New EDITION(s) and a BRIGHT Outlook DEVOTE(d) to DELIVER(ing) Improved Patient Care with Second- Generation Basal Insulin Analogs

Transcription

1 New EDITION(s) and a BRIGHT Outlook DEVOTE(d) to DELIVER(ing) Improved Patient Care with Second- Generation Basal Insulin Analogs Matthew D. Stryker, Pharm.D., BCACP, CLS Matthew.Stryker@acphs.edu Assistant Professor Clinical Pharmacy Specialist Albany College of Pharmacy and Health Sciences Albany Medical Center Division of Community Endocrinology Albany College of Pharmacy and Health Sciences

2 Conflicts of Interest DISCLOSURES Clinical Investigator Novo Nordisk A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes Mellitus (PIONEER 6; NCT ) Efficacy and Safety of Oral Semaglutide Versus Empagliflozin in Subjects With Type 2 Diabetes Mellitus (PIONEER 2; NCT ) Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects with Type 2 Diabetes Mellitus (PIONEER 4; NCT ) Amgen Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management: A Registry of High Cardiovascular Risk Subjects in the United States (GOULD; NCT ) Grant Recipient/Research Support AstraZeneca Pharmaceuticals, LP Speakers Bureau Amgen Regeneron Pharmaceuticals, Inc. Albany College of Pharmacy and Health Sciences 2

3 Learning Objectives SECOND-GENERATION BASAL INSULIN ANALOGS Articulate pharmacokinetic differences between the new long-acting basal insulin analogs Describe the efficacy (e.g., change in HbA 1c, fasting plasma glucose) seen with the new longacting basal insulin analogs Recognize the clinical utility, notably impact on hypoglycemia, with the new long-acting basal insulin analogs Albany College of Pharmacy and Health Sciences 3

4 Abbreviations Used Throughout SECOND-GENERATION BASAL INSULIN ANALOGS ± standard deviation α-gi α-glucosidase inhibitor aor adjusted odds ratio BID twice daily BMI body mass index CCI Charlson Comorbidity Index CDC Centers for Disease Control CI confidence interval CKD chronic kidney disease CV cardiovascular CVD cardiovascular disease DPP-4i dipeptidyl peptidase-4 inhibitor(s) ED emergency department egfr estimated glomerular filtration rate ER extended-release Flex flexible FOB follow-on biologic GLIN glinide (i.e., meglitinide) GLP-1 (RA) glucagon-like peptide-1 (receptor agonist) ICD International Classification of Diseases IDeg insulin degludec IDet insulin detemir IGlar insulin glargine Invest. investigator MACE major adverse cardiovascular events MET metformin mitt modified intent-to-treat Mult. Symp. multiple symptomatic NPH neutral protamine Hagedorn OAD(s) oral antidiabetic drug(s) PIO pioglitazone PO by mouth PPYE per patient-year of exposure QDay once daily QW once weekly RRR relative risk reduction SFU sulfonylurea SGLT2(i) sodium-glucose cotransporter-2 (inhibitor) SMPG self-monitored plasma glucose SQ subcutaneously T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus Top. topically TZD thiazolidinediones US United States Albany College of Pharmacy and Health Sciences 4

5 HISTORY OF PRESENT ILLNESS EL is 47-year-old female with type 2 diabetes mellitus (T2DM). She was diagnosed with T2DM 15 years ago and her glycemic control has been adequate until recently. You, her primary care provider, have elected to proceed with an insulin-based regimen (basal). Dyslipidemia Rosacea Hypertension Type 2 diabetes mellitus Obesity (class II) PAST MEDICAL HISTORY CURRENT MEDICATIONS Atorvastatin 10 mg: 1 PO QDay Brimonidine 0.33% gel: top. QDay Chlorthalidone 25 mg: 1 PO QDay Dulaglutide 1.5 mg/0.5 ml: 1.5 mg SQ QW Empagliflozin 25 mg: 1 PO QDay Metformin 1 g ER: 2 PO QDay Pioglitazone 30 mg: 1 PO QDay Image: Albany College of Pharmacy and Health Sciences 5

6 Lab Blood Pressure Reference Range / Target September 2018 June 2018 February 2018 November 2017 < 140/90 mm Hg 138/86 132/86 134/88 134/86 Height Inches Weight Lbs. (Kg) 270 (123) 272 (124) 268 (122) 269 (122) BMI Pulse kg/m to 100 beats per minute HbA 1c 6.5% LDL-C < 70 mg/dl Non-HDL-C < 100 mg/dl egfr (MDRD) PERTINENT VITALS AND LABORATORY DATA 90 to 120 ml/min/1.73 m Abbreviations: BMI body mass index; egfr estimated glomerular filtration rate; kg kilograms; lbs. pounds; LDL-C lowdensity lipoprotein cholesterol; MDRD Modification of Diet in Renal Disease; non-hdl non-high-density lipoprotein cholesterol Albany College of Pharmacy and Health Sciences 6

7 EL S INSURANCE S FORMULARY (COMMERCIAL PLAN) DRUG NAME ANTIDIABETICS, INSULINS DRUG TIER REQUIREMENTS/ LIMITS HUMULIN R INJ U PD HUMULIN R INJ U QL (6 PENS PER 30 DAYS) NOVOLIN INJ 70/30 2 OTC; PD, OTC NOVOLIN N INJ U OTC; PD, OTC NOVOLIN R INJ U OTC; PD, OTC NOVOLOG INJ 100/ML 2 PD NOVOLOG INJ FLEXPEN 2 PD NOVOLOG INJ PENFILL 2 PD NOVOLOG MIX INJ 70/30 2 PD NOVOLOG MIX INJ FLEXPEN 2 PD TOUJEO INJ 300UNIT 3 PD Image: TRESIBA INJ 100/200UNIT 3 PD Albany College of Pharmacy and Health Sciences 7

8 Pre-Lecture Question Which basal insulin are you most likely to initiate for EL based on the information provided? A. Humulin R U units SQ QDay B. Novolin R U units SQ QDay C. Toujeo U units SQ QDay D. Tresiba U units SQ QDay Albany College of Pharmacy and Health Sciences 8

9 Insulin Approvals Through the Decades BACKGROUND Insulin Lispro Insulin Aspart Insulin Glargine U-100 Inhaled Human Insulin (Afrezza) Fast-Acting Insulin Aspart Insulin Lispro FOB NPH Insulin First clinical use of insulin Lente Insulin* Insulin Regular * No longer commercially available Insulin Glulisine Insulin Detemir Inhaled Human Insulin (Exubera)* Insulin Degludec Insulin Glargine U-100 FOB Insulin Glargine U-300 Albany College of Pharmacy and Health Sciences 9

10 1.Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2018 Executive Summary. Endocr Pract. 2018;24(1): Epub 2018/01/26. doi: /cs PubMed PMID: Albany College of Pharmacy and Health Sciences 10

11 ** **IGlar U-300 and IDeg: 3 to 4 days between dose increases 2,3 1.Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2018 Executive Summary. Endocr Pract. 2018;24(1): Epub 2018/01/26. doi: /cs PubMed PMID: Tresiba [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; Albany College of Pharmacy and Health Sciences 11

12 Commercially Available Basal Insulins SINGLE-ENTITY INSULIN FORMULATIONS Intermediate-Acting Insulins First-Generation Basal Insulin Analogs Second-Generation Basal Insulin Analogs Albany College of Pharmacy and Health Sciences 12

13 Clinical Considerations 4 PHARMACOKINETICS AND PHARMACODYNAMICS Basal Insulin Formulation Peak Duration of Action Half-Life Time to Steady State Dosing Frequency Insulin Degludec U-100 or U-200 Insulin Glargine U-300 Close to peakless Close to peakless 26+ hours 4 ; up to hours 3 to 4 Once days 2 daily > 24 hours 4 ; up 19 hours ~5 days 3 Once to 36 5 daily Insulin Glargine U-100 Close to peakless Up to 24 hours 12 hours ~2.5 days Once daily Insulin Detemir U-100 Close to peakless Up to 24 hours 5 to 7 hours ~1.5 days Once or twice daily Insulin NPH U to 8 hours 8 to 14 hours 4 hours ~1 day Once or twice daily Albany College of Pharmacy and Health Sciences 13

14 Glucose-Lowering Effects of Insulin Glargine 300 and 100 PHARMACOKINETICS AND PHARMACODYNAMICS On a unit-per-unit basis, Toujeo had 27% less of a glucose-lowering effect compared to Lantus over 24 hours (Treatment Ratio: 0.73; 90% CI 0.56 to 0.94) Data reflect steady state concentrations (8 days of daily insulin injections) in a euglycemic clamp study in subjects with T1DM receiving 0.4 units/kg of glargine U-300 or U-100 Image: 5. Becker RH, Dahmen R, Bergmann K, et al. New Insulin Glargine 300 Units * ml-1 Provides a More Even Activity Profile and Prolonged Glycemic Control at Steady State Compared with Insulin Glargine 100 Units * ml-1. Diabetes Care. 2015;38(4): Epub 2014/08/26. doi: /dc PubMed PMID: Albany College of Pharmacy and Health Sciences 14

15 Glucose-Lowering Effects of Insulin Glargine 300 and 100 PHARMACOKINETICS AND PHARMACODYNAMICS A STACKED DECK?!? On a unit-per-unit basis, Toujeo had 27% less of a glucose-lowering effect compared to Lantus over 24 hours (Treatment Ratio: 0.73; 90% CI 0.56 to 0.94) Data reflect steady state concentrations (8 days of daily insulin injections) in a euglycemic clamp study in subjects with T1DM receiving 0.4 units/kg of glargine U-300 or U-100 Image: 5. Becker RH, Dahmen R, Bergmann K, et al. New Insulin Glargine 300 Units * ml-1 Provides a More Even Activity Profile and Prolonged Glycemic Control at Steady State Compared with Insulin Glargine 100 Units * ml-1. Diabetes Care. 2015;38(4): Epub 2014/08/26. doi: /dc PubMed PMID: Albany College of Pharmacy and Health Sciences 15

16 Time to Treatment Intensification with Insulin Following Oral Antidiabetic Therapy 6 OAD QUANTIFYING CLINICAL INERTIA OAD In patients with an HbA 1c 7.0% * HbA 1c at therapy intensification with insulin OAD > 7.2 YEARS Mean HbA 1c 9.4%* > 7.2 YEARS Mean HbA 1c 9.8%* > 7.1 YEARS Mean HbA 1c 9.7%* Albany College of Pharmacy and Health Sciences 16

17 Intensive vs. Less Intensive Treatment T2DM Trial Microvascular Finding During Study BACKGROUND Long- Term Follow- Up Macrovascular Finding During Study Long- Term Follow- Up During Study Mortality Long- Term Follow- Up ACCORD 7 / ACCORDION 8 N/A N/A ADVANCE 9 / ADVANCE-ON 10 UKPDS 33 11/ UKPDS VADT 13 / VADT-F 14,15 Abbreviations: decreased rate; increased rate; no effect; N/A not available; T2DM type 2 diabetes mellitus Albany College of Pharmacy and Health Sciences 17

18 Image: Albany College of Pharmacy and Health Sciences 18

19 Image: Albany College of Pharmacy and Health Sciences 19

20 Historical Head-to-Head Hypoglycemia Data GENERAL HYPOGLYCEMIA NOCTURNAL HYPOGLYCEMIA Glargine vs. NPH 16 (QDay or BID NPH) Documented* symptomatic hypoglycemia with IGlar Nocturnal^ documented* symptomatic hypoglycemia with IGlar Detemir vs. NPH 17 (QDay NPH) Confirmed hypoglycemia with IDet Nocturnal confirmed hypoglycemiawith IDet Glargine vs. Detemir 18 Any hypoglycemic event with IDet No statistically significant difference in any nocturnal⁰ hypoglycemic events Data represent absolute risk reductions; p < 0.05 for all comparisons unless otherwise noted * 72 mg/dl; ^ While subject was asleep, after the evening insulin injection, and before getting up in the morning < 56 mg/dl; 2300 to 0600; ⁰ 2300 to 0559 Albany College of Pharmacy and Health Sciences 20

21 BEGIN T2DM Clinical Trials* Insulin Degludec U-100 and U-200 EDITION T2DM Clinical Trials* Insulin Glargine U-300 Basal-Bolus Added to: ASPART ± MET ± PIO LOW VOLUME Added to: MET ± DPP-4i EDITION 1 Added to: Bolus ± MET Once Long Added to: MET ± DPP-4i FLEX Added to: ± OAD (± MET ± [SFU or GLIN] ± PIO) EDITION 2 Added to: OAD (EXCEPT SFU) EDITION 3 Added to: OAD (EXCEPT SFU AND GLIN) Additional Clinical Studies DEVOTE Cardiovascular safety trial (IDeg U-100 vs. IGlar U-100) BRIGHT Comparative clinical outcome study (IDeg U-100 vs. IGlar U-300) SENIOR Comparative clinical outcome study in older adults (IGlar U-300 vs. IGlar U-100) Real-World Data CONFIRM The DELIVER Program LIGHTNING * Not inclusive of all clinical studies in each program Albany College of Pharmacy and Health Sciences 21

22 BEGIN Trial Basal-Bolus 19 Once Long 20 FLEX 21 LOW VOLUME 22 Study Design Key Inclusion Criteria Interventions 18-years-old T2DM for 6 months Current insulin use for 3 months ± OAD BMI 40 kg/m 2 7% HbA 1c 10% Randomized, phase 3, multicenter, international, non-inferiority, treat-to-target, open-label, parallel group studies 18-years-old T2DM for 6 months OAD(s)*^ use for 3 months BMI 40 kg/m 2 7% HbA 1c 10% 18-years-old T2DM for 6 months Insulin naїve and 7% HbA 1c 11% OR any basal insulin use ± OAD and 7% HbA 1c 10% BMI 40 kg/m 2 Insulin degludec 100 units/ml or glargine 100 units/ml SQ QDay Insulin aspart IDeg: QDay or Flex QDay Duration 52 weeks 26 Weeks Primary Endpoint Adults T2DM for 6 months Insulin naїve Previous treatment with metformin ± other OAD(s) $ for 3 months BMI 45 kg/m 2 7% HbA 1c 10% Insulin degludec 200 units/ml or glargine 100 units/ml SQ QDay Confirm the noninferiority of insulin degludec to insulin glargine, as assessed by change in HbA 1c from baseline to week 26 (FLEX, LOW VOLUME) or week 52 (Basal-Bolus, Once Long) * Permitted OAD(s) included metformin alone or in combination with insulin secretagogues or α-glucosidase-inhibitor; ^ DPP-4i not approved with basal insulin and sulfonylurea/glinides were discontinued for the study; $ DPP-4i not approved with basal insulin were discontinued for the study Albany College of Pharmacy and Health Sciences 22

23 Study Results BEGIN CLINICAL TRIAL PROGRAM (T2DM) BEGIN Trial Basal-Bolus 19 Once Long 20 FLEX 21 LOW VOLUME 22 Sample Size Key Baseline Demographics Treatment- Related Withdraw 59-years-old 54% male BMI: 32 kg/m 2 T2DM duration: 13 years HbA 1c : 8.3% Degludec 100: 4% Glargine 100: 4% 59-years-old 63% male BMI: 31 kg/m 2 T2DM duration: 9 years HbA 1c : 8.2% Degludec 100: 2.6% Glargine 100: 1.9% 56-years-old 54% male BMI: 29.6 kg/m 2 T2DM duration: 10.6 years HbA 1c : 8.4% Degludec 100 (Flex): 0.9% Glargine 100: 0.9% 57-years-old 53% male BMI: 32 kg/m 2 T2DM duration: 8.4 years HbA 1c : 8.3% Degludec 200: 2.2% Glargine 100: 1.8% Albany College of Pharmacy and Health Sciences 23

24 Change in HbA 1c from Baseline to Study Completion (%) No Significant Differences in HbA 1c Changes Between Degludec and Glargine 100 BEGIN CLINICAL TRIAL PROGRAM (T2DM) 0 BASAL-BOLUS 19 ONCE LONG 20 FLEX 21 LOW VOLUME * * Flex-based regimen p > 0.05 for all comparisons Added to: ASPART ± MET ± PIO Added to: MET ± DPP-4i Insulin Degludec 100 units/ml (LOW VOLUME 200 units/ml) Added to: ± OAD (± MET ± [SFU or GLIN] ± PIO) Added to: MET ± DPP-4i ± SFU ± GLIN ± α-gi Insulin Glargine 100 units/ml Albany College of Pharmacy and Health Sciences 24

25 Rate of Nocturnal (0001 to 0559) Confirmed (< 56 mg/dl) Hypoglycemia, Baseline to Study Completion (PPYE) Hypoglycemia Data BEGIN CLINICAL TRIAL PROGRAM (T2DM) 2.5 BASAL-BOLUS 19 ONCE LONG 20 FLEX 21 LOW VOLUME 22 Added to: ASPART ± MET ± PIO Added to: MET ± DPP-4i Added to: ± OAD (± MET ± [SFU or GLIN] ± PIO) Added to: MET ± DPP-4i ± SFU ± GLIN ± α-gi %^ %^ * * Flex-based regimen ^ p < 0.05; RRR 0 Insulin Degludec 100 units/ml (LOW VOLUME 200 units/ml) Insulin Glargine 100 units/ml Albany College of Pharmacy and Health Sciences 25

26 Study Design Key Inclusion Criteria Interventions Duration Primary Endpoint Main Secondary Endpoint Type 2 Diabetes Mellitus EDITION Clinical Studies EDITION 1 23 EDITION 2 24 EDITION 3 25 Randomized, phase, 3 multicenter, international, non-inferiority, open-label, parallel group studies 18-years-old T2DM 1 year Basal-bolus regimen for 1 year (basal: 42 units/day) 7% HbA 1c 10% 18-years-old T2DM for 1 year Basal insulin use for 6 months ( 42 units/day) OAD(s)* 7% HbA 1c 10% 18-years-old T2DM for 1 year Insulin naїve Use of OAD^ for 6 months 7% HbA 1c 11% Insulin glargine 300 units/ml or 100 units/ml SQ QDay 6 months with a 6-month open-label extension Change in HbA 1c from baseline to month 6 Confirmed ( 70 mg/dl) or severe nocturnal ( ) hypoglycemia from week 9 to month 6 * Recent (< 2 months) use of a sulfonylurea was not permitted before entry or during the study ^ OAD not approved with basal insulin and sulfonylurea/glinides were discontinued for the study Albany College of Pharmacy and Health Sciences 26

27 Type 2 Diabetes Mellitus EDITION Clinical Studies EDITION 1 23 EDITION 2 24 EDITION 3 25 Sample Size Key Baseline Demographics 60-years-old 53% male BMI: 36.6 kg/m 2 T2DM duration: 16 years HbA 1c : 8.15% 58-years-old 46% male BMI: 34.8 kg/m 2 T2DM duration: 13 years HbA 1c : 8.24% 57.7-years-old 57.7% male BMI: 33.0 kg/m 2 T2DM duration: 9.8 years HbA 1c : 8.54% Treatment Discontinuation Glargine 300: 7.4% Glargine 100: 7.7% Glargine 300: 8.9% Glargine 100: 9.3% Glargine 300: 14% Glargine 100: 17% Change in Basal Insulin Dose at Month 6 (units) Glargine 300: +33^ Glargine 100: +23^ Glargine 300: +27^ Glargine 100: +17^ Glargine 300: +41 $ Glargine 100: +34 $ ^ Statistically significant difference $ Initial dose calculated based on baseline body weight (95.3 kg * 0.2 units/kg = units [round down to first whole number divisible by 3]); statistical significance (or lack thereof) was not stated Albany College of Pharmacy and Health Sciences 27

28 Change in HbA 1c from Baseline to Month 6 (%) Noninferiority Was Met Across All Trials Between Glargine 300 and 100; Superiority Was Not EDITION CLINICAL TRIAL PROGRAM 0 EDITION 1 23 EDITION 2 24 EDITION 3 25 EDITION Meta-Analysis Added to: Bolus ± MET Added to: OAD (Except SFU) Added to: OAD (Except SFU and GLIN) Insulin Glargine 300 units/ml Insulin Glargine 100 units/ml Albany College of Pharmacy and Health Sciences 28

29 Nocturnal (0000 to 0559) Confirmed ( 70 mg/dl) or Severe Hypoglycemia, Week 9 to Month 6 (%) Hypoglycemia Data EDITION CLINICAL TRIAL PROGRAM EDITION 1 23 EDITION 2 24 EDITION 3 25 EDITION Meta-Analysis 26 Added to: Bolus ± MET -10%* 46 Added to: OAD (Except SFU) Added to: OAD (Except SFU and GLIN) %* Data not available * p < 0.05; RRR Insulin Glargine 300 units/ml Insulin Glargine 100 units/ml Albany College of Pharmacy and Health Sciences 29

30 DEVOTE Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes MARSO SP, MCGUIRE DK, ZINMAN B, ET AL. Image: Albany College of Pharmacy and Health Sciences 30

31 Study Design DEVOTE (DEGLUDEC 100 VS. GLARGINE 100 UNITS/ML) MULTICENTER, INTERNATIONAL, DOUBLE-BLIND, TREAT-TO-TARGET, NON-INFERIORITY/SUPERIORITY, ACTIVE TREATMENT-CONTROLLED, RANDOMIZED TRIAL Key Inclusion Criteria T2DM HbA 1c 7% OR if HbA 1c < 7%, treated with 20 units of basal insulin Treated with 1 antidiabetic medication (oral or injectable) 50-years-old with established CVD or CKD stage 3 (egfr 30 to 59 ml/min/1.73 m 2 ) OR 60-years-old with 1 CV risk factor Key Exclusion Criteria egfr < 30 ml/min/1.73 m 2 or recipient of hemodialysis or peritoneal dialysis Acute coronary or cerebrovascular event occurring 60 days before randomization or planned revascularization 27. Marso SP, McGuire DK, Zinman B, et al. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med Epub 2017/06/13. doi: /NEJMoa PubMed PMID: Albany College of Pharmacy and Health Sciences 31

32 Study Design 27 DEVOTE (DEGLUDEC 100 VS. GLARGINE 100 UNITS/ML) Screening Insulin degludec 100 units/ml SQ QDay via 10 ml vial between dinner and bedtime Insulin-naïve: 10 units SQ QDay Insulin-experienced: unit-for-unit conversion unless dosed 2 times daily, then dose was reduced by 20% to 30% n = 3818 Insulin glargine 100 units/ml SQ QDay via 10 ml vial between dinner and bedtime Insulin-naïve: 10 units SQ QDay Insulin-experienced: unit-for-unit conversion unless dosed 2 times daily, then dose was reduced by 20% to 30% n = Day Post-Treatment Visit No changes were made to background glucose-lowering therapy(ies) except basal and pre-mixed insulins, which were discontinued Albany College of Pharmacy and Health Sciences 32

33 Outcomes and Statistics 27 DEVOTE (DEGLUDEC 100 VS. GLARGINE 100 UNITS/ML) HIERARCHICAL TESTING Noninferiority for primary MACE* outcome if the upper bound of the 95% CI is less than 1.3 Superiority for severe hypoglycemic episodes if the upper bound of the 95% CI is less than 1.0 SEVERE HYPOGLYCEMIA An episode requiring the assistance of another person to actively administer carbohydrate or glucagon or to take other corrective actions. * First occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke Albany College of Pharmacy and Health Sciences 33

34 Baseline Characteristics in DEVOTE 27 IDeg 100 (n = 3818) IGlar 100 (n = 3819) Male, n (%) 2396 (62.8) 2382 (62.4) Race, White, n (%) 2903 (76.0) 2872 (75.2) Region, North America, n (%) 2625 (68.8) 2646 (69.3) Age (years) 64.9 ± ± 7.5 Duration of Type 2 Diabetes Mellitus (years) 16.6 ± ± 8.9 HbA 1c (%) 8.4 ± ± 1.7 Body Mass Index (kg per m 2 ) 33.6 ± ± 6.8 Established Cardiovascular Disease or CKD, 50-years-old, n (%) Cardiovascular Disease Risk Factors, 60-years-old, n (%) 3265 (85.5) 3244 (84.9) 538 (14.1) 567 (14.8) egfr, CKD-EPI (ml/min/1.73 m 2 ) 68.1 ± ± 21.6 Low-Density Lipoprotein Cholesterol (mg/dl) 84.8 ± ± 36.5 Systolic Blood Pressure (mm Hg) ± ± 18.1 Diastolic Blood Pressure (mm Hg) 76.1 ± ± 10.4 Abbreviations: ± standard deviation; CKD chronic kidney disease; CKD-EPI Chronic Kidney Disease Epidemiology Collaboration; egfr estimated glomerular filtration rate Albany College of Pharmacy and Health Sciences 34

35 Secondary Outcomes 27 DEVOTE (DEGLUDEC 100 VS. GLARGINE 100 UNITS/ML) SEVERE HYPOGLYCEMIA* * An episode requiring the assistance of another person to actively administer carbohydrate or glucagon or to take other corrective action Albany College of Pharmacy and Health Sciences 35

36 Secondary Outcomes 27 DEVOTE (DEGLUDEC 100 VS. GLARGINE 100 UNITS/ML) NOCTURNAL SEVERE HYPOGLYCEMIA* * An episode requiring the assistance of another person to actively administer carbohydrate or glucagon or to take other corrective action with an onset between 0001 and 0559 Albany College of Pharmacy and Health Sciences 36

37 Outcomes and Statistics 27 DEVOTE (DEGLUDEC 100 VS. GLARGINE 100 UNITS/ML) HIERARCHICAL TESTING Noninferiority for primary MACE outcome if the upper bound of the 95% CI is less than 1.3 Superiority for severe hypoglycemic episodes if the upper bound of the 95% CI is less than 1.0 SEVERE HYPOGLYCEMIA An episode requiring the assistance of another person to actively administer carbohydrate or glucagon or to take other corrective actions. * First occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke Albany College of Pharmacy and Health Sciences 37

38 The prescribing information for Tresiba now reflects the observed safety findings from DEVOTE (hypoglycemia and cardiovascular) 2. Tresiba [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; Albany College of Pharmacy and Health Sciences 38

39 BRIGHT More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial ROSENSTOCK J, CHENG A, RITZEL R, ET AL. Image: Albany College of Pharmacy and Health Sciences 39

40 Study Design BRIGHT (GLARGINE 300 VS. DEGLUDEC 100 UNITS/ML) MULTICENTER, INTERNATIONAL, OPEN-LABEL, 24-WEEK NON-INFERIORITY, ACTIVE-CONTROLLED, RANDOMIZED TRIAL Key Inclusion Criteria T2DM 7.5% HbA 1c 10.5% Currently managed with oral glucose-lowering agents ± GLP-1 RA for 6 months Key Exclusion Criteria T2DM < 1 year Current or previous use of insulin Initiation of new glucose-lowering agents and/or weight-loss medications < 3 months before screening 25 kg/m 2 > BMI > 40 kg/m 2 End-stage renal disease Non-insulin glucose-lowering drugs not approved for use in combination with insulin according to local labeling/local treatment guideline 28. Rosenstock J, Cheng A, Ritzel R, et al. More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial. Diabetes Care Epub 2018/08/15. doi: /dc PubMed PMID: Albany College of Pharmacy and Health Sciences 40

41 Study Design BRIGHT (GLARGINE 300 VS. DEGLUDEC 100 UNITS/ML) Randomization (1:1) Insulin glargine 300 units/ml: 0.2 units/kg SQ QDay between 1800 to 2000* n = 466 Insulin degludec 100 units/ml: 10 units SQ QDay between 1800 to 2000* n = 463 No changes were made to background glucose-lowering therapy(ies) unless safety concerns necessitated Duration: 24 weeks * Current Food and Drug Administration-approved starting doses for insulin naïve patients 28. Rosenstock J, Cheng A, Ritzel R, et al. More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial. Diabetes Care Epub 2018/08/15. doi: /dc PubMed PMID: Albany College of Pharmacy and Health Sciences 41

42 Baseline Characteristics in BRIGHT Baseline Characteristics IGlar 300 (n = 466) IDeg 100 (n = 463) Male, n (%) 247 (53) 250 (54) Age (years) 60.6 ± ± 9.8 Duration of Type 2 Diabetes Mellitus (years) 10.5 ± ± 6.5 HbA 1c (%) 8.71 ± ± 0.80 HbA 1c 8%, n (%) 380 (81.5) 378 (81.6) Body Mass Index (kg per m 2 ) 31.7 ± ± 4.4 egfr, (ml per min per 1.73 m 2 ) 92.4 ± ± 26.0 Number of Prior Noninsulin Glucose- Lowering Agents Used, > 2, n (%) 217 (46.6) 210 (45.4) Prior Metformin Use, n (%) 428 (91.8) 422 (91.1) Prior Sulfonylurea Use, n (%) 301 (64.6) 309 (66.7) Prior DPP-4i Use, n (%) 121 (26.0) 106 (22.9) Prior SGLT2i Use, n (%) 62 (13.3) 62 (13.4) Prior GLP-1 RA Use, n (%) 46 (9.9) 65 (14.0) 28. Rosenstock J, Cheng A, Ritzel R, et al. More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial. Diabetes Care Epub 2018/08/15. doi: /dc PubMed PMID: Albany College of Pharmacy and Health Sciences 42

43 The Temporal Driver for Reduced Hypoglycemia With Glargine U-300 Occured During The Titration Phase 29. Bolli GB, Cheng Abosnyak Z, et al. Lower Hypoglycemia Rates with Insulin Glargine 300 U/mL (Gla-300) vs Insulin Degludec 100 U/mL (IDeg-100) in Insulin-Naïve Adults with T2DM on Oral Antihyperglycemic Therapy ± GLP-1 RA: The BRIGHT Randomized Study. Presentation 1032-P, American Diabetes Association (ADA) 78th annual congress in Orlando, Florida, U.S., June 23, Albany College of Pharmacy and Health Sciences 43

44 The Temporal Driver for Reduced Hypoglycemia With Glargine U-300 Occured During The Titration Phase No Adjustments for Multiplicity Testing Descriptive Only 29. Bolli GB, Cheng Abosnyak Z, et al. Lower Hypoglycemia Rates with Insulin Glargine 300 U/mL (Gla-300) vs Insulin Degludec 100 U/mL (IDeg-100) in Insulin-Naïve Adults with T2DM on Oral Antihyperglycemic Therapy ± GLP-1 RA: The BRIGHT Randomized Study. Presentation 1032-P, American Diabetes Association (ADA) 78th annual congress in Orlando, Florida, U.S., June 23, Albany College of Pharmacy and Health Sciences 44

45 CONFIRM Clinical Outcome Assessment of the Effectiveness of Insulin Degludec in Real-Life Medical Practice (CONFIRM): A Comparative Effectiveness Study of Degludec and Insulin Glargine 300 Units/mL in Insulin-Naïve Patients with Type 2 Diabetes TIBALDI J, HALDRUP S, SANDBERG V, ET AL. Image: Albany College of Pharmacy and Health Sciences 45

46 Study Design Key Inclusion Criteria Comparisons Duration Primary Endpoint Secondary Endpoints Retrospective, observational, multicenter, US-based study 18-years-old T2DM Insulin naїve Inadequately controlled on OAD(s) ± GLP-1 RA Insulin degludec 100 or 200 units/ml Insulin glargine 300 units/ml Up to 6 months Change in HbA 1c from start of basal insulin therapy until 3 to 6 months of follow-up Rates of hypoglycemic episodes Change in proportion of patients with 1 episode of hypoglycemia End-of-study basal insulin dose Time-to-discontinuation of initial basal insulin Albany College of Pharmacy and Health Sciences 46

47 Hypoglycemia Data CONFIRM (DEGLUDEC VS. GLARGINE 300) Study design: Retrospective, observational, multicenter, US-based study comparing clinical outcomes of IDeg U-100 or U-200 to IGlar U-300 in insulin naïve patients with T2DM inadequately controlled on OAD ± GLP-1 RA for up to 6 months. 30. Tibaldi J, Haldrup S, Sandberg V, et al. Clinical Outcome Assessment of the Effectiveness of Insulin Degludec (Degludec) in Real-life Medical Practice (CONFIRM): A Comparative Effectiveness Study of Degludec and Insulin Glargine 300U/mL (Glargine U300) in 4,056 Insulin-Naïve Patients with Type 2 Diabetes (T2D) Oral/poster presentation. 78th Annual Scientific Sessions of the American Diabetes Asosciation (ADA), Orlando, Florida, US; June Albany College of Pharmacy and Health Sciences 47

48 Study Design Key Inclusion Criteria Comparisons Duration Primary Endpoint DELIVER D 31 DELIVER D+ 32 Retrospective, observational, comparative, multicenter, cohort, US-based studies 18-years-old T2DM Switching from IGlar 100 to IGlar 300 or IDeg 18-years-old T2DM Switching from IGlar 100 or IDet to IGlar 300 or IDeg 3% HbA 1c 15% Insulin glargine 300 units/ml vs. insulin degludec Up to 6 months Compare clinical outcomes (i.e., HbA 1c reduction, HbA 1c goal attainment and hypoglycemia) Albany College of Pharmacy and Health Sciences 48

49 Type 2 Diabetes Mellitus DELIVER Studies DELIVER D 31 DELIVER D+ 32 Sample Size Key Baseline Demographics Change in HbA 1c at Follow-Up (Up to 6 Months) HbA 1c < 7.0% Hypoglycemia Incidence 58-years-old 47% male BMI: 35 kg/m 2 HbA 1c : 9.14% Glargine 300: -0.49% Degludec: -0.48% p = 0.97 Glargine 300: 12.9% Degludec: 15.9% p = 0.24 Glargine 300: 11.9% Degludec: 12.7% p = 0.45* * Adjusted for baseline hypoglycemia incidence 59-years-old 50% male BMI: 35 kg/m 2 Commercially insured: 41% HbA 1c : 9.1% Glargine 300: -0.63% Degludec: -0.58% p = Glargine 300: 15.1% Degludec: 16.1% p = Glargine 300: 12.7% Degludec: 12.7% p = 0.745* Albany College of Pharmacy and Health Sciences 49

50 Hypoglycaemia incidence (%) Temporal Hypoglycemia Data 32 DELIVER D+ (GLARGINE 300 UNITS/ML VS. DEGLUDEC) 10 aor 1.04 (95% CI ); P =.766 aor 0.83 (95% CI ); P = months 4 6 months Gla-300 switchers IDeg switchers Intent-to-treat population; p-values adjusted for hypoglycemia incidence Albany College of Pharmacy and Health Sciences 50

51 Healthcare Resource Utilization Hypoglycemia Data 32 DELIVER D+ (GLARGINE 300 UNITS/ML VS. DEGLUDEC) Intent-to-treat population Albany College of Pharmacy and Health Sciences 51

52 HISTORY OF PRESENT ILLNESS EL is 47-year-old female with type 2 diabetes mellitus (T2DM). She was diagnosed with T2DM 15 years ago and her glycemic control has been adequate until recently. You, her primary care provider, have elected to proceed with an insulin-based regimen (basal). Dyslipidemia Rosacea Hypertension Type 2 diabetes mellitus Obesity (class II) PAST MEDICAL HISTORY CURRENT MEDICATIONS Atorvastatin 10 mg: 1 PO QDay Brimonidine 0.33% gel: top. QDay Chlorthalidone 25 mg: 1 PO QDay Dulaglutide 1.5 mg/0.5 ml: 1.5 mg SQ QW Empagliflozin 25 mg: 1 PO QDay Metformin 1 g ER: 2 PO QDay Pioglitazone 30 mg: 1 PO QDay Image: Albany College of Pharmacy and Health Sciences 52

53 Lab Blood Pressure Reference Range / Target September 2018 June 2018 February 2018 November 2017 < 140/90 mm Hg 138/86 132/86 134/88 134/86 Height Inches Weight Lbs. (Kg) 270 (123) 272 (124) 268 (122) 269 (122) BMI Pulse kg/m to 100 beats per minute HbA 1c 6.5% LDL-C < 70 mg/dl Non-HDL-C < 100 mg/dl egfr (MDRD) PERTINENT VITALS AND LABORATORY DATA 90 to 120 ml/min/1.73 m Abbreviations: BMI body mass index; egfr estimated glomerular filtration rate; kg kilograms; lbs. pounds; LDL-C lowdensity lipoprotein cholesterol; MDRD Modification of Diet in Renal Disease; non-hdl non-high-density lipoprotein cholesterol Albany College of Pharmacy and Health Sciences 53

54 EL S INSURANCE S FORMULARY (COMMERCIAL PLAN) DRUG NAME ANTIDIABETICS, INSULINS DRUG TIER REQUIREMENTS/ LIMITS HUMULIN R INJ U PD HUMULIN R INJ U QL (6 PENS PER 30 DAYS) NOVOLIN INJ 70/30 2 OTC; PD, OTC NOVOLIN N INJ U OTC; PD, OTC NOVOLIN R INJ U OTC; PD, OTC NOVOLOG INJ 100/ML 2 PD NOVOLOG INJ FLEXPEN 2 PD NOVOLOG INJ PENFILL 2 PD NOVOLOG MIX INJ 70/30 2 PD NOVOLOG MIX INJ FLEXPEN 2 PD TOUJEO INJ 300UNIT 3 PD Image: TRESIBA INJ 100/200UNIT 3 PD Albany College of Pharmacy and Health Sciences 54

55 Post-Lecture Question Which basal insulin are you most likely to initiate for EL based on the information provided? A. Humulin R U units SQ QDay B. Novolin R U units SQ QDay C. Toujeo U units SQ QDay D. Tresiba U units SQ QDay Albany College of Pharmacy and Health Sciences 55

56 Conclusions SECOND-GENERATION BASAL INSULIN ANALOGS Despite the documented microvascular benefit associated with early and intensive glycemic control, 7-15 there remains a significant amount of time until insulin utilization 6 Insulins degludec and glargine U-300 have a longer duration of action compared to existing basal insulin therapies, 2,3,4,5 which may provide dosing flexibility for patients Their is no added HbA 1c -lowering benefit associated with insulins degludec and glargine U-300 compared to available basal insulins, but utilization has been associated with a reduced incidence/rate of hypoglycemia compared to existing therapies 19,20,23,24,27 Recognize that insulin glargine U-300 is 27% less potent than insulin glargine U-100 at lowering blood glucose 5 Albany College of Pharmacy and Health Sciences 56

57 New EDITION(s) and a BRIGHT Outlook DEVOTE(d) to DELIVER(ing) Improved Patient Care with Second- Generation Basal Insulin Analogs Matthew D. Stryker, Pharm.D., BCACP, CLS Matthew.Stryker@acphs.edu Assistant Professor Clinical Pharmacy Specialist Albany College of Pharmacy and Health Sciences Albany Medical Center Division of Community Endocrinology Albany College of Pharmacy and Health Sciences

58 References 1. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2018 Executive Summary. Endocr Pract. 2018;24(1): Epub 2018/01/26. doi: /cs PubMed PMID: Tresiba [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; Goldman J, Kapitza C, Pettus J, et al. Understanding How Pharmacokinetic and Pharmacodynamic Differences of Basal Analog Insulins Influence Clinical Practice. Curr Med Res Opin. 2017;33(10): Epub 2017/05/26. doi: / PubMed PMID: Becker RH, Dahmen R, Bergmann K, et al. New Insulin Glargine 300 Units * ml-1 Provides a More Even Activity Profile and Prolonged Glycemic Control at Steady State Compared with Insulin Glargine 100 Units * ml-1. Diabetes Care. 2015;38(4): Epub 2014/08/26. doi: /dc PubMed PMID: Khunti K, Wolden ML, Thorsted BL, et al. Clinical Inertia in People with Type 2 Diabetes: A Retrospective Cohort Study Of More than 80,000 People. Diabetes Care. 2013;36(11): Epub 2013/07/24. doi: /dc PubMed PMID: ; PubMed Central PMCID: PMCPMC Gerstein HC, Miller ME, Byington RP, et al. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med. 2008;358(24): Epub 2008/06/10. doi: /NEJMoa PubMed PMID: ; PubMed Central PMCID: PMCPMC Nine-Year Effects of 3.7 Years of Intensive Glycemic Control on Cardiovascular Outcomes. Diabetes Care. 2016;39(5): Epub 2016/01/30. doi: /dc PubMed PMID: ; PubMed Central PMCID: PMCPMC Patel A, MacMahon S, Chalmers J, et al. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2008;358(24): Epub 2008/06/10. doi: /NEJMoa PubMed PMID: Zoungas S, Chalmers J, Neal B, et al. Follow-Up of Blood-pressure Lowering and Glucose Control in Type 2 Diabetes. N Engl J Med. 2014;371(15): Epub 2014/09/23. doi: /NEJMoa PubMed PMID: Albany College of Pharmacy and Health Sciences 58

59 References 11. Intensive Blood-Glucose Control with Sulphonylureas or Insulin Compared with Conventional Treatment and Risk of Complications in Patients with Type 2 Diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131): Epub 1998/09/22. PubMed PMID: Holman RR, Paul SK, Bethel MA, et al. 10-Year Follow-Up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med. 2008;359(15): Epub 2008/09/12. doi: /NEJMoa PubMed PMID: Duckworth W, Abraira C, Moritz T, et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med. 2009;360(2): Epub 2008/12/19. doi: /NEJMoa PubMed PMID: Agrawal L, Azad N, Bahn GD, et al. Long-Term Follow-Up of Intensive Glycaemic Control on Renal Outcomes in the Veterans Affairs Diabetes Trial (VADT). Diabetologia. 2018;61(2): Epub 2017/11/05. doi: /s PubMed PMID: ; PubMed Central PMCID: PMCPMC American Diabetes Association 2018 Scientific Sessions. June 24, 2018; Orlando, Florida. Symposium: The Veterans Affairs Diabetes Trial (VADT) at 15 years symposium. 16. Rosenstock J, Dailey G, Massi-Benedetti M, et al. Reduced Hypoglycemia Risk with Insulin Glargine: A Meta-analysis Comparing Insulin Glargine with Human NPH Insulin in Type 2 Diabetes. Diabetes Care. 2005;28(4): Epub 2005/03/29. PubMed PMID: Philis-Tsimikas A, Charpentier G, Clauson P, et al. Comparison of Once-Daily Insulin Detemir with NPH Insulin Added to a Regimen of Oral Antidiabetic Drugs in Poorly Controlled Type 2 Diabetes. Clin Ther. 2006;28(10): Epub 2006/12/13. doi: /j.clinthera PubMed PMID: Meneghini L, Kesavadev J, Demissie M, et al. Once-Daily Initiation of Basal Insulin as Add-on to Metformin: A 26-week, Randomized, Treat-to-target Trial Comparing Insulin Detemir with Insulin Glargine in Patients with Type 2 Diabetes. Diabetes Obes Metab. 2013;15(8): Epub 2013/02/21. doi: /dom PubMed PMID: Garber AJ, King AB, Del Prato S, et al. Insulin Degludec, an Ultra-Longacting Basal Insulin, Versus Insulin Glargine in Basal-Bolus Treatment with Mealtime Insulin Aspart in Type 2 Diabetes (BEGIN Basal-Bolus Type 2): A Phase 3, Randomised, Open-Label, Treat-to-Target Non-Inferiority Trial. Lancet. 2012;379(9825): Epub 2012/04/24. doi: /s (12) PubMed PMID: Albany College of Pharmacy and Health Sciences 59

60 References 20. Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin Degludec Versus Insulin Glargine in Insulin-Naive Patients with Type 2 Diabetes: A 1-Year, Randomized, Treat-to-target Trial (BEGIN Once Long). Diabetes Care. 2012;35(12): Epub 2012/10/09. doi: /dc PubMed PMID: ; PubMed Central PMCID: PMCPMC Meneghini L, Atkin SL, Gough SC, et al. The Efficacy and Safety of Insulin Degludec Given in Variable Once-daily Dosing Intervals Compared with Insulin Glargine and Insulin Degludec Dosed at the Same Time Daily: A 26-Week, Randomized, Open-Label, Parallel-Group, Treat-to-Target Trial in Individuals with Type 2 Diabetes. Diabetes Care. 2013;36(4): Epub 2013/01/24. doi: /dc PubMed PMID: ; PubMed Central PMCID: PMCPMC Gough SC, Bhargava A, Jain R, et al. Low-Volume Insulin Degludec 200 Units/mL Once Daily Improves Glycemic Control Similarly to Insulin Glargine with a Low Risk of Hypoglycemia in Insulin-Naive Patients with Type 2 Diabetes: A 26-week, Randomized, Controlled, Multinational, Treat-to-Target Trial: The BEGIN LOW VOLUME Trial. Diabetes Care. 2013;36(9): Epub 2013/05/30. doi: /dc PubMed PMID: ; PubMed Central PMCID: PMCPMC Riddle MC, Bolli GB, Ziemen M, et al. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People with Type 2 Diabetes Using Basal and Mealtime Insulin: Glucose Control and Hypoglycemia in a 6-month Randomized Controlled Trial (EDITION 1). Diabetes Care. 2014;37(10): Epub 2014/08/01. doi: /dc PubMed PMID: Yki-Jarvinen H, Bergenstal R, Ziemen M, et al. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People with Type 2 Diabetes Using Oral Agents and Basal Insulin: Glucose Control and Hypoglycemia in a 6-month Randomized Controlled Trial (EDITION 2). Diabetes Care. 2014;37(12): Epub 2014/09/07. doi: /dc PubMed PMID: Bolli GB, Riddle MC, Bergenstal RM, et al. New Insulin Glargine 300 U/mL Compared with Glargine 100 U/mL in Insulin- Naive People with Type 2 Diabetes on Oral Glucose-Lowering Drugs: A Randomized Controlled Trial (EDITION 3). Diabetes Obes Metab. 2015;17(4): Epub 2015/02/03. doi: /dom PubMed PMID: ; PubMed Central PMCID: PMCPMC Albany College of Pharmacy and Health Sciences 60

61 References 26. Ritzel R, Roussel R, Bolli GB, et al. Patient-Level Meta-Analysis of the EDITION 1, 2 and 3 Studies: Glycaemic Control and Hypoglycaemia with New Insulin Glargine 300 U/mL Versus Glargine 100 U/mL in People with Type 2 Diabetes. Diabetes Obes Metab. 2015;17(9): Epub 2015/05/02. doi: /dom PubMed PMID: ; PubMed Central PMCID: PMCPMC Marso SP, McGuire DK, Zinman B, et al. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med Epub 2017/06/13. doi: /NEJMoa PubMed PMID: Rosenstock J, Cheng A, Ritzel R, et al. More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial. Diabetes Care Epub 2018/08/15. doi: /dc PubMed PMID: Bolli GB, Cheng Abosnyak Z, et al. Lower Hypoglycemia Rates with Insulin Glargine 300 U/mL (Gla-300) vs Insulin Degludec 100 U/mL (IDeg-100) in Insulin-Naïve Adults with T2DM on Oral Antihyperglycemic Therapy ± GLP-1 RA: The BRIGHT Randomized Study. Presentation 1032-P, American Diabetes Association (ADA) 78th Annual Congress in Orlando, Florida, U.S., June 23, Tibaldi J, Haldrup S, Sandberg V, et al. Clinical Outcome Assessment of the Effectiveness of Insulin Degludec (Degludec) in Real-life Medical Practice (CONFIRM): A Comparative Effectiveness Study of Degludec and Insulin Glargine 300U/mL (Glargine U300) in 4,056 Insulin-Naïve Patients with Type 2 Diabetes (T2D) Oral/poster presentation. 78th Annual Scientific Sessions of the American Diabetes Asosciation (ADA), Orlando, Florida, US; June Blonde L, Zhou FL, Bosnyak Z, et al. Real-world Evidence Demonstrates Comparable Clinical Outcomes of Switching from Insulin Glargine 100 U/mL (Gla-100) to Insulin Glargine 300 U/mL (Gla-300) Vs Insulin Degludec (IDeg) in Patients with Type 2 Diabetes (T2D)." World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease in Los Angeles, CA, U.S., November 30 December Sullivan SD, Bailey TS, Roussel R, et al. Clinical Outcomes in Real-world Patients with Type 2 Diabetes Switching from First- to Second-Generation Basal Insulin Analogues: Comparative Effectiveness of Insulin Glargine 300 Units/mL and Insulin Degludec in the DELIVER D+ Cohort Study. Diabetes Obes Metab. 2018;20(9): Epub 2018/06/26. doi: /dom PubMed PMID: ; PubMed Central PMCID: PMCPMC Albany College of Pharmacy and Health Sciences 61

62 References 33. American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018;41(Suppl. 1): S73 S Mauricio D, Meneghini L, Seufert J, et al. Glycaemic Control and Hypoglycaemia Burden in Patients with Type 2 Diabetes Initiating Basal Insulin in Europe and the USA. Diabetes Obes Metab. 2017;19(8): Epub 2017/03/03. doi: /dom PubMed PMID: ; PubMed Central PMCID: PMCPMC Jauch-Chara K, Schultes B. Sleep and the Response to Hypoglycaemia. Best Pract Res Clin Endocrinol Metab. 2010;24(5): Epub 2010/11/30. doi: /j.beem PubMed PMID: Centers for Disease Control and Prevention. Diabetes Public Health Resource Hypoglycemia. Accessed 17 Sept Available at: Ginde AA, Espinola JA, Camargo CA, Jr. Trends and Disparities in U.S. Emergency Department Visits for Hypoglycemia, Diabetes Care. 2008;31(3): Epub 2007/11/21. doi: /dc PubMed PMID: Cheng A, Rosenstock J, Ritzel R, et al. Similar Glycemic Control and Less or Comparable Hypoglycemia with Insulin Glargine 300 U/mL (Gla-300) vs Degludec 100 U/mL (IDeg-100) in Insulin-Naïve T2DM on Antihyperglycemic Drugs ± GLP- 1 RAs: The BRIGHT Randomized Study. Presentation 301-OR, American Diabetes Association (ADA) 78th annual congress in Orlando, Florida, U.S., June 25, Ye, F, Agarwal R, Kaur A, et al, Real-World Assessment of Patient Characteristics and Clinical Outcomes of Early Users of the New Insulin Glargine 300U/mL. Poster Presentation 943-P. American Diabetes Association 76th Scientific Sessions, New Orleans, LA, U.S. Saturday, June 11, Zhou FL, Ye F, Berhanu P, et al. Real-World Evidence Concerning Clinical and Economic Outcomes Of Switching to Insulin Glargine 300 Units/mL Vs Other Basal Insulins in Patients with Type 2 Diabetes Using Basal Insulin. Diabetes Obes Metab. 2018;20(5): Epub 2017/12/23. doi: /dom PubMed PMID: ; PubMed Central PMCID: PMCPMC Zhou FL, Ye F, Gupta V, et al. Older Adults with Type 2 Diabetes (T2D) Experience Less Hypoglycemia When Switching to Insulin Glargine 300 U/mL (Gla-300) vs Other Basal Insulins (DELIVER 3 Study). Poster 986-P. American Diabetes Association (ADA) 77th Scientific Sessions. San Diego, CA, U.S., June 10, Albany College of Pharmacy and Health Sciences 62

63 References 42. Ritzel R, Harris SB, Baron H, et al. A Randomized Controlled Trial Comparing Efficacy and Safety of Insulin Glargine 300 Units/mL Versus 100 Units/mL in Older People With Type 2 Diabetes: Results From the SENIOR Study. Diabetes Care. 2018;41(8): Epub 2018/06/14. doi: /dc PubMed PMID: Meneghini L, Zhou FL, Bosnyak Z, et al. Hypoglycemia Risk Associated with Basal Insulin Use in Type 2 Diabetes (T2DM): The Lightning Study. World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease in Los Angeles, CA, U.S. November 30 December 2. Albany College of Pharmacy and Health Sciences 63