High Dose Insulin Therapy: The case for CONCENTRATED Insulin

High Dose Insulin Therapy: The case for CONCENTRATED Insulin 21 st Annual Diabetes Fall Symposium Charleston, SC Wendy Lane MD September 18, 2015 Mountain Diabetes and Endocrine Center Asheville, North Carolina 1

Wendy Lane MD Disclosure Board Member/Advisory Panel: Novo Nordisk; Insulet Consultant: Eli Lilly, Inc.; Novo Nordisk; Thermalin Research Support: Novo Nordisk Speaker s Bureau: Novo Nordisk, Insulet Objectives 1. To identify how the global obesity epidemic is contributing to insulin resistance, type 2 diabetes, and the need for high insulin doses. 2. To identify appropriate candidates for concentrated insulin. 3. To discuss available concentrated insulin formulations and those in development. 4. To review the use of U500 insulin in injection regimens and in continuous subcutaneous insulin infusion* (insulin pump therapy). * Off-label use 2

Obesity in the USA:1986 US Obesity Rates in 2010 3

US Self-Reported Obesity Rates in 2012 http://www.cdc.gov/obesity/data/adult.html US Self-Reported Obesity Rates in 2013 http://www.cdc.gov/obesity/data/adult.html 4

The Diabetes Belt www.cdc.gov 2011 5

Treatment Options in Type 2 Diabetes Oral Agents: Metformin Sulfonylureas/Meglitinides Thiazolidinediones Alpha glucosidase inhibitors DPP-IV inhibitors (sita, saxa, lina, alogliptin) Dopamine agonist (bromocriptine) Bile acid sequestrant (colesevelam) SGLT-2 inhibitors (cana, dapa,empagliflozin) Injectable agents: GLP-1 Receptor Agonists (exenatide, liraglutide, albiglutide, dulaglutide) Pramlintide (amylin) Insulin: Basal; Bolus; Basal/Bolus; CSII 6

Insulin doses are increasing Obesity-induced insulin resistance has led to high insulin requirements in a sizable percentage of people with T2DM. Approximately 35% of subjects with T2DM require a maintenance dose of basal insulin of 60 U or more. 1 In a treat-to-target basal insulin trial involving insulin-naïve patients with T2DM, 21% of subjects required > 80 units of basal insulin at the end of the trial. 2 1.Rodbard H, Handelsman Y, Gough S. et al. AACE 21 st Annual Scientific Meeting and Clinical Congress 2012 (Abstract 241) 2. Gough S, Bhargava A, Jain R. et al. Diab Care 2013 36: 2536-2542 17% of patients use > 100 U/day % Frequency 14% 12% 10% 8% 6% 4% % frequency of total daily insulin units - Type 2 only 17% of Type 2 diabetes insulin users (injectors and pumpers) use >100 units of insulin per day. 2% 0% 10 40 70 100 130 160 190 220 250 280 310 340 370 400 Total Daily Insulin Units N = 595 Data from 2011 US Roper Diabetes Patient Market Study provided by GfK Custom Research LLC and distributed only with express written permission of GfK Custom Research LLC. This study is an annual survey of over 2,000 diabetes patients (n=2,104 in 2011; 692 who use insulin) via telephone and Internet. 7

Potential Candidates for Concentrated Insulin Obese type 2 diabetes with severe insulin resistance 1 : Multiple daily injections Continuous subcutaneous insulin infusion (CSII)* Type 2 diabetes requiring high dose insulin 1,2 : Post-operatively or post-transplant On high-dose glucocorticoid therapy Severe systemic infection Those with genetic defects of insulin action 1 : Lipoatrophic diabetes Type A insulin resistance syndrome Others Gestational diabetes mellitus with severe insulin resistance 1 Those with rare forms of immune-mediated diabetes such as anti-insulin receptor antibodies (type B insulin resistance syndrome) 1 1. Cochran E, et al. Diabetes Care. 2005;28(5):1240-4. 2. Garg R, et al. Diabetes Metab Res Rev. 2007;23:265-8. *off-label use 8

Potential advantages of concentrated insulin use in patients with severe insulin resistance Improved insulin absorption from smaller volume injection leads to improved glycemic control Improved insulin absorption leads to more predictable insulin action Fewer injections and lower volume injections enhance patient comfort and enhance compliance Concentration of the insulin can prolong the insulin action, depending on the method of protraction* Cost savings when used in CSII (fewer cartridge and battery changes) *Sindelka G, Heinemann L, Berger M et al. Diabetelogia 1994; 37(4): 377-380 Why do we need a concentrated basal insulin? In a basal/bolus regimen, the largest daily injection for continuous background glucose control is the basal injection (usually 50% total daily insulin dose and 3 times average bolus dose). Current U100 insulin syringes deliver a maximum of 100 units of insulin, and current pen devices deliver a maximum dose of 60 to 80 units. In insulin-resistant patients requiring over 100 units of basal insulin, this will require more than one injection (1 ml) of insulin by syringe, and will require more than 1 pen injection in patients requiring more than 80 units per day. There is some evidence that large insulin volumes are poorly and inconsistently absorbed, leading to suboptimal glycemic control. 1 1. Binder C, Lauritzen T, Faber O et al. Insulin Pharmacokinetics Diabetes Care 1984; 7:188 9

Do we need a concentrated prandial insulin? In MDI regimens, possibly, to keep the injection volume comfortable for patients injecting large (>35 units) doses of mealtime insulin. In CSII, definitely, to facilitate adequate insulin absorption of high basal and bolus infusion rates and allow adequate insulin pump operability. Concentrated Basal Insulin U500 Regular Human Insulin (Eli Lilly) (basal and prandial) U300 Glargine (Sanofi Aventis) U200 Degludec (Novo Nordisk; approved in EU, not yet in US) U400 Biodel 531 (Biodel; in development) (basal and prandial) Znsulin (Thermalin; in development) 10

Insulin glargine U300 (300 U/mL) Contains the same molecule as glargine (U100) but in a lower volume Reduction of volume by 2/3 Reduction of depot surface by 1/2 Same amount of units Gla 100 Gla 300 Gla 100 Gla 300 3 The decrease in volume decreases depot surface area, which can be predicted to slow down the rate of glargine release U300 Glargine 11

IGlar U300: single dose clamp profile GIR (mg/kg/min) INS (µu/ml) PK and PD profiles in a single dose clamp study (T1DM) 1 20 10 0 3 2 1 0 SC INJECTION 0 6 12 18 24 30 36 SC INJECTION 0 6 12 18 24 30 36 Time (hour) U100 LLOQ U300 U100 0.4 U/kg U300 0.4 U/kg U300 0.6 U/kg U300 0.9 U/kg U100 0.4 U/kg U300 0.4 U/kg U300 0.6 U/kg U300 0.9 U/kg U500 IGlar U100 and U300 are not equivalent in bioavailability (exposure) and bio-efficacy (activity) 2 Exposure and activity after administration of U300 were less by ~40% as compared to exposure and activity after administration of the same amount (0.4U/kg) from U100 2 U1000 Crystalline structures 2 For Internal Use Only 1. ADA 2013, 920-P; 2. Insulin Glargine U300 European Patient Application, European Patient Office. Date of publication: 23.11.2011. EP 2 387 989 A2 U300 Glargine Advantages: Lower volume, may improve comfort Flatter pharmacokinetic profile than U100 glargine Less hypoglycemia Longer duration of action than U100 glargine Disadvantages: Current pen can still only deliver up to 80 units per injection Lower bioavailability requires uptitration of insulin dose 12

U200 DEGLUDEC Insulin degludec: mechanism of protraction IDeg forms multi-hexamers upon subcutaneous injection, resulting in a soluble depot from which insulin monomers are slowly and continuously released and absorbed into the circulation. Jonassen I, Havelund S, Hoeg-Jensen T et al. Pharm Res. 2012: 29: 2104-14 13

PD profile of U100 degludec Euglycemic clamp study in subjects with T2DM (n=49) shows flat, stable glucoselowering profiles during the entire dosing interval for 3 doses of IDeg. Heise T, Nosek L, Bøttcher SG et al. Diabetes Obes Metab 2012a;14:944 50. PK/PD profile of U200 degludec is bioequivalent to U100 degludec 8 day crossover euglycemic clamp study comparing PK profile of U100 to U200 IDeg at 0.4 u/kg in subjects with T1DM (n=33) showed flat, stable PK/PD profiles for both insulin concentrations. Korsatko S, Deller S, Koehler G et al, Clin Drug Investig (2013) 33: 515-521 14

Concentrated Prandial Insulin U200 Lispro (Eli Lilly) U300 Biochaperoned Lispro (Adocia/ Eli Lilly; in development) U400 Biodel 531 (Biodel; in development; basal and prandial) U500 Regular Human Insulin (Eli Lilly) (basal and prandial) U200 Lispro 15

PK Bioequivalence: Lispro U-200 versus Insulin Lispro U-100 1 Average Free Immunoreactive Insulin Concentration (pmol/l) 1000 900 800 700 600 500 400 300 200 20 units, IL U-100 20 units, IL U-200 100 0 0 1 2 3 4 5 6 7 8 Time (hr) IL U-100 = insulin lispro 100 U/mL; IL U-200 = insulin lispro 200 U/mL 1. EMA/CHMP:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Assessment_Report_-_Variation/human/000088/WC500176634.pdf Biodel 531: U400 insulin with basal and prandial action BIOD-531 is a concentrated (U-400) EDTA/citrate/MgSO 4 formulation of recombinant human insulin (RHI) with a biphasic pharmacokinetic (PK) profile characterized by ultra-rapid insulin absorption and a secondary long term basal phase. The estimated duration of action of BIOD-531 when given by subcutaneous injection is 18 hours. 1 Insulin products marketed as providing both prandial and basal coverage in single injections are associated with slow rates of absorption, making them not well suited for coverage of meal time glucose excursions 1-3 ADA 75 th Scientific Sessions June 5-9, 2015, Boston, MA Poster #977-P 16

Absorption Speed (T ins50%early ) of Representative Prandial & Prandial/Basal Insulins on the Market vs. BIOD-531 50 40 Minutes 30 20 10 0 Humalog Mix 75/25 (U-100) Humulin R U-500 (U-500) Humulin R (U-100) Increased Speed of Absorption Humalog (U-100) BIOD-531 (U-400) ADA 75 th Scientific Sessions June 5-9, 2015, Boston, MA Poster #977-P Pharmacokinetic Profiles 120 100 BIOD-531 before meal Humalog Mix 75/25 before meal Humulin R U-500 before meal BIOD-531 after meal Insulin (mu/l) 80 60 40 20 0 0 120 240 360 480 600 720 Test insulin (Before or After Standard Breakfast) Standard Lunch (No insulin) Minutes Post-Dose 17

Mean Glucose Responses to BIOD-531 Vs. Humalog Mix 75/25 & Humulin R U-500 over 12 Hour Period of Observation 300 275 BIOD-531 before meal Humalog Mix 75/25 before meal Humulin R U-500 before meal 250 BIOD-531 after meal Blood Glucose (mg/dl) 225 200 175 150 125 100 75 Minutes -60 0 60 120 180 240 300 360 420 480 540 600 660 720 Test insulin (Before or After Standard Breakfast) Standard Lunch (No insulin) Average Glucose Concentrations: BIOD-531 Vs. Humalog Mix 75/25 Vs. Humulin R U-500 Average Glucose Concentration (mg/dl) 275 250 225 200 175 BIOD-531 before meal Humalog Mix 75/25 before meal * # Humulin R U-500 before meal BIOD-531 after meal * # * # * # * 150 After Breakfast After Lunch Overall Test Period * p<0.05 for before meal BIOD-531 comparison # p<0.05 for after meal BIOD-531 comparison 18

Results Continued Percentage of Glucose Values Between 70-180 mg/dl Target Range: BIOD-531 Vs. Humalog Mix 75/25 Vs. Humulin R U-500 70 BIOD-531 before meal Humalog Mix 75/25 before meal Percent Within 70-180 mg/dl Target Range 60 50 40 30 20 10 * Humulin R U-500 before meal BIOD-531 after meal # * # * # * # 0 After Breakfast After Lunch Overall Test Period * p<0.05 for before meal BIOD-531 comparison # p<0.05 for after meal BIOD-531 comparison 3 subjects required IV glucose during dosing studies (1 required 15-30 grams for all 4 dosing sessions; 1 required 15 grams after treatment with BIOD-531 administered after meal; 1 required 30 grams after treatment with BIOD-531 administered before meal) U500 Insulin Data on File Eli Lilly and Company 19

Humulin R U-500 Is Highly Concentrated Humulin R U-500 contains 500 units of insulin in each milliliter (5 times more concentrated than Humulin R U-100) Humulin R U-500 allows a patient to inject 1/5 the insulin volume when compared to injecting the same dose of a U-100 insulin 100 units of U-100 insulin in a U-100 syringe (100 unit markings) = OR 100 units of U-500 insulin in a U-100 insulin syringe (20 unit markings) 100 units of U-500 insulin in a volumetric syringe (0.2 ml) U-500 = 500 units/ml, U-100 = 100 units/ml 1. U-500 Regular Insulin prescribing information, 2013. This shows the same dose (actual units) R U 500 Is Highly Concentrated U 500 R contains 500 units of insulin in each milliliter (5 times more concentrated than U 100) U 500 R allows a patient to inject 1/5 the insulin volume when compared to injecting the same dose of a U 100 insulin 100 units of U 100 insulin in a U 100 syringe (100 unit markings) = OR 100 units of U 500 insulin in a U 100 insulin syringe (20 unit markings) 100 units of U 500 insulin in a volumetric syringe (0.2 ml) This shows the same dose (actual units) U 500 = 500 units/ml, U 100 = 100 units/ml 1. Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly & Co; 2013. 20

Pharmacokinetics of Concentrated Insulin: U500 R 100 90 Serum Insulin (μu/ml) 80 70 60 50 40 30 20 10 ARI U-500 Insulin NRI U-100 Insulin NPH Insulin 0 0 1 2 3 4 5 6 7 8 Time in Hours Adapted from Galloway JA, et al. Diabetes Care. 1981;4:366 Pharmacokinetic/pharmacodynamic modeling of U-500R doses at steady-state during 24 hours of Day 5: 500 U QD, 250 U BID, 165 U TID de la Pena A et al. J Diabetes Sci Technol 2014; DOI: 10.1177/1932296814532326 21

U-500R: Trends of Use Numbers of Patients Using U-500R per Year from 2005 to 2013 6000 5500 5000 4500 All U 500R Treated Patients Incident (New) Prevalent (Existing) 5175 5481 5389 ADA 75 th Scientific Sessions June 2015, Boston MA Poster #265 Number of Patients 4000 3500 3000 2702 2500 2214 1903 2000 1670 1978 1859 1500 834 1415 1000 536 955 500 500 475 447 237 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 Year 3944 6000 U 500R Treated Patients with Type 2 Diabetes 5500 Type 2 Incident (New) 5212 5000 Type 2 Prevalent (Existing) 5144 4500 4890 4000 Number of Patients 3500 3000 2500 2000 2562 3721 2104 1807 1500 1568 1873 1777 ADA 75 th Scientific Sessions June 2015, Boston MA Poster # 265 1350 1000 772 502 895 470 500 414 447 223 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 22

350 U 500R Treated Patients with Type 1 Diabetes* Number of Patients 300 250 200 Type 1 Incident (New) Type 1 Prevalent (Existing) 150 140 110 102 96 100 105 62 82 50 34 65 30 60 33 28 14 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 * Y axis scale is different from previous 2 graphs Year 223 285 269 245 The total numbers of patients treated with U-500R increased approximately 10-fold from 2005 to 2013. The number of incident users of U-500R increased between 2007 and 2010 but remained steady from 2010 to 2013. ADA 75 th Scientific Sessions June 2015, Boston MA Poster # 265 Recent review and meta analysis 9 MDI series (310 patients): 1.59% decrease in A1C (95% CI, 1.26 1.92) 51.9 unit increase in insulin dose over 6 36 mean months of use (95% CI, 19.6 84.1) 4.38 kg weight gain (95% CI, 2.35 6.41) 6 CSII series (55 patients): Clinical Case Series Results (Literature Review 2003 2012) 1.64% decrease in A1C (95% CI, 1.14 2.14) 13.6 unit decrease in insulin dose over 3 to 30 mean months of use (95% CI, 42.4 to 15.2; NS) 2.99 kg weight gain (95% CI, 1.83 7.81; NS) U 500 = 500 units/ml, A1C, glycated hemoglobin; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injections; NS, nonsignificant. U 500 regular insulin is not approved for use by CSII Reutrakul S, et al. J Diabetes Sci Technol. 2012;6(2):412 420. 23

Off-Label Pump Use in Patients using U-500R Percent (%) 100 90 80 70 60 50 40 30 20 10 0 Type 2 Patients Incident Type 2 Patients Prevalent Patients with Type 2 Diabetes 16.14 27.98 23.77 Year Percent (%) 100 90 80 70 60 50 40 30 20 10 0 Patients with Type 1 Diabetes Type 1 Patients Incident Type 1 Patients Prevalent 2005 2009 2013 Year The proportion of patients using U-500R in a pump increased from less than 20% in 2005 to over 30% in 2013. The majority of patients with type 1 diabetes treated with U-500R in 2009 and 2013 used the pump. U-500R is not FDA-approved for use in pumps ADA 75 th Scientific Sessions June 2015, Boston MA Poster # 265 U-500 Regular Insulin: Use by CSII (Study 1) Design: Retrospective study of patients with type 2 diabetes switched from multiple daily injections or lispro in CSII to U-500 regular insulin by CSII (N = 4) Results: Improved glycemic control with mean A1C decreasing from 10.8% at baseline to 7.6% at 3 months and to 7.3% at 6 months Dramatically decreased daily insulin requirements in 2 patients from mean 446 units to 201 units Essentially unchanged insulin dosage in the other 2 patients despite A1C improvement Mean volume of daily insulin infused decreased by at least 4-fold Estimated cost savings for treatment projected to 12 months = $2,600 for insulin; $3,400 for pump supplies (2002 AWP) U-500 regular insulin is not approved for use by CSII. Knee TS, et al. Endocr Pract 2003;9(3):181-186. 24

U-500 Regular Insulin: Use in CSII* (Study 2) Design: Retrospective study of patients with type 2 diabetes on prior MDI or CSII using U-100 insulin analogs (N = 9) Results: Decrease in mean A1C from 8.8% to 7.66% (p=0.026) after 3 months of U-500 insulin in CSII No clinically significant hypoglycemia No statistically significant weight gain was observed A1C (%) 9 8.8 8.6 8.4 8.2 8 7.8 7.6 7.4 7.2 7 Baseline p=0.026 3 Months *off-label use Lane, WS. Endocrine Practice. 2006;12(3):251-6. U-500 Regular Use In CSII* (Study 3) Retrospective study: 6 patients with Type 2 DM with mean U- 100 insulin requirement 391 + 91 units/day, mean HbA1c 9.1% + 1.8% At 6 months on U-500 by CSII, mean insulin dose 296 + 68 units/day (59.2 pump units ) Mean HbA1c at 6 months on U- 500 by CSII 6.9% + 0.9% (p = 0.03). Mean weight loss of 6.1 lbs at 6 months on U-500 by CSII No clinically significant hypoglycemia Higher patient satisfaction with U-500 by CSII p = 0.03 *off-label use Adapted from: Bulchandani DG, et al. Endocrine Practice. 2007;13(7):721-5. 25

U-500 Regular Insulin: Use by CSII (Study 4) Design: Prospective study of patients with type 2 diabetes on prior MDI or CSII using U-100 insulin or insulin analogs (N = 20 completers) Results: Mean decrease of 1.23% (endpoint A1C 7.37%) (p<0.001) after 12 months of U-500 regular insulin in CSII Mean weight gain was 5.4 kg at 12 months (p<0.001) No significant change in total daily insulin dose (from 196.4 units at baseline to 208.6 units at 12 months) A1C (%) 9.5 9 8.5 8 7.5 7 6.5 6 5.5 5 4.5 4 * U-500 regular insulin is not approved for use by CSII. Lane WS, et al. Endocr Pract 2010;16(5):778-784. *p <0.001 26

U-500 Insulin by Omnipod*: CGM Results Glycemia at Baseline and 12 Months Percent of Time 80 70 60 50 40 30 20 10 0 p =.149 p <.0001 Hypoglycemia <70 Normal Glycemia 70-180 p <.0001 Hyperglycemia >180 Baseline 12 Month Lane WS et al Endocrine Practice. 2010; 16(4) 778-784 *Off-label use PJ: Baseline CGM 27

PJ: CGMS on U-500 by CSII at 52 weeks U 500 Regular Insulin: Use by CSII DESIGN Retrospective study of patients with 60 insulin resistant T2DM and high insulin requirements (N = 59) treated with U 500 regular insulin by CSII for 40 1 to 9.5 years RESULTS 20 Mean decrease in A1C of 1.0% from baseline of 8.3% (P =.003) within 3 months 0 60% of the patients achieved a sustained A1C <7.5%, while 31% achieved A1C <7.0% No statistically significant weight gain at any time point No significant change in TDD from baseline to any time point up to 114 months after initiation of U 500 insulin Rate of severe hypoglycemia was 0.1 per patient per year U 500 = 500 units/ml, A1C: glycated hemoglobin; CSII, continuous subcutaneous insulin infusion; TDD, total daily insulin dose. U 500 regular insulin is not approved for use by CSII Lane WS, et al. Endocr Pract. 2012;27:1 18. Patients (n) Total A1C 7.5% A1C 7.0% 12 24 36 48 Months 28

Glycemic Durability of U-500 by CSII: 9 year data (n=59) Lane WS et al. Endocrine Practice 2013: Vol 19 No.2, 196-201 U 500 Insulin: Patient Satisfaction Patients (N = 36) receiving U 500 for 6 months were given a QoL questionnaire to assess whether satisfaction changed after starting U 500 1 Significant (P <.001) improvement in satisfaction with Diabetes treatment 1 Ability to determine blood sugar 1 Time needed for Overall diabetes control 1 diabetes management 1 Knowledge about diabetes 1 Factors contributing to patient satisfaction with U 500 use: Smaller injection volumes with less insulin leakage 1 Less burning or pain 1 Fewer injections 1 3 U 500 = 500 units/ml, QoL, quality of life 1. Dailey AM, et al. Diabetes Res Clin Pract. 2010;88(3):259 264. 2. Boldo A, Comi RJ. Endocr Pract. 2012;18(1):56 61. 3. Quinn SL, et al. Pharmacotherapy. 2011;31(7):695 702. 29

Adherence to Index Insulin Regimens Adherence to the index regimen (PDC index) during the post index period was significantly greater in the U 500 vs the U 100 cohort (mean PDC index: 65.2% vs 39.5%, P <.0001) Proportion of Individuals, % 40 35 30 25 20 15 10 5 0 A <20% 20% <40% 40% <60% 60% <80% 80% Proportion of Individuals, % 40 35 30 25 20 15 10 5 0 B <20% 20% <40% 40% <60% 60% <80% 80% PDC Index Categories U 500 U 100 PDC 200 Categories U 500 = 500 units/ml, U 100 = 100 units/ml, PDC index, the proportion of days covered using the index insulin regimen; PDC 200, the proportion of days covered using a minimum daily dose >200 units. Eby EL, et al. J Med Econ. 2013;16(4):529 538. U 500 Regular Insulin: Dosage and Administration Use a U 100 insulin syringe or tuberculin syringe 1 3 The actual unit dose of U 500 R does not match the unit markings on a U 100 syringe 1 3 When prescribing U 500 R, the amount should be written in actual units and unit markings on the U 100 syringe OR actual units and volume (ml) on a tuberculin syringe 1 3 U 500 = 500 units/ml, U 100 = 100 units/ml 1. Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly & Co; 2013. 2. Lane WS. et al. Endocr Pract. 2009;15(1):71 79. 3. Segal AR, et al. Am J Health Syst Pharm. 2010;67(18):1526 1535. 30

U 500 Regular Insulin: Dosage and Administration (cont d) Because U 500 R insulin takes effect within 30 minutes, a meal should follow within 30 minutes of administration 1 3 U 500 R should only be administered subcutaneously 1,3 Most patients require 2 or 3 injections daily 1 3 No data support mixing U 500 regular insulin with other insulins or concurrent use with OADs 1 U 500 = 500 units/ml, U 100 = 100 units/ml 1. Humulin R U 500 [package insert]. Indianapolis, IN: Eli Lilly & Co; 2013. 2. Lane WS. et al. Endocr Pract. 2009;15(1):71 79. 3. Segal AR, et al. Am J Health Syst Pharm. 2010;67(18):1526 1535. Dosage Conversion Charts Conversion using tuberculin syringe U 500 insulin Volume (ml) dose (units) 0.1 50 0.2 100 0.3 150 0.4 200 0.5 250 0.6 300 0.7 350 0.8 400 0.9 450 1.0 500 Conversion using U 100 insulin syringe U 100 syringe (units) U 500 insulin dose (units) 0.1 50 0.2 100 0.3 150 0.4 200 0.5 250 0.6 300 0.7 350 0.8 400 0.9 450 1.0 500 31

Algorithm for U 500 Regular Insulin Therapy TDI Dose (units/day) 150 300 Injection Frequency/ Delivery Method a 2 injections/day (AM & PM) with or without basal insulin 3 injections/day (AM, noon, and PM) with or without basal insulin CSII Dosage Distribution (% of TDD) b AM injection 60% TDD PM injection = 40% TDD (ie, 60/40) 40/30/30 or 45/35/20 or 40/40/20 24 hour basal insulin infusion + 3 mealtime boluses (eg, 50% TDD for basal rate and 20/15/15 for mealtime boluses or 20% TDD for basal rate and 30/25/25 for mealtime boluses) U 500 = 500 units/ml, AM refers to pre breakfast; noon refers to pre lunch; PM refers to pre evening meal; CSII: continuous subcutaneous insulin infusion, TDD: total daily dose (of insulin), TDI: total daily insulin a U 500 regular boluses recommended at least 30 minutes premeal; dosage titration is according to frequent self monitored blood glucose; b Empirically reduce the conversion dose from U 100 insulins by 10% to 20% if baseline glycated hemoglobin (A1C) is 8%, and increase the dose by 10% to 20% if A1C 10%. U 500 regular insulin is not approved for use by CSII Adapted from Lane WS, et al. Endocr Pract. 2009;15(1):71 79. U 500 Insulin: BID or TID? 325 patients with T2DM with mean baseline U 100 insulin dose 287.5 U/day in 5 injections/day with mean baseline HbA1c 8.7% were randomized to receive U 500 insulin BID or TID. Results showed both regimens had comparable HbA1c reduction at 24 weeks (BID: 1.22%; TID 1.12%; p <.001 vs. baseline for each regimen), comparable increases in total daily insulin dose for each regimen, comparable weight gain (BID: 4.9 kg, TID: 5.4 kg) and comparable incidence of severe hypoglycemia for each regimen, HOWEVER: Incidence and rates of documented symptomatic and nocturnal hypoglycemia (BG <70 mg/dl) and nocturnal hypoglycemia (BG < 50) were significantly lower for TID vs. BID. Hood, RC, Arakaki, RF, Wysham C. et al: Endocr Practice 2015;21: 782 793 64 32

Algorithm for U 500 Regular Insulin Therapy (cont d) TDI Dose (units/day) Injection Frequency/ Delivery Method a 3 injections/day (AM, noon, and PM) with or without basal Dosage Distribution (% of TDD) b 40/30/30 or 45/35/20 or 40/40/20 300 600 4 injections/day (AM, noon, PM, bedtime) 30/30/30/10 CSII Same as above U 500 = 500 units/ml, AM refers to pre breakfast; noon refers to pre lunch; PM refers to pre evening meal; CSII: continuous subcutaneous insulin infusion, TDD: total daily dose (of insulin), TDI: total daily insulin a U 500 regular boluses recommended at least 30 minutes premeal; dosage titration is according to frequent self monitored blood glucose; b Empirically reduce the conversion dose from U 100 insulins by 10% to 20% if baseline glycated hemoglobin (A1C) is 8%, and increase the dose by 10% to 20% if A1C 10%. U 500 regular insulin is not approved for use by CSII Adapted from Lane WS, et al. Endocr Pract. 2009;15(1):71 79. Algorithm for U 500 Regular Insulin Therapy (cont d) TDI Dose (units/day) Injection Frequency/ Delivery Method a Dosage Distribution (% of TDD) b >600 4 injections/day (AM, noon, PM, and bedtime) 25/25/25/25 or 30/30/30/10 U 500 = 500 units/ml, AM refers to pre breakfast; noon refers to pre lunch; PM refers to pre evening meal; CSII: continuous subcutaneous insulin infusion, TDD: total daily dose (of insulin), TDI: total daily insulin a U 500 regular boluses recommended at least 30 minutes premeal; dosage titration is according to frequent self monitored blood glucose; b Empirically reduce the conversion dose from U 100 insulins by 10% to 20% if baseline glycated hemoglobin (A1C) is 8%, and increase the dose by 10% to 20% if A1C 10% U 500 regular insulin is not approved for use by CSII Adapted from Lane WS, et al. Endocr Pract. 2009;15(1):71 79. 33

U 500 Regular Insulin: Safety Extreme caution must be used in measuring U 500 dosage; inadvertent overdose may result in serious adverse reaction or life threatening hypoglycemia Hypoglycemia is the most common adverse reaction of all insulin therapies, including U 500 Hypoglycemia can occur suddenly, symptoms may vary among individuals, and be different or less pronounced under certain conditions Severe hypoglycemia may develop 18 to 24 hours after the original injection of U 500 U 500 = 500 units/ml Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly & Co; 2013. U 500 Regular Insulin: Safety (cont d) Any change of insulin therapy should be made cautiously and only under medical supervision 1 When initiating U 500 R insulin, patients require close observation until the appropriate dosage is established 1 As with all patients with T2DM Frequent glucose monitoring is recommended 2,3 Patients must be taught the signs and symptoms of hypoglycemia and the importance of testing their blood glucose 1 3 Family members or others close to the patient should be instructed on the appropriate use of glucagon 2,3 U 500 = 500 units/ml 1. Humulin R U-500 [package insert]. Indianapolis, IN: Eli Lilly & Co; 2013. 2. Lane WS, et al. Endocr Pract. 2009;15(1):71 79. 3. Segal AR, et al. Am J Health Syst Pharm. 2010;67(18):1526 1535. 34

Distinctive Labeling Differentiates U 500 from U 100 U 500 carton and vial label are marked with diagonal brown stripes and labeled U 500 (Concentrated), 500 units/ml, and Important See instructions for use in bold, red letters Carton states: Warning High Potency Not for Ordinary Use in bold, red letters U 500 vial contains 20 ml (10,000 units) versus the U 100 vial, which contains 10 ml (1000 units) U 500 = 500 units/ml, U 100 = 100 units/ml 1. Segal AR, et al. Am J Health Syst Pharm. 2010;67(18):1526 1535. Potential Algorithm to Initiate U 500 Regular Insulin by CSII* Determine 24 hour basal insulin requirement Divide by 24 and divide this amount by 5 (for pump units) Administer as a single 24 hour basal rate by CSII Example: 24 hour basal insulin requirement = 120 units = 5 units per hour basal rate (U 100 insulin) = 5 units (1 pump unit) per hour basal rate (U 500 insulin) *off label use 35

Initial Meal Bolus Ratio: Potential Algorithm to Initiate U 500 Insulin by CSII* (cont d) If carb counting: Multiply carb ratio factor by 5. Example: Patient uses 1 unit U 100 insulin per 3 grams carbohydrate = 5 units U 500 insulin (1 pump unit) per 15 grams carbohydrate If not carb counting: Divide usual meal boluses by 5 (for pump units) Example: Patient takes 30 units U 100 insulin per meal = 30 units U 500 (6 pump units) per meal *off label use Initial Correction Bolus: Potential Algorithm to Initiate U 500 Insulin by CSII* (cont d) Use target BG of 100 (or as appropriate); use insulin sensitivity factor of 100 Example: BG = 200. Correction dose U 500 = 200 minus 100=100 divided by 100 = 1 pump unit (5 total units insulin) *off label use 36

Initiation of U 500 Insulin by CSII*: Safety Be sure to: Have patient monitor CBGs frequently and report them 24 to 48 hours after CSII initiation for pump setting adjustments Expect improved insulin sensitivity and possible decrease in insulin requirement, especially in night basal rate, within the first few days. Good communication with pump nurse for first few weeks is mandatory! Insulin requirement may drop dramatically initially, requiring ongoing CSII adjustments. *off label use To limit insulin associated weight gain, U 500 insulin can be combined with other glucose lowering agents, including: Metformin Combining U 500 Insulin with Insulin Sparing Agents GLP 1 receptor agonists (exenatide, liraglutide) SGLT 2 inhibitors (canagliflozin, dapagliflozin) Note: U 500 insulin should NOT be administered with thiazolidinediones Combination associated with excessive weight gain, edema, and heart failure. 37

Concomitant Use of U 500 Regular Insulin with Liraglutide 1 DESIGN Retrospective, observational case series in patients with T2D treated with U 500 regular insulin (MDI or CSII), liraglutide with/without metformin (N = 15) RESULTS At 12 weeks, A1C% decreased by 1.4 from a baseline value of 8.5% (P =.0001) TDD was reduced by 28% (mean change 53 ±35 units/day, P =.0001) Body weight decreased by an average of 5.1 ±3.9 kg (P =.0001) No severe episodes of hypoglycemia A1C (%) 12 10 8 6 4 2 0 Baseline * 12 Weeks *P =.0001 U 500 = 500 units/ml, A1C: glycated hemoglobin; CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injections; TDD, total daily insulin dose 1. Lane WS, et al. Diabetes Technol Ther. 2011;13(5):592 595. Sometimes size does matter 38