn (NPH) Novolin N, Humulin N Pre-mixed Lispro 70/30, 75/25, 50/50 Aspart 70/30, Ryzodeg 70/30 Long-acting Glargine (Lantus, Basaglar ), Detemir (Levemir ), Degludec (Tresiba ) Rapid-acting Inhaled Lispro (Humalog ), Aspart (Novolog ), Glulisine (Apidra ) Concentrated Humulin R U-500 Glargine U-300 (Toujeo ) Degludec (Tresiba ) Lispro (Humalog ) Diab Care 201739:S52-S59 Choice of Basals NPH Levemir Toujeo Choice of Bolus Tresiba U-100 Lantus Tresiba /GLP-1 RA Combos Lixisenatide + glargine in a fixed-ratio pen (Soliqua ) - Daily dose range: 10-60 units corresponding to lixisenatide 5-20mcg Novolog Humalog U-100 Humalog Liraglutide + degludec in a fixed-ratio pen (Xultophy ) - Max dose 50 units corresponding to liraglutide 1.8mg Apidra Afrezza Regular 2
New Drug Approvals 2015-2016 Long-acting - degludec (Tresiba U-100 ) - degludec/aspart 70/30 (Ryzodeg ) - glargine U-100 (Basaglar ) Concentrated - degludec (Tresiba ) - glargine U-300 (Toujeo ) - Humulin R U-500 Kwikpen - lispro (Humalog ) Degludec (Tresiba ) Mechanism of action - After injection, Ideg dihexamers join together creating long, soluble multiheximer chains that prolong duration of action Available in U-100,, and aspart 70/30 combo (Ryzodeg ) kwik pens - Ryzodeg not available in U.S. Tresiba Pacakge Insert, NovoNordisk, 2015 Tresiba Clinical Data Study Design Intervention Results: Efficacy 52 weeks, controlled, openlabel, multinational, parallel design, treat-totarget, noninferiority trial 52 weeks, controlled, openlabel, treat-totarget, multinational, noninferiority trial Adults with T2DM randomized to degludec (n=773) or glargine (n=257) both in combination with metformin. Adults with T2DM randomized to degludec (n = 755) or glargine (n=251) both in combination with aspart before meals, +/- metformin and/or pioglitazone. degludec and glargine decreased mean A1C by 1.06 and 1.19%, respectively (95% CI 0.04 to 0.22%), meeting criteria for non-inferiority. Nocturnal hypoglycemia and severe hypoglycemia occurred less with degludec (p < 0.05). degludec and glargine decreased mean A1C by 1.10 and 1.18%, respectively. (95% CI 0.05 to 0.21%), meeting criteria for non-inferiority. Rates of overall hypoglycemia and nocturnal hypoglycemia were lower with degludec. Diabetes Care 35:2464 2471, 2012. Lancet 379:1498 1507, 2012. degludec Tresiba Vs. Lantus Longer half-life More forgiving if a dose is missed True once daily dosing Max 80 (U-100)-160 () units per injection Ability to mix with aspart No vial available glargine Easier to treat hypoglycemia Quicker to make dose adjustments Max 80 (pen) to 100 units (vial) per injection More years of experience Cheaper alternative basaglar available Both available in combo with GLP-1 RA Glargine U-300 (Toujeo ) Toujeo Clinical Data Offers a smaller depot surface area, leading to a reduced rate of absorption Provides flatter and prolonged PK and PD profiles and more consistency Structurally identical to glargine May need higher doses than Lantus Longer half-life Longer duration of action Limited to 80 units/dose via pen, no vial Product information for Toujeo. Sanofi-Aventis U.S. LLC. Bridgewater, NJ 08807. September 2015. Toujeo Clinical Data Available at: https://www.toujeopro.com/toujeo-clinical-trials. Accessed 11/15/16 3
Glargine U-100 (Basaglar ) Identical amino acid sequence to glargine (Lantus ) - Different excipients Demonstrated non-inferiority to Lantus Available in 3mL Kwikpen, no vial Not technically approved as a biosimilar - Follow on abbrev approval process Cheaper price Basaglar Clinical Data Study Design Intervention Results: Efficacy/Safety Element 1 52 weeks, open-label Element 2 24 weeks, controlled, double-blind Adults with T1DM randomized to Lantus (n=267) or Basaglar (n=257) both in combination with lispro. Adults with T2DM randomized to Lantus (n 380) or Basaglar (n=376) both in combination with 2 or more oral anti-diabetes agents. Lantus and basaglar decreased mean A1C by 0.46% and 0.35%, respectively (95% CI -0.002 to 0.219, P>0.05%), meeting criteria for non-inferiority. Similar adverse effects between group, 4% severe hypoglycemia Mean A1c change in both groups was 1.3% (CI: -0.70 to 0.0175, P>0.05) meeting criteria for noninferiority. Similar adverse effects between group, <1% severe hypoglycemia Basaglar [Prescribing Information]. Indianapolis, IN: Eli Lilly and Company. Diabetes Obes Metab. 2015 Aug;17(8):726-33 Diabetes Obes Metab. 2015 Aug;17(8):734-41 Humulin R U-500 Pen FDA approved Jan, 2016 5x concentration compared to U-100 Delivers up to 300 units in a single injection Acts like intermediate acting Most ideal for patients with resistance - Patients injecting >200 units/day Unlike the vial, no dosing conversions Vial is still available New U-500 syringe now available Inhaled 2006 2015 human inhalation power Onset: 12-15 minutes, Peak: 1 hour, DOA: 3 hours Available in prepackaged blister packs containing 15 cartridges Each blister pack, once opened, is good for 10 days Inhaler must be changed everydays Warnings Acute bronchospasm in patients with asthma or COPD Contraindicated with chronic lung diseases Before initiating, perform a detailed medical history, physical exam and spirometry Side effects: hypoglycemia, cough, throat pain package insert Fiasp Meal time aspart formulation with niacinamide (vitamin B3) - Faster absorption - Quicker onset Inject 2 min before start of meal up to 20 min after Duration of action 10% shorter vs. Novolog Available in Canada (not U.S.) http://www.novonordisk.ca/content/dam/canada/affiliate/www-novonordisk-ca/ourproducts/pd fiasp-product-monograph.pdf 4
Profiles Cornell, S. ICHP 2016 Annual Meeting Property Long-Acting Comparison Glargine (U-300) Toujeo Glargine (U-100) Lantus Degludec (U-100) Tresiba Degludec () Tresiba Humulin R U-500 KwikPen Concentration 300 units/ml 100 units/ml 100 units/ml 200 units/ml 500 units/ml Onset 6 hours 4-5 hours 1-2 hours 1-2 hours 30 min Duration of 24-36 hours 24 hours > 42 hours > 42 hours 12-24 hours Half-life ~ 19 hours ~ 12 hours 25 hours 25 hours 4.5 hours Time to Steady State Units per pen Max units injected/dose 5 days 1 day 3 days 3 days 1 day 450 units in 1.5mL 300 units in 3mL 300 units in 3mL 600 units in 3mL 1500 units in 3 ml 80 units 80 units 80 units 160 units 300 units Dial 1 unit 1 unit 1 unit 2 units 5 units Pen or Vial? Pen Pen/vial Pen Pen Pen/vial Expiration 42 days 28 days 56 days 56 days 28 days pen 40 days vial Detail-Document; Pharmacist's Letter 2015; 31(4):310402, Lantus pacakge insert, Diabetes Care 2015 Apr; 38(4): 637-643, Tresiba Pacakge Insert, NovoNordisk, 2015 Levemir, NPH, Regular Property Determir Levemir NPH Humulin N, Novolin N Regular Humulin R, Novolin R Type Long acting Intermediate acting Short acting Concentration 100 units/ml 100 units/ml 100 units/ml Onset 1.1-2 hours 1-2 hours 30 minutes Peak None 4-10 hours 3 hours Duration of 20-24 hours 14 hours 8 hours Timing 1-2x daily 1-2x daily 30 minutes before meals Cloudy or Clear? Clear Cloudy Clear Pen or Vial? Pen/vial Pen/vial Vial Expiration 42 days 31 days 31 days Detail-Document; Pharmacist's Letter 2015; 31(4):310402, Lantus pacakge insert, Diabetes Care 2015 Apr; 38(4): 637-643, Tresiba Pacakge Insert, NovoNordisk, 2015 Property Lispro Humalog Rapid-Acting Comparison Lispro Humalog () Aspart Novolog Glulisine Apidra Inhaled Onset 15-30 min 15-30 min 10-20 min 25 min 12-15 min Duration of Meal Timing 3-6.5 hours 3-6.5 hours 3-5 hours 4-5.3 hours 160 min SC up to 15 min before or immediately after meal SC up to 15 min before or immediately after meal SC 5-10 min before meals SC within 15 min before or 20 min after starting meal Units per pen 300 units in 3mL 600 units in 3mL 300 units in 3mL 300 units in 3mL NA Max units injected/dose Inhaled at beginning of meal 60 units 60 units 60 units 80 units 4,8,12 unit cartridges Pens/box 5 2 5 5 NA Available as vial? Yes No Yes Yes NA Expiration 28 days 28 days 28 days 28 days 3 days Detail-Document; Pharmacist's Letter 2015; 31(4):310402 http://www.humalog.com/humalog-u200-kwikpen.aspx. Accessed Sept 5 th, 2016 http://pi.lilly.com/us/humalog-kwikpen-um.pdf Accessed Sept 5th, 2016 Tips and Tricks Long-acting with rapid-acting (or pump) best for T1DM or -dependent T2DM NPH-great for pregnancy and steroid induced diabetes Regular, NPH, Novolin 70/30 are available OTC and cheap - Co-pay cards available for the newer s 70/30 and other combos good for limiting to 2 injections/day, but less dose flexibility All can cause weight gain and hypoglycemia 5
Selection Which of the following s are available in a U-300 formulation? Cost Adherence Formulary A. detemir B. glargine Onset of Hypoglycemia Duration of C. regular D. degludec Volume Weight Gain Patient Preference Which of the following s are available in a vial? Key Points New s offer more treatment options A. Humulin R U-500 B. degludec U-100 (Tresiba ) C. glargine (Toujeo ) D. glargine (Basalgar ) The goal is to mimic the body s natural production of (basal/bolus) Several factors guide selection including side effect profile, onset/duration of action, volume of injection, and patient preferences Navigating New s Diana Isaacs isaacsd@ccf.org 6