9/8/2016. Faculty. Examining the Role of Long-Acting Insulin within the Physiologic Approach to Glucose Control. Disclosures. Learning Objectives

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1 9/8/21 Faculty Examining the Role of Long-Acting within the Physiologic Approach to Glucose Control Dace Trence, MD, FACE Professor, Division of Metabolism, Endocrinology and Nutrition Director, Diabetes Care Center University of Washington Medical Center Seattle, Washington Supported by educational grants from Novo Nordisk, Inc. and Boehringer Ingelheim and Lilly USA, LLC Disclosures Learning Objectives Dr. Trence: Stockholder Medtronic, Sanofi Discuss clinical and economic implications associated with clinical inertia Review the safety and benefits of early insulin initiation in patients with type 2 diabetes mellitus Implement strategies for timely initiation and intensification of insulin therapy Evaluate current data for new basal insulins to ensure appropriate use in the management of patients with type 2 diabetes mellitus Natural History of T2DM Stages of T2DM by Beta-Cell Function Prediabetes Duration of Diabetes Mellitus Frank Diabetes Mellitus Resistance Hepatic Glucose Production Endogenous Microvascular Complications Macrovascular Complications Time Years to Typical Diagnosis of Decades Diabetes Mellitus T2DM = type 2 diabetes mellitus; BG = blood glucose. Ramlo-Halsted BA, et al. Clin Diabetes. 2;18(2):8-85. Postprandial BG Fasting BG -Cell Function (%) IGT IGT = impaired glucose tolerance. Lebovitz H. Diabetes Review. 1999;7: Postprandial T2DM Hyperglycemia Phase 1 T2DM Phase 2 T2DM Phase Years from Diagnosis 1

2 9/8/21 ADA/EASD 215 Guidelines ADA/EASD 215 Guidelines (cont) Healthy eating, weight control, increased physical activity Initial drug monotherapy Efficacy ( HbA1c) Hypoglycemia Weight Side effects Costs Metformin low risk neutral/loss GI / lactic acidosis low If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination (order not meant to denote specific preference) Dual Therapy Efficacy ( HbA1c) Hypoglycemia Weight Major side effect(s) Costs Triple Therapy Metformin + Metformin + Metformin + Metformin + Metformin + Metformin + TZD DPP-4-i SGLT2-i GLP-1 RA (basal) intermediate intermediate est moderate risk low risk low risk low risk low risk risk gain gain neutral neutral loss gain edema, HF, fx s rare rare GI low variable If needed to reach individualized A1C target after ~3 months, proceed to 3-drug combination (order not meant to denote specific preference) Metformin + Metformin + Metformin + Metformin + Metformin + Metformin + + TZD + DPP-4-I + SGLT2-i + GLP-1 RA + (basal) + TZD TZD or DPP-4-i or DPP-4-i or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or TZD or SGLT2-i or GLP-1-RA or GLP-1-RA or or or or GLP-1-RA or or If combination therapy that includes basal insulin has failed to achieve A1C target after 3- months, proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents Combination injectable therapy Basal + Mealtime insulin or GLP-1 RA ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes; HbA1c = glycosylated hemoglobin; GI = gastrointestinal. ADA. Diabetes Care. 215;38(Suppl 1):S41-S48. = sulfonylurea; TZD = thiazolidinedione; DPP-4-i = dipeptidyl peptidase 4 inhibitor; SGLT2-i = sodium-glucose cotransporter 2 inhibitor; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HF = heart failure. Diabetes Care. 215;38(Suppl 1):S41-S48. AACE: Glycemic Control Algorithm AACE: Algorithm for Adding/Intensifying *Order of medications listed represents a suggested hierarchy of usage. AACE = American Association of Clinical Endocrinologists. SGLT 2i = sodium glucose cotransporter-2 inhibitor; DPP-4i = dipeptidyl peptidase 4 inhibitor; AGi = alpha-glucosidase inhibitor; /GLN = sulfonylurea/meglitinide. Garber AJ, et al. Endocr Pract. 21;22(1): TDD = total daily dose. Garber AJ, et al. Endocr Pract. 21;22(1): Clinical Inertia Leads to Delayed Initiation Potential Cost of Clinical Inertia Patients (%) % SOLVE: Baseline A1C Distribution at Initiation A1C (%) Retrospective cohort study using United Kingdom Clinical Practice Research Datalink 15,477 newly diagnosed T2DM from 199 with follow-up data available until 212 Mean HbA1c 8.1% at diagnosis,11% had history of cardiovascular disease, and 7.1% experienced at least one CVE during 5.3 years of median follow-up 1-year delay in receiving intensified therapy (goal HbA1c <7.%) was associated with significantly increased risk of MI (7%), stroke (51%), HF (4%), and composite CVE (2%) SOLVE = Observational Study on Safety of Self-titration of Once Daily Levemir. Khunti K, et al. Diabetes. 211;(Suppl 1):A3. MI = myocardial infarction; CVE = cardiovascular event. Paul SK, et al. Cardiovasc Diabetol. 215;14:1. 2

3 9/8/21 Individualizing A1C Targets for Patients with T2DM Most Intensive Less Intensive Least Intensive.% 7.% 8.% Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, and Comprehensive Support Systems Low Moderate Ismail-Beigi F, et al. Ann Intern Med. 211;154(8): Patient Age Hypoglycemia Risk Disease Duration Other Comorbidities None Few/Mild Multiple/Severe None None Psychosocioeconomic Considerations Less motivated, Non-adherent, Limited Insight, Poor Self-Care Capacities, and Weak Support Systems High Established Vascular Complications Cardiovascular Disease Early Microvascular Advanced Micro The Benefits of The most predictable glucose reduction Most effective Effective targeting of fasting glucose Also enhances postprandial insulin response as well Potential for preservation of beta-cell function Evidence of prevention of diabetes mellitus in ORIGIN trial Evidence of improved insulin secretion when added to oral agents Evidence of beta-cell preservation/prolonged remission when used early in T2DM Good safety record other than No evidence of increased cancer or heart disease with glargine in ORIGIN trial ORIGIN = Outcome Reduction With Initial Glargine Intervention. ADA. Diabetes Care. 215;38 (Suppl 1):S41-S48; Weng J, et al. Lancet. 28;371:1753-; Pennartz C, et al. Diabetes Care. 211; 34: ORIGIN Trial Investigators, et al. N Engl J Med. 212;37(4): When to Consider in T2DM Basal insulin may be a second agent after metformin When combination oral/injectable agents become inadequate High FPG or PPG Unacceptable side effects of other agents Patient with advanced hepatic or renal disease Special circumstances (eg, corticosteroids, infection, pregnancy) Patients with hyperglycemia in the hospital Severely uncontrolled diabetes mellitus* *Defined as fasting glucose >25 mg/dl, random glucose > 3 mg/dl, A1C >1%, ketonuria, or symptomatic (polyuria, polydipsia, and weight loss) by ADA 29 Consensus Statement. After glucose controlled, oral agents can be added and insulin withdrawn if preferred. FPG = fasting plasma glucose; PPG = postprandial glucose. Nathan DM, et al. Diabetes Care. 29;32: Inzucchi SE, et al. Diabetes Care. 212;35(): ADA. Diabetes Care. 214:37(Suppl 1):S14-S8. Early Increased Remission in Newly Diagnosed T2DM Percentage of Patients in Remission CSII (N=137) MDI (N=124) OHA (N=121) Days in Remission Target glycemic control was achieved in less time (4 and 5. days) and in more CSII and MDI patients (97.1% and 95.2%) than OHA patients (9.3 days and 83.5%) CSII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections; OHA = oral hypoglycemic agents. Weng J, et al. Lancet. 28;371: Treatment was stopped after normoglycemia was maintained for 2 weeks 51% 45% 27% P=.12 Early Increased Remission in Newly Diagnosed T2DM (cont) vs in Newly Diagnosed T2DM Acute Response (pmol/l/min) CSII in the Remission Group MDI in the Remission Group OHA in the Remission Group Non-Remission Group Before Therapy After Therapy *P<.5 P<.1 P=. At 1 Year Beta-cell function was measured at the end of therapy and 1 year after Patients treated with continuous insulin therapy had an increase in activity of 1% compared with 15% for those treated with oral agents C-Peptide Response (mmol/l) Baseline P=.9 Day 1 End of Study P=. Day 2 Newly diagnosed T2DM patients were randomly assigned to glibenclamide (N=2) or 7/3 NPH/R insulin (N=23) 18 patients in group and 1 patients in insulin group completed -year follow-up Patients on more prone to loss of insulin secretion than patients on early insulin treatment Window of opportunity for beneficial effects of insulin treatment occurs early in the course of diabetes mellitus Weng J, et al. Lancet. 28;371: NPH = neutral protamine hagedorn; = sulfonylurea. Alvarsson M, et al. Rev Diabet Stud. 21;7(3):

4 9/8/21 T2DM Patients Switched from to Preprandial : Impact on β-cell Function The Evolution of Products Beta-Cell Dysfunction (%) Stage 3a Stage Day 7 Day 14 Glimepiride P<.5 Stage 1 2 3a 3b Active Beta-Cell Secretion Disease Progression Patients with T2DM were randomized to continue glimepiride for another 7 days or switch to insulin aspart 8 U before each meal Day 7 Day 14 OGTTs at days 7 and 14 Aspart 5% of the T2DM patients shifted back from stage 3a beta-cell function to early stage 2 in the preprandial insulin group while beta-cell function deteriorated more with glimepiride therapy Proinsulin First Regular 1922 Protamine Zinc (PZI) NPH First Human s Lente s Rapid- Acting Analogs s 2s 215 Prolonged Basal Analogs Inhaled Human Ultra Long- Acting Basal s OGTT = oral glucose tolerance test. Pfutzner A, et al. Diabetes Technol Ther. 2;8(3): Tibaldi JM. Am J Med. 214;127(1 Suppl):S25-S38. How to Choose Therapies? What are the advantages and disadvantages of various insulin regimens? Basal only Basal plus Basal bolus Premixed Current Available s Type Onset Peak, hours Duration of Action, hours Rapid-acting analogs lispro, aspart, glulisine human inhaled Short-acting Regular human (U1) Regular human (U5) 15 minutes minutes 3- minutes 3- minutes ~ Intermediate-acting Human NPH insulin 1-3 hours Long-acting (basal) glargine detemir 2-4 hours 1-3 hours No pronounced peak Ultra long-acting (basal) glargine U3 degludec (U1/U2) Develops over hours 3-9 minutes Nearly peakless Nearly peakless 3 >42 Walia M, et al. JAMA. 214;311(22): Nasrallah SN, et al. Clin Med Insights Endocrinol Diabetes. 212:5: Premixed (Biphasic) Analogs Comparative Trials in T2DM Premixed insulins Humalog 75/25, 5/5: Intermediate + rapid-acting Novolog 7/3: Intermediate + rapid-acting Humulin 7/3: Intermediate + short-acting Novolin 7/3: Intermediate + short-acting Degludec Novolog 7/3: Long-acting + rapid-acting Summary of key findings Any insulin will lower glucose and A1C All insulins are associated with some weight gain and some risk of The larger the doses and the more aggressive the titration, the lower the A1C, but often with a greater possibility of adverse effects Long-acting insulin analogs reduce the incidence of overnight Rapid-acting insulin analogs reduce PPG excursions (compared with corresponding human insulins [NPH, regular]), but they generally do not result in clinically, significantly lower A1C Edelman S, et al. Osteopath Med Prim Care. 27;1:9. Riddle MC, et al. Diabetes, Obesity and Metabolism. 214;1(5): Orozco-Beltran D, et al. Diabetes. 213;2(Suppl 1):A11 [abstract 397-P]. Little S, et al. Diabetes Technol Ther. 211;13(Suppl 1):S3-S4. 4

5 9/8/21 Adding to OADs Improves Glycemic Control (Results of Large RCTs) Study Treatment Baseline A1C Resulting A1C STEPWISE (211) DET + -3 ASP* weeks DET + -3 ASP T (27) ASP TID a b 52 weeks BIASP BID a b Riddle et al (211) weeks DURABLE (211) 24 weeks DET QD a GLAR QD + -3 GLU c GLAR QD + GLU QD d BIASP BID LM 75/25 BID GLAR QD Davidson et al (211) GLAR QD weeks *Measured PPG; Estimated meal size; a a second type of insulin could be added beginning at 24 weeks if HbA1C 8.% on 2 consecutive readings or >1%; b P<.1 vs DET QD; c P<.5 vs BIASP; d P<.25 vs BIASP. OAD = oral antidiabetic agent; RCT = randomized controlled trial; ASP = aspirin. Meneghini L, et al. Endocr Pract. 211;17(5): Holman RR, et al. N Engl J Med. 27;357: Riddle MC, et al. Diabetologia. 211;54(Suppl 1):S1-S542. Buse JB, et al. Diabetes Care. 211;34: Davidson MB, et al. Endocr Pract. 211;17(3): Strategies for Selection Convenience (once daily vs twice or three times daily) Proven safety NPH: A little more hypoglycemic risk than analogs Analogs: ORIGIN study showed low hypoglycemic risk, no adverse CV effects, and no cancer risk Cost NPH: $ Analogs: $$-$$$ Insurance coverage Analogs: Coverage varies and may require prior authorization ORIGIN Trial Investigators. N Engl J Med. 212;37(4): Riddle M, et al. Diabetes Care. 23; 2(11): Currently Available s Currently Available Premixed s Inhaled insulin Aspart, lispro, glulisine Regular Plasma Levels Intermediate (NPH insulin) Long (insulin detemir) Long (insulin glargine) Ultra long-acting (U3 glargine) Ultra long-acting (insulin degludec) Type Onset Peak, hours 7% NPH / 3% Regular.5-1 hours 75% NPL / 25% Lispro 5-15 minutes 5% NPL / 5% Lispro 5-15 minutes 7% NPA / 3% Aspart 5-15 minutes 3-12 (dual) 1-4 (dual) 1-4 (dual) 1-4 (dual) Duration of Action, hours Time (hours) Hirsch IB. N Engl J Med. 25;352(2): Flood TM. J Fam Pract. 27;5(Suppl 1):S1-S12. Becker RH, et al. Diabetes Care. 215;38(4): PDR.net. Accessed July 1, 215. Hompesch M, et al. Clin Ther. 214;3(4): % Degludec / 3% Aspart 5-15 minutes 1-4 >42 Walia M, et al. JAMA. 214;311: PL Detail-Document, Comparison of s and Injectable Diabetes Meds. Pharmacist s Letter/Prescriber s Letter. March 215. Preferential Glucose Effect of s Regimens Rapid-acting/short-acting insulin (meal-time insulins) Reduces predominantly PPG Ideal for controlling postprandial hyperglycemia Intermediate-acting (NPH) Reduces mostly FPG Not an ideal basal insulin due to intermediate duration of action Long-acting/ultra long-acting (basal insulins) Reduces essentially only FPG, little effect on PPG Not useful in patients with well-controlled FPG Walia M, et al. JAMA. 214;311: Advantages Basal only Convenient, 1 shot only, low risk of especially with analogue insulin Appropriate for most patients starting insulin Basal plus Two injections only, bolus typically targeted to largest meal of day Appropriate for patients not achieving goal A1C on basal insulin and wanting only 2 shots daily Disadvantages Basal only Does not address PPG may not provide sufficient insulin in advance disease Basal plus May not cover all prandial needs Plank J, et al. Arch Intern Med. 25;15: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD513. Davies M, et al. Diabetes Care. 25;28: Yki-Jarvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85:

6 9/8/21 Regimens (cont) Regimens (cont) Advantages Basal bolus Flexible regimen, basal plus bolus whenever eating meal, allows for correction insulin use Appropriate for patients willing to do multiple injections daily with frequent BG monitoring and capable of managing the complexity Disadvantage Basal bolus Many injections, adds complexity to daily insulin regimen Advantages Premixed Can minimize daily injection number Appropriate for patients who cannot use basal bolus, wanting only 2 injections, and who have regular lifestyles and eat similar amounts at similar times each day (similar total calories and similar content for carbohydrate/fat/protein) Disadvantage Premixed Fixed ratio, does not allow flexibility in dosing, increased risk of Plank J, et al. Arch Intern Med. 25;15: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD513. Davies M, et al. Diabetes Care. 25;28: Yki-Jarvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85: Plank J, et al. Arch Intern Med. 25;15: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD513. Davies M, et al. Diabetes Care. 25;28: Yki-Jarvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85: Premixed vs Basal Analogs in T2DM 1 Premixed 9.7 Basal Glargine 9.8 Premixed vs Basal Analogs in T2DM (cont) 1 Premixed 9.7 Basal Glargine 9.8 A1C (%) * 2.4 A1C (%) * Premixed Basal P Value 5 A1C<7% % 4% P<.1 4 Baseline Week 28 BID Bisphasic Aspart 7/3 (N=117) Baseline Week 28 QD Glargine (N=11) Hypoglycemia 4 (events/yr) Baseline Wk Baseline Wk 28 P<.5 Weight (kg) BID Bisphasic 5.4 QD 3.5 P<.1 dose (units/d) Aspart 7/3 79±4 (N=117) Glargine 51±27 (N=11) P<.5 *P<.1 vs glargine. Raskin P, et al. Diabetes Care. 25;28:2-25. *P<.1 vs glargine. Raskin P, et al. Diabetes Care. 25;28:2-25. Basal only Options in T2DM 1 injection Added to oral agents Basal plus 2 injections or 1 injection + 1 inhalation Adding rapid-acting analog sequentially starting with largest meal Basal bolus 4 injections or 1 injection + 3 inhalations Rapid-acting analog before each meal Premixed 2 injections # INJECTIONS 1 Recommendations for Advancing Basal (usually with metformin ± other noninsulin agent) If not controlled after FBG target is reached (or if dose >.5 U/kg/d), treat PPG excursions with mealtime insulin. (Consider initial GLP-1-RA trial) COMPLEXITY LOW 2 MOD Add 1 rapid insulin injection Change to before largest meal premixed insulin twice daily Add 2 rapid insulin If not controlled, If not controlled, 3+ consider basal bolus Injections before meals consider basal bolus HIGH ( basal bolus ) FLEXIBILITY MORE FLEXIBLE LESS FLEXIBLE ADA. Diabetes Care. 215;38(Suppl 1):S41-S48. FBG = fasting blood glucose. ADA. Diabetes Care. 215;38(Suppl 1):S41-S48.

7 9/8/21 Benefits Start with Basal Added to Oral Agents Effective in reaching A1C goals for most Convenient: Once daily and easy titration Proven safe (particularly with glargine) ORIGIN trial showed no increased risk of CVD or cancer Low risk of, particularly with analog basal insulins Therefore, addresses several barriers to insulin use Dosing Start: 1 U/d or.1-.2 U/kg/d Adjust: by 1% to 15% or 2-4 U once or twice weekly to reach target For : Assess cause and correct or dose 4 U or 1% to 2% CVD = cardiovascular disease. ORIGIN Investigators. N Engl J Med. 212;37: ADA. Diabetes Care. 215; 38(Suppl 1)S41-S48. When Basal Alone Is Not Enough When A1C values are still not at target AND Basal insulin dose titrated to.4-. U/kg/d Fasting BG levels at or approaching target Postprandial BG values remain above target Options Advance insulin therapy with additional prandial insulin Add GLP-1 agonist therapy if tolerated, not contraindicated, and is affordable for the patient ADA. Diabetes Care. 215;38(Suppl 1):S41-S48. Regimens: Basal Plus Advantages Basal plus Two injections only, bolus typically targeted to largest meal of day Adherence is greater for twice- daily than more-frequent dosing Eliminates the barrier of lunch dosing Nearly as effective in lowering A1C as full basal bolus therapy in many patients Disadvantages Basal plus May not cover all prandial needs May not reach goal in some patients Plank J, et al. Arch Intern Med. 25;15: Horvath K, et al. Cochrane Database Syst Rev. 27;(2):CD513. Davies M, et al. Diabetes Care. 25;28: Yki-Jarvinen H, et al. Diabetes Care. 27;3: Crasto W, et al. Postgrad Med J. 29;85: How to Intensify Using the Basal Plus Approach Choose a target meal to initiate prandial insulin Breakfast or the largest meal of the day Start rapid-acting insulin analog 4 U,.1 U/kg or 1% of basal dose 1-15 minutes before meal If A1C is <8.%, consider decreasing basal by 1% Adjust Increase dose 1-2 U or 1%-15% once or twice weekly until SMBG following that meal is at target 2-hour PPG -> target <18 mg/dl Next pre-prandial or HS BG -> target <13 mg/dl For Determine cause and correct; corresponding dose by 2-4 U or 1% to 2% Once titrated to goal, if A1C remains above target, add second prandial dose SMBG = self-monitoring of blood glucose. ADA. Diabetes Care. 215;38(Suppl 1):S41-S48. Characteristics of the Ideal Basal Ultra Long-Acting Basal s Have Minimal Glycemic Variability Pharmacodynamic profile should be flat (ie, peakless) Low risk of Duration of action of 24 hours Low variability within individual patients Arnolds S, et al. Int J Clin Pract. 21;4(1): a 2-period crossover study in T1DM; n=5. b 3-period crossover study in T2DM. T1DM = type 1 diabetes mellitus. Becker RH, et al. Diabetes Obes Metab. 215;17: Haahr H, et al. Clin Pharmacokinet. 214;53: Porcellati F, et al. Diabetes Care. 211;34:

8 9/8/21 U3 Glargine U3 insulin glargine offers a smaller depot surface area leading to a reduce rate of absorption Provides a flatter, prolonged pharmacokinetic and pharmacodynamic profile and more consistency Half-life is ~23 hours Steady state in 4 days Duration of action 3 hours FDA approved February 215 FDA = US Food and Drug Administration. Garber AJ. Diabetes Obesity Metab. 214;1: Owens DR, et al. Diabetes Metab Res Rev. 214;3(2):14-119; Steinstraesser A, et al. Diabetes Obes Metab. 214;1: Accessed March 11, 214. Fiore K. Medpage Today. Accessed January 21. Pharmacokinetic and Pharmacodynamics of U3 Glargine vs U1 Glargine INS [µu/ml -1 ] GIR [mg/kg -1 /min -1 ] LLOQ Time (hours) INS = insulin concentration; LLOQ = lower limit of quantification; GIR = glucose infusion rate; PK = pharmacokinetic; PD = pharmacodynamic. Becker RH, et al. Diabetes Care. 215;38(4): Gla-1.4 U/kg -1 Gla-3.4 U/kg -1 N=3 U3 glargine displays a more even and prolonged PK/PD profile compared with U1 glargine, offering BG control beyond 24 hours 3 U3 Glargine vs U1 Glargine in T2DM Meta-Analysis of Phase 3 Trials EDITION 1, 2, and 3 Baseline to Month Glar U3 (N=1247) Glar U1 (N=1249) RR (95% CI) A1C (%), LS mean NS Weight (kg), LS mean P=.58 Any in 24 hours* (.87-.9) Any nocturnal * (.9-.85) Confirmed BG <54 mg/dl or severe * (.72-.9) Confirmed nocturnal BG <54 mg/dl or severe * ( ) *% people 1 event. LS = least squares; RR = relative risk; CI = confidence interval. RA, et al. Presentation 93; 5th EASD Annual Meeting; September 15-19, 214, Vienna, Austria. Efficacy and Safety of U3 Glargine vs U1 Glargine in -Naïve T2DM a n = 439 (U3), n = 439 (U1), mean age = 57.7 years, duration of diabetes mellitus = 9.8 years, BL AIC = 8.54%, BL wt = 95.3 kg, BL BMI = 33 kg/m 2 ; a plasma glucose 7 mg/dl or severe; c between midnight and : am; d requiring assistance, baseline to month. Bolli GB, et al. Diabetes Obes Metab. 215;17: Percentage of Injections (%) Flexible vs Fixed-Dosing U3 -Month Treatment Period (main study) U3 once daily every 24 hours Months (randomization, sub-study) Edition 1 Sub-Study N=19 <1 h 1-3 h Sub-Studies of Phase 3 Trials -Month Extension Period (main study) U3 once daily every 3 hours >3 h sub-study U3 once daily every 24 hours Edition 2 Sub-Study N=89 Flexible Dosing Fixed Dosing Ritzel R, et al. Presentation 919-P; 74th ADA Scientific Sessions; June 13-17, 214; San Francisco, CA. Accessed August 15, 214. <1 h 9 Months (end of sub-study) 1-3 h >3 h No difference in A1C between flexible vs fixed dosing No difference in severe or nocturnal within each sub-study U3 Glargine Only available in pens 3 U/mL, 1.5 ml Maximum dose per shot is 8 U with 1-U increments using current pen New pen in development will allow a maximum dose of 24 U U3 glargine pen is white and green with the concentration lighted in orange to distinguish it from U1 glargine purple and gray PDR.net. Accessed March 2, 215. PDR.net. Accessed March 2,

9 9/8/21 U3 Glargine Dosing -naïve patients T1DM: Start with one-third to one-half of the total daily insulin dose calculated by using.2-.4 U/kg/d; give the remainder of the total daily insulin dose as a short-acting insulin and divide between each daily meal T2DM: Start with.2 U/kg/d T1DM or T2DM Changing from once-daily long-acting or intermediate-acting insulin Initial dose can be the same as the once daily long-acting dose; for patients controlled on U1 insulin glargine, expect that a er daily dose of U3 glargine will be needed to maintain the same level of glycemic control Changing from twice-daily NPH insulin Initial dose is 8% of the total daily NPH dosage PDR.net. Accessed March 28, 215. Degludec desb3 insulin acylated (1 carbon fatty-acid chain) at LysB29 Has prolonged pharmacokinetic and pharmacodynamic profiles, offering more consistency Duration of action >42 hours Half-life ~25 hours Detectable for at least 5 days Steady state in 2 to 3 days FDA approved September 215 Garber AJ. Diabetes Obesity Metab. 214;1: Owens DR, et al. Diabetes Metab Res Rev. 214;3(2): Degludec (cont) Pharmacodynamics of Degludec Only available in pens 1 U/mL (3. ml), maximum dose per injection 8 U 2 U/mL (3. ml), maximum dose per injection 1 U Degludec U1 pen is yellow and blue, whereas degludec U2 is green and blue with the concentration lighted in blue Individualize dose Glucose-Lowering Effect on Day (mg/kg/min) Degludec.8 U/kg Degludec. U/kg Degludec.4 U/kg Time since Injection (hours) FDA. el_approvalhistory#labelinfo. Accessed October, 215. Josse RG, et al. Diabetes Obes Metab. 213;15(12): Cumulative Events per Participant Degludec vs U1 Glargine in T2DM: Equal Efficacy, Less Nocturnal Hypoglycemia, and Less Overall Documented Hypoglycemia with Degludec degludec once-daily (N=744) glargine once-daily (N=248) Time (weeks) Cumulative per 1.8 Nocturnal confirmed 12 participant per 24 hours P= P= Time (weeks) Time (weeks) A1C (%) Garber AJ, et al. Lancet. 212;379(9285): Cumulative Events per Participant A1C (mmol/mol) BEGIN Flex: Degludec Alternating Dosing BEGIN Flex = Efficacy and Safety of Degludec in a Flexible Dosing Regimen vs Glargine in Patients With Type 1 Diabetes: A 2-Week Randomized, Treat-to-Target Trial With a 2-Week Extension. Matheiu C, et al. J Clin Endocrinol Metab. 213;98:

10 9/8/21 Flexible Timing with Degludec Guideline Recommendations for Initiating and Titrating Basal in Patients with T2DM American Diabetes ADA/EASD Association. Guidelines Diabetes Care. 21;39(suppl 1):S1-S112. Initial 1 U/d or.1-.2 U/kg dose Titration 1%-15% or 2-4 U once or twice weekly to FBG of 8-13 mg/dl Hypoglycemia: Determine and address cause; reduce dose by the greater of 4 U or 1%-2% Once-daily basal insulin, with injection timing based on patient s schedule and glucose profile, is a convenient way to initiate insulin Matheiu C, et al. J Clin Endocrinol Metab. 213;98: American Diabetes Association. Diabetes Care. 21;39(Suppl 1):S1-S112. Ultra Long-Acting Basal s Allow Flexible Dosing: Study Outcomes a 2-wk and Study randomized Flexible controlled Glycemic trial in patients Hypoglycemia with T2DM, Weight N = 317, Gain Design Dosing Control BL A1C = 8.4%, BL BMI = 29. kg/m 2 ; b fixed dosing intervals = 24 h; Interval c pooled results from 2, 3-mo randomized controlled trial in patients U1 DEG flex vs 8-4 Equivalent Similar rates of Equivalent U1 DEG with T2DM, fixed vsn = hours 197, BL A1C = 7.3%, BL BMI = weight kg/mgain 2. U1 GLAR fixed U3 GLAR flex vs U3 GLAR fixed hours A1C Equivalent insulin dose Equivalent A1C Equivalent insulin dose confirmed and severe Similar rates of confirmed, nocturnal, and severe No results reported Stacking? Meneghini L, et al. Diabetes Care. 213;3: Riddle MC, et al. Diabetes Technol Ther. 21 Feb 3 [Epub ahead of print]. Bansal V, et al. Endocr Pract. 214;2: When Might Ultra Long-Acting Be Considered? Patient wanting basal insulin with the lowest risk of Patient experiencing nocturnal with current basal insulins Patient on current basal insulins not lasting throughout the day Specific insulin requiring populations Cystic fibrosis Hypoglycemia unawareness Very thin SWITCH 1 and SWITCH 2 SWITCH 1, T1DM; SWITCH 2, T2DM; insulin glargine vs insulin degludec SWITCH 1 participants to qualify: at least 1 severe hypoglycemic in the past year, moderate chronic renal failure, diabetes mellitus for at least 15 years, a hypoglycemic event in the past 12 weeks degludec: 11% lower rate of symptomatic or severe BG-confirmed, 3% lower rate of severe or BG-confirmed symptomatic nocturnal, 35% lower rate of severe SWITCH 2: degludec compared with insulin glargine Lower rates of severe or BG-confirmed symptomatic in the maintenance period (3%) and full (23%) treatment periods Lower rates of severe or BG-confirmed symptomatic nocturnal in the maintenance (42%) or full (25%) treatment periods Much lower rate (51%) of severe across the full treatment period involving a smaller share of patients Lane WS, et al. Diabetes. 21; 5(Suppl1): 87-LB. Wysham C, et al. Diabetes. 21;5(Suppl1):9-LB. 1

11 9/8/21 Summary of Key Findings What s the Take Home? Any insulin will lower glucose and A1C All insulins are associated with some weight gain and some risk of The larger the doses and the more aggressive the titration, the lower the A1C, but often with a greater possibility of Long-acting insulin analogs reduce the incidence of nocturnal s Rapid-acting insulin analogs reduce PPG excursions (compared with corresponding human insulins [NPH, regular]) and tend to reduce, but they generally do not result in clinically, significantly lower A1C Premixed insulin preparations are effective in reducing A1C but are associated with more and weight gain than using individual short and long-acting insulin T2DM is marked by progressive beta-cell dysfunction requiring progressive pharmacologic therapy to maintain glucose control Available guidelines promote step-wise advancement of therapy that includes basal insulin as an option after metformin Early use of insulin appears to retard progression of beta-cell loss and promotes improvement in first- and second-phase insulin secretion Basal insulin initiation followed by bolus insulin as indicated can control all hyperglycemia Long-acting basal insulins offer an alternative to twice-daily basal insulin use, decrease risk of, and can offer flexibility in timing of use Questions? 11