New Insulin Formulations Guillermo Umpierrez, MD, FACP, FACE Professor of Medicine Emory University School of Medicine Part 2 1

Hypoglycemia* (events/patient year) Insulin Glargine vs 70/30 Premixed Insulin in OHA Failures N=371 insulin-naïve patients Insulin Glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeks Twice-daily premixed insulin Insulin Glargine + OADs p=0.0003 9 5 5.7 1.3% 1.7% 4 8 Hypoglycemia* (events/patient year) p=0.0009 3 7.5% HbA1c (%) 7 7.2% 2.6 2 70/30 IS NOT BETTER THAN BASAL AND IS ASSOCIATED WITH HIGHER RATE OF HYPOGLYCEMIA 6 1 5 *Confirmed symptomatic hypoglycemia (blood glucose <60 mg/dl [<3.3 mmol/l]) Janka H, et al. Diabetes Care 2005;28:254−259.

Stepwise Intensification: 1-2-3 Study Design Group 1:GLAR + OADs + 1GLU Poorly controlled on OADs (N=785) A1C >7.0% (n=343) N=113 Group 2: GLAR + OADs + 2GLU Switched to GLAR for 14 weeks Group 3: GLAR + OADs + 3GLU N=115 Randomization and 24 week F/U Multicenter, open-label, randomized, 3-arm, parallel-group (1:1:1) study in adult patients with T2DM On a stable dose of 2 or 3 OADs (rosiglitazone reduced from 8mg to 4mg per label) Had an A1C >8.0% at screening visit 14-week run-in treatment phase Added insulin glargine to current OAD regimen Insulin glargine initiated at 10 U/d and titrated every 2 days to target FG 70-109 mg/dL Patients with A1C >7.0% at end of run-in were randomized to receive prandial injections of insulin glulisine Randomized treatment phase 3 arms: Insulin glargine + insulin glulisine before The meal with greatest glycemic index (1) The 2 meals with greatest glycemic index (2) All 3 meals (3) Insulin glulisine was administered 0-15 minutes before meals Initial glulisine dose was 1/10th of the glargine does at randomization Weekly titration to target PPG 70-109 mg/dL and HS level 70-129 mg/dL Insulin glulisine was administered 0-15 minutes before greatest glycemic index meal Initial glulisine dose was 1/10th of the glargine does at randomization Weekly titration to target PPG 70-109 mg/dL and HS level 70-129 mg/dL OADs were continued. GLAR = insulin glargine; GLU = insulin glulisine; OADs=oral antidiabetic agents. Davidson MB et al. Endocr Pract. February 16, 2011. 3 3

A1C Change From Baseline to Week 24 Following 14-week run-in with insulin glargine Mean A1C decreased from >10.0% to ~8.0% 288 patients achieved A1C 7.0% Final dose was 0.55 U/kg regardless of reaching target Figure 3 mITT = modified intent to treat. Davidson MB et al. Endocr Pract 2011

Characteristics of Available Basal Insulin Analogs Benefits over NPH Longer duration of action Less variability Less weight gain Less hypoglycemia Room for Improvement More consistent 24+ hour coverage Flat time-action profile Less day-to-day variability Less weight gain Less hypoglycemia More suppression of hepatic glucose production FXCX: Simon pdf in Zotero Grunberger pef in Zotero Simon ACR. Diabetes Technol Ther. 2011;13(suppl 1):S103-108. Grunberger G. Diab Obes Metab. 2013; 15(suppl 1):1-5.

*Glargine U-300 *Degludec *Pegylated Lispro New Basal Insulin Formulations *Glargine U-300 *Degludec *Pegylated Lispro * Not FDA Approved

High concentration glargine (U300)* U300 insulin glargine offers a smaller depot surface area leading to a reduced rate of absorption Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and more consistency Half-life is ~23 hours Steady state in 4 days Duration of action ≤36 hours FXCX: Simon pdf in Zotero Grunberger pef in Zotero *Not FDA approved Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19. Steinstraesser A, et al. Diabetes Obes Metab. 2014 Feb 26. [Epub ahead of print]. http://www.australianprescriber.com/magazine/19/3/76/8. Accessed March 11, 2014.

Pharmacokinetics of U-300 Insulin Glarginea in Healthy Volunteers 35 30 25 20 15 10 5 2 4 6 8 12 14 16 18 22 24 26 28 Concentration (uIV/mL) Time U-100 0.4 U/kg (n = 24) U-300 0.4 U/kg (n = 23) Becker R, Hahn A, Boderke P, Fuerst C, Mueller W, Tertsch K, Werner U, Loos P. Long-acting formulations of insulin. Sanofi-Aventis Deutschland GmbH, Frankfurt am Main. Filed 5/17/2011. 0.4 U/kg dose: [0010] Healthy volunteers: [0565] a U-300 insulin glargine is not FDA approved for clinical use. Becker R, et al. European Patent EP 2 387 989 A2. 2011.

Pharmacodynamics of U300 Glargine vs U100 Glargine 3.0 SC Injection U100 0.4 U/kg-1 U300 0.4 U/kg-1 U300 0.6 U/kg-1 U300 0.9 U/kg-1 2.5 2.0 GIR (mg/kg-1 min-1)* 1.5 1.0 0.5 6 12 18 24 30 36 Time (hours) The U-300 glargine has a flatter more prolonged effect The time it takes for 50% of the effect of a single injection U-100 = 12.1 hours U-300 = 16.7 hours FXCX: Bullet 1=Found i abstract 920-P Could not find figure Permissions needed to reuse figure Bullet 2 could not find data in abstract 920-P GIR = glucose infusion rate. Tillner J, et al. Poster 920P 73rd ADA Scientific Sessions June 21-25, 2013, Chicago, IL. http://ada.apprisor.org/epsAbstract.cfm?compid=1&id=1. Accessed March 21, 2014.

U300 Glargine vs U100 Glargine in Type 2 Diabetes Mean A1C (%) 8.5 6.5 Baseline Month 6 LOCF Time Month 6 Week 12 8.0 U300 U100 7.5 7.0 Mean change in A1C for both treatment groups -0.83% No difference in A1C change Lower rate of severe or confirmed hypoglycemia, particularly overnight Time period U100 U300 RR with U300 CI 0-6 months Nocturnal 57.5% 44.6% 0.78 0.68 – 0.89 9 weeks – 6 mo 46.0% 36.1% 0.79 0.67 – 0.93 24 hours 87.8% 81.9% 0.93 0.89 – 1.04 FXCX: Abstract 43-LB in zotero Cannot find the figure Found abstract 43-LB; A1C data contained in abstract but not the graph itself Hypoglycemia data in table: abstract contains data for 9weeks-6mo only; does not contain other time points (nocturnal or 24 hours) Permissions needed to reuse figure and table Riddle MC et al. Presentation 43-LB 73rd ADA Scientific Sessions June 21-25, 2013, Chicago, IL. http://ada.apprisor.org/epsAbstract.cfm?compid=1&id=1. Accessed March 21, 2014.