What s My Line? Identifying the Role of New Ultralong- Acting Insulins for the Treatment of T2DM

Transcription

1 What s My Line? Identifying the Role of New Ultralong- Acting Insulins for the Treatment of TDM Learning Objectives. Compare the pharmacodynamics and therapeutic characteristics of ultralong-acting basal insulins with previously approved insulins. Calculate appropriate doses of ultralong-acting basal insulin for patients with and without prior insulin treatment. Identify simplified, patient-centered treatment regimens incorporating ultralong-acting insulin for advancing therapy in patients with TDM Faculty Davida F. Kruger, MSN, APN-BC, BC-ADM Certified Nurse Practitioner Division of Endocrinology, Diabetes, Bone and Mineral Disease Henry Ford Health System Detroit, Michigan Pablo F. Mora, MD, FACE, MSc, CDE Staff Endocrinologist Diabetes America Clinical Associate Professor of Medicine Division of Endocrinology, Diabetes and Metabolism Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas Slides are current as of the time of printing and may differ from the live presentation due to copyright issues. Please reference for the most up-to-date version of slide sets. Regional Philadelphia Conference Philadelphia, Pennsylvania June -,

2 Glucose, mg/dl Relative Amount TDM Is a Progressive Disease Prediabetes (obesity, IFG, IGT) - Diabetes diagnosis β-cell failure Postmeal glucose Fasting glucose Insulin resistance Insulin level - - TDM Years onset Disease progression occurs no matter how well patients self-manage: insulin therapy should not be used as a threat or described as failure Kendall DM, et al. Am J Med. 9;( suppl):s-s; Kendall DM, et al. Am J Manag Care. ;(suppl):s-s; DeFronzo RA. Diabetes. 9;8:-9; Inzucchi SE, et al. Diabetes Care. ;8:-9; American Diabetes Association. Diabetes Care. ;9(suppl ):S-S. At diagnosis In combination with non-insulin agents - In long-duration disease, Insulin Is the Universal Agent for Achieving Control Benefit especially likely in: Treatment-naive individuals with hyperglycemic symptoms and AC > 9% Latent autoimmune diabetes in adults (LADA) Individuals with hyperlipidemia and/or hypertension Recommended for use in combination with most other major classes of antihyperglycemic agents Combinations reduce glycemic variability compared with insulin-only regimens Loss of β-cell function is inevitable as TDM progresses With appropriate dose adjustment, insulin can be used in any patient (including those with comorbidities that preclude the use of other agents). Owens DR. Diabetes Technol Ther. ;:-8;. Drugs@FDA. Accessed October, ;. American Diabetes Association. Diabetes Care. ;9(suppl ):S-S;. Garber AJ, et al. Endocr Pract. ;:8-;. Hirsch IB, et al. Diabetes. ;(suppl ):A [abstract 8-OR];. Lebovitz HE. Diabetes Rev. 999;:9-. Waiting Until Patients Are Poorly Controlled Before Initiating Insulin Is t Logical Benefits and Limitations of Early Initiation of Insulin Therapy vs Conventional Care In the UKPDS, most adults with newly diagnosed TDM needed insulin within 9 years In ORIGIN,.% of adults with impaired fasting glucose (IFG), impaired glucose tolerance (IGT,) or TDM in the standard-care arm used insulin within years In TODAY, % of adolescents with newly diagnosed TDM required insulin within year Rapid normalization of blood glucose levels Reduces risk of progression from prediabetes to TDM Consistently better long-term glycemic control Even in patients with years of AC > 8%, insulin initiation was often postponed, although they were already using to oral antihyperglycemic agents Patients who start insulin earlier in the disease progression have better long-term glycemic control than patients who start insulin later, Reduces risk of microvascular complications if AC >.% increased CVD risk Limitation: Increased risk of severe. Turner RC, et al. JAMA. 999;8:-.. ORIGIN Trial Investigators, et al. N Engl J Med. ;:9-8.. TODAY Study Group, et al. N Engl J Med. ;:-.. Khunti K, et al. Diabetes Care. ;:-.. Nichols GA, et al. Diabetes. ;(suppl ):A9. Hanefeld M, et al. Diabetes Ther. Feb. [Epub ahead of print]. Current Recommendations for Individualizing Therapy in TDM Using Insulin Regimens Understanding Your Choices Can Help You Further Individualize Therapy ADA/EASD General target: AC < % insulin-specific target AACE/ACE General target: AC.% Insulin-specific target: AC < % More or less intensive targets may be needed depending on disease duration, age, comorbidities, and effort required for self-management, In TDM, insulin is almost always used with other agents, Avoidance of and prevention of weight are high priorities in both algorithms a particular challenge with insulin therapy, Reduce or discontinue sulfonylureas when insulin is added to the regimen, Stepwise introduction of insulin is advocated may minimize weight and, Prandial (bolus) insulins Basal insulins Inhaled Rapid-acting Short-acting Intermediate-acting Premixed Long-acting Ultralong-acting. a 8 Approximate Maximum Duration of Action After Administration, h. American Diabetes Association. Diabetes Care. ;9(suppl ):S-S.. Garber AJ, et al. Endocr Pract. ;:8-.. Inzucchi SE, et al. Diabetes Care. ;8:-9. a Aspart = h, glulisine = h, lispro =. h. Scripts/cder/DrugsatFDA. Accessed January 8,. American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. rd ed. Alexandria, VA: American Diabetes Association;.

3 Current Options Among Insulin Products Type Basal Insulins Prandial Insulins Premixed Insulins Human U- NPH U- regular U- / RHI human insulin (RHI) U- RHI Technosphere inhaled insulin Analogue U- glargine U- glargine equivalent a U- detemir U- degludec U- degludec U- glargine a In the US, U- glargine equivalent is not approved as a biosimilar product. U- lispro U- aspart U- glulisine U- lispro U- / lispro U- / aspart U- / lispro U- / degludec/aspart All recently approved insulins are only available in pens,e; red text denotes which insulins are only available in prefilled pens Analogue insulins are associated with less than human insulins, although these differences are not always statistically significant. Scripts/cder/DrugsatFDA. Accessed January 8, ;. Singh SR, et al. CMAJ. 9;8: Insulins Are Available in Different Concentrations Concentrations and Number of Units per Container Concentration Units/mL Units/Vial Units/Pen U- a b U- t available in vials b U- t available in vials c U-, d c Insulin pens significantly reduce the risk of dosing errors and hypoglycemic events Pens completely eliminate the need for converting doses based on the volume of insulin injected Dosing errors with U- insulin vials are especially dangerous, but pens are now available,e a units/vial; b ml/pen; c. ml/pen; d units/vial; e given the potential for a -fold higher insulin dose relative to the same volume of a U- insulin. Insulin pens with dose window. Drugs@FDA. Newton C, et al. AACE Annual Meeting. [abstract ].. Segal AR, et al. Am J Health Syst Pharm. ;:-. Summary Most patients with TDM will eventually need insulin therapy Insulin is recommended throughout the progression of TDM Earlier insulin use is associated with better long-term glycemic control than postponed insulin use With appropriate dose adjustment, insulin can be used alone or in combination with other antihyperglycemic agents in essentially all patients Insulin offers unmatched flexibility to individualize glycemic control, with 8 products in different time-action categories Blood Glucose, mg/dl Pharmacodynamic Profile of a Hypothetical Ideal Basal Insulin : : : 8: : : : An ideal basal insulin would have biological activity that, : Lasts hours Is as consistent in the first hours as the last hours Is consistent from day to day (no intra-patient variability) Is consistent from patient to patient (no inter-patient variability). Zinman B. N Engl J Med. 989;:-.. Garber AJ. Diabetes Obes Metab. ;:8-9. Glucose Infusion Rates Needed to Keep Blood Glucose Levels as Flat as Possible Using Older Basal Insulins Patient Patient Patient Elapsed, hours Patient Patient Patient Elapsed, hours Patient Patient Patient Elapsed, hours N = patients with TDM. Euglycemic glucose clamp study,. units/kg, trials/patient. Heise T, et al. Diabetes. ;:-. NPH Insulin Insulin Glargine Insulin Detemir GIR, mg/kg/min GIR, mg/kg/min GIR, mg/kg/min Severe Hypoglycemia Rate, events/ person-years Hypoglycemia May Limit Attainment of Goals With Insulin Therapy Any Exposure to Medication in Category a..8 Prandial insulin, Basal insulin, including premixed including NPH and insulin premixed insulin.9 Sulfonylureas, glinides. Other (MET, TZDs, AGIs, DPP-is, GLP- RAs) a control and medication exposure adjusted for age and sex. Data shown are weighted means, SUPREME-DM datalink, - (includes 9, adults withtdm and TDM). Pathak RD, et al. Diabetes Care. ;9:-.

4 Efficacy and Safety of U- Glargine Equivalent (LY9) vs U- Glargine in Insulin-naive Patients With TDM a Overall Hypoglycemia b. P = NS...9. Overall Hypoglycemia, episodes/patient-year.... LY GLAR cturnal Hypoglycemia c. P = NS 8... cturnal Hypoglycemia, episodes/patient-year.... LY GLAR Severe Hypoglycemia d P = NS a n = (LY), n = (GLAR), mean age = 8 y, duration of diabetes = y, BL AC = 8.-8.%, BL wt = 89-9 kg, BL BMI = kg/m ; b plasma glucose mg/dl or sign or symptom of ; c between bedtime and waking; d requiring assistance, baseline to month. Rosenstock J, et al. Diabetes Obes Metab. ;:-. Severe Hypoglycemia, number of episodes LY GLAR ΔAC, % ΔWeight, kg Insulin dose, U/kg LY GLAR. +.. Biosimilar insulins, including LY9, have the same amino acid sequence, form, and concentration as the reference product For regulatory reasons, LY9 is not called a biosimilar insulin in the US Achieving Physiologic Insulin Replacement Change the route of administration Potential methods to consider, Modify the insulin molecule Modify the beta cell (gene therapy). Zinman B. N Engl J Med. 989;:-.. Mason C, Manzotti E. Regen Med. 9;:-. Ultralong-Acting Insulins: Mechanisms of Action U- Insulin Glargine, Same amino acid substitutions as U- insulin glargine Forms microprecipitates after injection Higher concentration = smaller injection volume = smaller surface area Surprising and unexpected differences in exposure and activity for U- vs U- glargine Long multihexamer chains assemble Insulin degludec injected Phenol from the vehicle diffuses quickly, and insulin degludec links up via single side-chain contacts U- and U- Insulin Degludec, Dihexamers (9 kda) form soluble multihexamers after injection Multihexamers (> kda) disassemble slowly Monomers are released rapidly after hexamers disassemble Exposure and activity are similar for U- vs U- degludec. Drugs@FDA. Jonassen I, et al. Pharm Res. ;9:-.. Haahr H, Heise T. Clin Pharmacokinet. ;:8-8. Blood Glucose, mg/dl Blood Glucose, mg/dl Ultralong-Acting Basal Insulins Have Flat Pharmacodynamic Profiles U- glargine,a Clamp level a -period crossover study in TDM; n =. b -period crossover study in TDM., h Period Period 8 U- degludec Individual patient profiles Mean profile Since Injection, h 8 Plasma Glucose, mg/dl Older Basals,b 9 NPH Detemir Glargine Target Level 8 8 Since Injection, h. Becker RH, et al. Diabetes Obes Metab. ;:-.. Haahr H, Heise T. Clin Pharmacokinet. ;:8-8.. Lucidi P, et al. Diabetes Care. ;:-. Efficacy and Safety of U- Glargine vs U- Glargine in Insulin-naive TDM,a U- glargine U- glargine Overall Hypoglycemia,b,e cturnal Hypoglycemia,c,e Severe Hypoglycemia,d,f Cumulative Number of Events % reduction, P <. Cumulative Number of Events. % reduction, P = NS , weeks, weeks Severe Hypoglycemia, episodes/patient-year. P = NS U- U- ΔAC, % ΔWeight, kg,g Insulin dose, U/kg U- GLAR U- GLAR. +.. Cumulative Number of Events per Person Efficacy and Safety of U- Degludec vs U- Glargine in Insulin-naive TDM,a U- glargine U- degludec Overall Hypoglycemia,b,e cturnal Hypoglycemia,c,e Severe Hypoglycemia,d,f % reduction, P =.. % reduction, P =. Cumulative Number of Events per Person. 9 9, weeks, weeks.8... Severe Hypoglycemia, episodes/patient-year 9% reduction, P = DEG GLAR ΔAC, % ΔWeight, kg Insulin dose, U/kg U- DEG. +.. U- GLAR. +.. a n = 9 (U-), n = 9 (U-), mean age =. y, duration of diabetes = 9.8 y, BL AC = 8.%, BL wt = 9. kg, BL BMI = kg/m ; b plasma glucose mg/dl or severe; c between midnight and : am; d requiring assistance, baseline to month ; e overall and nocturnal rates were consistently lower in a meta-analysis of registration trials ; f severe rates were similar in a meta-analysis of registration trials ; g significantly less weight for U- glargine in a meta-analysis of registration trials.. Bolli GB, et al. Diabetes Obes Metab. ;:8-9.. Ritzel R, et al. Diabetes Obes Metab. ;:89-8. a n = (degludec), n = (glargine), mean age = 9 y, duration of diabetes = 9 y, BL AC = 8.%, BL wt = 89-9 kg, BL BMI = - kg/m ; b plasma glucose < mg/dl or severe; c between midnight and : am; d requiring assistance; e reductions in overall and nocturnal only observed in TDM ; f reductions in severe only observed in insulin-naive TDM.. Rodbard HW, et al. Diabet Med. ;:98-;. Ratner RE, et al. Diabetes Obes Metab. ;:-8.

5 U- Glargine Equivalent units/ml Biologically equivalent to U- glargine Compared with U- glargine: Equally effective Equivalent Equivalent weight U- glargine equivalent has the same therapeutic characteristics as U- glargine Summary U- Glargine units/ml Same molecule as U- glargine but more concentrated Compared with U- glargine: Equally effective Less a Equivalent weight a Significantly less overall in insulin-naive patients. b Significantly less nocturnal in insulin-naive patients. U- and U- Degludec or units/ml vel molecular configuration Compared with U- glargine a : Equally effective Less b Equivalent weight Ultralong-acting basal insulins have a flatter time-action profile, with less glycemic variability, and may be less likely to cause than first-generation insulin analogues History & Vital Signs Woman, white years old TDM for years Height: ft in Weight: lb BMI: 8. kg/m BP: 8/8 mm Hg Heart rate: beats/minute (bpm) Meet Betsey Current Medications control Metformin R: mg/d Glimepiride: mg/d Other medications ACE inhibitor Statin Laboratory Results Fasting plasma glucose (FPG): 8 mg/dl AC: 9.% Lipids: Within normal limits (WNL) egfr: ml/min/. m Liver function tests (LFTs): WNL Increasing AC over past years, despite increased dose of sulfonylurea Admits to missing her medication day per week due to irregular schedule and work-related travel Has had minor with glimepiride and would like to avoid going through that a Is hesitant but willing to consider adding insulin to her regimen if necessary Guideline Recommendations for Initiating and Titrating Basal Insulin in Patients With TDM Initial dose Titration ADA/EASD Guidelines U/d or.-. U/kg %-% or - U once or twice weekly to fasting blood glucose (FBG) of 8- mg/dl Hypoglycemia: determine and address cause; reduce dose by the greater of U or %-% Once-daily basal insulin, with injection timing based on patient s schedule and glucose profile, is a convenient way to initiate insulin Guidance for Initiating and Titrating Newer Basal Insulins: U- Glargine Equivalent a Starting Dose of U- Glargine Equivalent for Insulin-Naive Patients. U/kg or U, once daily Starting Dose of U- Glargine Equivalent for Patients Switching From Another Basal Insulin U- glargine Same dose U- detemir U- NPH 8% of NPH dose U- degludec U- glargine 8% of U- dose Injection time Same time daily Titration step Maximum titration frequency Dwell time seconds American Diabetes Association. Diabetes Care. ;9(suppl ):S-S. a U- glargine equivalent, LY9. Scripts/cder/DrugsatFDA. Accessed January 8,. Guidance for Initiating and Titrating Newer Basal Insulins: U- Glargine Starting Dose of U- Glargine in Insulin-Naive Patients. U/kg, once daily Starting Dose of U- Glargine in Patients Switching From Another Basal Insulin U- glargine Same dose, but expect to increase the dose of U- glargine to maintain the same level of glycemic control U- detemir Same dose U- NPH 8% of NPH total daily dose (especially if using daily doses) U- degludec Injection time Titration step,a Max. titration frequency Dwell time a in prescribing information; titration methods from EDITION study shown. Same time daily Calculate median FPG from the preceding measurements: Uptitrate by U if SMBG is mg/dl Uptitrate by U if SMBG is between and mg/dl Downtitrate by U if SMBG < 9 mg/dl - days sec. Scripts/cder/DrugsatFDA. Accessed January 8,.. Yki-Järvinen H, et al. Diabetes Care. ;:-. Guidance for Initiating and Titrating Newer Basal Insulins: U- or U- Degludec Starting Dose of U- or U- Degludec in Insulin-Naive Patients U, once daily Starting Dose of U- or U- Degludec in Patients Switching From Another Basal Insulin U- glargine Same dose ; consider % dose reduction if switching from U- detemir twice-daily basal insulin dosing U- NPH U- degludec Same dose for U- and U- U- glargine (but % reduction may be prudent) Injection time Once daily, any time ( 8 h since last dose) Titration step Calculate average FPG from the preceding days, compare with goal: Uptitrate by U if above goal Maintain dose if at goal Downtitrate by U if below goal Max. titration - days, but no more than weekly may be better frequency Dwell time seconds. Scripts/cder/DrugsatFDA. Accessed January 8,.. Vora J, et al. Diabetes Res Clin Pract. ;9:9-.

6 Ultralong-Acting Basal Insulins Allow Flexible Dosing: Dosing Intervals Used in Trials Ultralong-Acting Basal Insulins Allow Flexible Dosing: s Degludec flexible dosing protocol 8 to hour intervals U- flexible dosing protocol ± hour intervals Day Mon Tue Wed Thu Fri Sat Sun Mon Dose injected AM PM AM PM AM PM PM AM Interval, h Injections, % Within - h Within - h Beyond - h FLE FIED. Meneghini L, et al. Diabetes Care. ;: Riddle MC, et al. Diabetes Technol Ther. Feb. [Epub ahead of print]. Insulin and Study Design U- DEG flex vs U- DEG fixed vs U- GLAR fixed,a,b U- GLAR flex vs U- GLAR fixed,b,c Flexible Dosing Interval Control 8- h Equivalent ΔAC Equivalent insulin dose - h Equivalent ΔAC Equivalent insulin dose a -wk randomized controlled trial in patients with TDM, N =, BL AC = 8.%, BL BMI = 9. kg/m ; b fixed dosing intervals = h; c pooled results from, -mo randomized controlled trial in patients with TDM, N = 9, BL AC =.%, BL BMI =.-.9 kg/m. Hypoglycemia Similar rates of confirmed and severe Similar rates of confirmed, nocturnal, and severe Weight Gain Equivalent weight results reported. Meneghini L, et al. Diabetes Care. ;: Riddle MC, et al. Diabetes Technol Ther. Feb. [Epub ahead of print]. Insulin Pens Can Improve Outcomes and Are Associated With Lower Risks of Dosing Errors and Hypoglycemia Than Vial-and-Syringe Insulin Human insulins are generally administered with a vial and syringe Analogue insulins are generally administered with a pen Patient copayments for pens may be the same as for vials Use the shortest possible needles ( 8 mm) After injecting, keep the needle in the skin for the recommended dwell time Rotate sites to avoid lipohypertrophy Calculating the Number of Pens to Prescribe Parameter U- Glargine Equivalent U- Glargine U- Degludec U- Degludec Insulin units/pen a Pens per carton Doing the math (with sample calculations for units/day): Daily dose d/mo = monthly dose units/d d = units/mo Monthly dose = pens needed (round up!) Units/pen Pens needed = cartons needed (round up!) Pens/carton U- glargine equivalent: / = pens U- glargine: / =. pens U- degludec: / = pens U- degludec: / =. pens U- glargine equivalent: / = carton U- glargine: / =. cartons U- glargine: / =.8 carton U- degludec: / = carton U- degludec: / = carton Perez-Nieves M, et al. Curr Med Res Opin. ;:89-899; Molife C, et al. Diabetes Technol Ther. 9;:9-8; Aetna. Aetna Pharmacy Plan Drug List. Accessed January, ; Becton Dickinson Diabetes. Step by step injection guide. Accessed January, ; Frid A, et al. Diabetes Metab. ;(suppl ):S-S8; Scripts/cder/DrugsatFDA. Accessed January 8,. a Calculated from dosage form information given in the prescribing information: units/ml ml/pen. Scripts/cder/DrugsatFDA. Accessed January 8,. Other Practical Aspects of Insulin Delivery for Newer Basal Insulins Parameter U- Glargine Equivalent Storage - Refrigerate until opened - Can store up to weeks at room temperature after opening U- Glargine U- or U- Degludec - Refrigerate until opened - Can store up to weeks at room temperature after opening Needles - t stated - BD Ultra-Fine - Ypsomed Clickfine - Owen Mumford Unifine Pentips - Refrigerate until opened - Can store up to 8 weeks at room temperature after opening - vofine - votwist Summary Newer basal insulins are initiated and titrated at doses similar to those for other basal insulins Dose adjustments may need to be made for patients switching between some basal insulins Ultralong-acting basal insulins are more forgiving of missed/mistimed doses than other basal insulins All newer basal insulins come in pen injectors and dispense in units regardless of concentration Needles are prescribed separately from insulin pens Scripts/cder/DrugsatFDA. Accessed January 8,.

7 History & Vital Signs Meet Joseph Current Medications Laboratory Results Hypothetical Effects of Changes in Insulin Regimen on Blood Glucose Profile Man, black years old TDM, years Myocardial infarction, years ago Height: ft 9 in Weight: lb BMI: kg/m BP: /8 mm Hg Heart rate: 8 bpm control Metformin R: mg/d Sitagliptin: mg/d U- glargine: 8 U/d, AM injection Other medications ARB and HCTZ Statin Aspirin FPG: mg/dl SMBG: - mg/dl AC: 8.% Lipids: WNL egfr: ml/min/. m LFTs ALT: U/mL AST: U/mL Glucose, mg/dl Poor control Adjust FPG Adjust PPG Target glucose range Glucose, mg/dl Glucose, mg/dl Recognizes that his FPG is not where it should be but doesn t want to increase his insulin dose because the injection volume is already uncomfortably large Does not want to split the insulin to AM and PM doses because he s a musician and is often busy in the evening, playing with his band : : : : Inadequate insulin doses : : : : : : : : Adjust basal insulin Adjust prandial insulin Zinman B. N Engl J Med. 989;:-. Bode BW, et al. Diabetes Care. ;8:-. Hirsch IB, et al. Clin Diabetes. ;:8-8. American Diabetes Association. Diabetes Care. ;9(suppl ):S-S. Treatment Algorithms for Advancing Beyond Basal Insulin Therapy: Stepwise Prandial Insulin Options for advancing therapy from basal insulin ADA AACE/ACE Consider trial of GLP- RA Stepwise prandial insulin a GLP- RA SGLT inhibitor DPP- inhibitor Stepwise prandial insulin Stepwise insulin means adding,, and then prandial injections, as needed, Do not use Sliding scale Step Basal Stepwise Insulin Therapy and Corresponding Insulin Regimens h h Step Basal plus Always the first step h Step Basal + Add doses only if goals are unmet on simpler regimen h Step Basal bolus Add doses per meal size or PPG level Less-preferred alternative Premixed/biphasic h h a Pharmacodynamic profiles of ASP /, LIS /, and LIS / are suboptimal to cover postprandial glucose excursions.. ADA. Diabetes Care. ;9(suppl ):S-S.. Garber AJ, et al. Endocr Pract. ;:8-. = insulin injection. American Diabetes Association. Diabetes Care. ;9(suppl ):S-S; Garber AJ, et al. Endocr Pract. ;:8-; American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. rd ed. Alexandria, VA: American Diabetes Association; ; Hirsch IB, et al. Clin Diabetes. ;:8-8; Hirsch IB. JAMA. 9;:-. Initiating and Titrating Prandial Insulin in TDM Initial dose Titration Prandial Insulin Titration If FBG target is reached or if basal dose >. U/kg/d, initiate prandial analogue before largest meal Initial dosing: U or. U/kg or % of basal dose If AC < 8%, consider reducing basal dose by same amount - U or %-% once or twice weekly until SMBG target is reached Hypoglycemia: determine and address cause; reduce corresponding dose by - U or %-% Follow same titration for second and third prandial doses, if needed Optimizing Outcomes severe control: AC < % weight Comparing Basal-Plus and Basal-Bolus Regimens : Meta-Analyses Control AC < %, % Study 8 Basal-plus Regimens Compared BBT Overall Hypoglycemia Episodes/patient-year ΔAC, % Basal-plus AC < %, % BBT Weight Gain ΔWeight, kg Hypo Rate, (all/noct/sev), EPY Basal-plus Weight Gain, kg BBT Insulin Dose, U/kg Basal-plus vs basal.% a + a. /. /. b +.9 a +. a BBT vs basal NR - vs 8-. vs c +. vs vs.8. American Diabetes Association. Diabetes Care. ;9(suppl ):S-S.. Zinman B, et al. Diabetes Obes Metab. ;:-8. a Mean difference, basal-plus minus basal; b rates after months on basal-plus regimen; c overall.. Lankisch MR, et al. Prim Care Diabetes. ;:-9.. Giugliano D, et al. Diabetes Res Clin Pract. ;9:-.

8 Comparing Premixed Insulin With Basal-Plus or Basal-Bolus Insulin Regimens Comparing Newly Approved Premixed Degludec/Aspart / With Biphasic Aspart / control - Usually equivalent ΔAC Hypoglycemia - Less symptomatic with basal-bolus but may not be significantly less Weight - Usually less with basal-plus or basal-bolus but may not be significantly less control Equivalent ΔAC Hypoglycemia Significantly less confirmed with degludec/ aspart (DEG/ASP) Weight Significantly less weight with DEG/ASP Equivalent Basal-bolus better a Equivalent to basal-plus Equivalent Equivalent Equivalent a Statistically significant superiority; P <.. Equivalent Basal-bolus better a Basal-plus better a Equivalent Equivalent Equivalent Basal-bolus better a Equivalent to basal-bolus Equivalent to basal-plus Equivalent Equivalent Premixed better a. Malek R, et al. Diabetes Metab. ;:-.. Riddle MC, et al. Diabetes Obes Metab. ;:9-.. Giugliano D, et al. Diabetes Care. ;:-8.. Miser WF, et al. Clin Ther. ;: Rodbard HW, et al. Diabetes Obes Metab. v. [Epub ahead of print]. ASP /.% DEG/ASP.% ASP /. events/ patient-year (severe.%) DEG/ASP 9. events/ patient-year a (severe.%) ASP / DEG/ASP. kg. kg b a P =.9; b P <.. -wk trial of patients with TDM (mean baseline characteristics: age, 9 y; diabetes duration, y; AC, 8.%-8.%; wt, 8 kg) previously using premixed or self-mixed insulin with or without oral agents. Both insulins were dosed twice daily. Confirmed, plasma glucose < mg/dl or assistance required. Fulcher GR, et al. Diabetes Care. ;:8-9. New and Emerging a Prandial Insulins: United States, May Overview of Therapeutic Characteristics of New and Emerging Prandial Insulins Human insulins (short acting) Regular human insulin (RHI) U- RHI U- RHI a Approved by the US FDA or NDA filed. b t currently approved by the US FDA. Prandial Human insulin (ultrarapid acting) Technosphere inhaled insulin Lispro U- lispro U- lispro Analogues (rapid acting) Aspart U- aspart Fasteracting aspart b Glulisine U- glulisine US FDA. Drugs@FDA. U- lispro (approved), Inhaled insulin (approved), Faster-acting aspart (submitted), a Randomized, -way crossover study in adults with TDM. b Randomized trial in adults with TDM treated with continuous subcutaneous insulin infusion. Bioequivalent to U- lispro -action characteristics similar to U- lispro, Prefilled pen injector Concentration permits smaller injection volume Much faster and shorter acting than subcutaneous (SC) insulins (variable bioavailability, inconsistent dosing effect) t as effective as SC but less weight Significantly less severe Limit use to nonsmokers without pulmonary disease, Greater glucose-lowering effect within 9 minutes after dosing vs currently available aspart,a Significantly lower PPG for faster-acting aspart vs currently available aspart,b. de la Peña A, et al. Clin Pharmacol Drug Dev. ;:9-.. Scripts/cder/DrugsatFDA. Accessed January 8,.. Pittas AG, et al. Lancet Diabetes Endocrinol. ;: Heise T, et al. Diabetes Obes Metab. ;: Bode B, et al. Diabetes. ;(suppl ):A [abstract 99-P]. Many Patients Do t Meet Generally Recommended Goals Using First-Generation Insulin Analogues in Intensified Insulin Regimens Treatment Algorithms for Advancing Beyond Basal Insulin Therapy: GLP- RA Option Patients, % 8 8 Premixed (n = 99) Basal Bolus Therapy (n = 8) AC <.% AC <.% AC <.% AC < 8.% AC Target Attained 8 88 Giugliano D, et al. J Diabetes Complications. ;:-8. Options for advancing therapy from basal insulin ADA AACE/ACE a Pharmacodynamic profiles of ASP /, LIS /, and LIS / are suboptimal to cover postprandial glucose excursions. Consider trial of GLP- RA Stepwise prandial insulin a GLP- RA SGLT inhibitor DPP- inhibitor Stepwise prandial insulin Albiglutide, exenatide BID, and liraglutide are FDA-approved for use in combination with basal insulin Exenatide QW is not recommended for use in combination with basal insulin. ADA. Diabetes Care. ;9(suppl ):S-S.. Garber AJ, et al. Endocr Pract. ;:8-.. Scripts/cder/DrugsatFDA. Accessed January, ;

9 Treatment Algorithms for Advancing Beyond Basal Insulin Therapy Have Been Updated ADA/EASD: consider a trial of a GLP- receptor agonist AACE/ACE: consider a GLP- receptor agonist, an SGLT inhibitor, or a DPP- inhibitor Approval Status for Use of GLP- receptor agonists in Combination With Insulin Agent Basal Prandial t Recommended Albiglutide - mg QW Dulaglutide.-. mg QW Exenatide - μg BID Exenatide mg QW Liraglutide.-.8 mg QD Lixisenatide (NDA accepted by US FDA) See note, Comparing a GLP- RA With Prandial Insulin to Intensify a Basal Insulin Regimen control - Better or equivalent ΔAC EN EN BID = LIS TID LIRA LIRA QD > ASP QD a LII LII QD > GLU QD a LII QD > GLU TID a ALBI ALBI QW = LIS TID Hypoglycemia - Significantly less with GLP- RA than with prandial insulin EN BID > LIS TID a,b LIRA QD > ASP QD a LIIQD> GLUQD a LII QD > GLU TID a ALBI QW > LIS TID Weight - Significantly less weight with GLP- RA than with prandial insulin EN BID > LIS TID a LIRA QD > ASP QD a LIIQD> GLUQD a LII QD > GLU TID a ALBI QW > LIS TID a te: Has been tested in combination with insulin glargine.,. American Diabetes Association. Diabetes Care. ;9(suppl ):S-S;. Garber AJ, et al. Endocr Pract. ;:8-;. Scripts/cder/DrugsatFDA. Accessed January, ;. Sanofi. Accessed January, ;. Riddle MC, et al. Diabetes Care. ;:9-;. Meier JJ, et al. Diabetes Care. ;8:-. a Statistically significant superiority; P <.; b Lower rates for all categories of, but statistically significant for minor and non-nocturnal confirmed only.. Diamant M, et al. Diabetes Care. ;:-;. Mathieu C, et al. Diabetes Obes Metab. ;:-;. Rosenstock J, et al. Diabetes. ;(suppl A):LB-LB8. [abstract -LB];. Rosenstock J, et al. Diabetes Care. ;:-; Comparative Safety: Cautions, Warnings, Contraindications, and Other Considerations Shared Decision-Making Points for Comparing a GLP- Receptor Agonist vs a Prandial Insulin Analogue Contraindications Warnings and precautions Adverse reactions Prandial Insulin Analogues Used With Basal Insulin Do not use during episodes of a-c Hypoglycemia (due to dose, timing, changes in regimen, or medication errors) a-c Glucose monitoring needed a-c Reduce dose in renal or hepatic impairment a-c Pregnancy category B a,b or category C c Hypoglycemia a-c GLP- Receptor Agonists Used With Basal Insulin Personal or family history of MTC d,e MEN syndrome type d,e Hypoglycemia (with SUs or insulin) d-f History of pancreatitis d-f Use caution initiating or escalating dose in renal impairment d,e,g Pregnancy category C d-f ; may cause fetal harm d,f Gastrointestinal (mild-severe) d-f Aspect of Care Number of additional injections, per week Dose adjustment for meals required? Dose adjustment for exercise required? Glucose monitoring needed multiple times daily? GLP- Receptor Agonist (GLP- RA) Prandial Insulin Analogue to to Yes Yes Yes a Insulin lispro; b insulin aspart; c insulin glulisine; d albiglutide; e liraglutide; f exenatide BID; g do not use exenatide BID in patients with severe renal impairment. Scripts/cder/DrugsatFDA. Accessed May,. Scripts/cder/DrugsatFDA. Accessed January 8,. Coformulations of Basal Insulin and a GLP- RA Offer Potential for Intensifying Basal Insulin Therapy With a Single Daily Injection Coformulated Liraglutide + Degludec,a Coformulated Lixisenatide + vs Degludec vs Liraglutide Glargine,b vs Glargine Patients Achieving Composite Endpoint, % 8 a Baseline AC, 8.%; Baseline Wt, 8 kg; weeks; b Baseline AC, 8.%; BL BMI,. kg/m ; weeks; * P <. vs DEG; P <. vs LIRA; P <. vs PBO + GLAR. All baseline characteristics stated as means values. *, DEG LIRA LIRA + DEG GLAR LII + GLAR Composite endpoint: AC < % without weight or FDA Advisory Committee recently recommended approval of fixed-ratio coformulations of DEG-LIRA and GLAR-LII, 9. Gough SC, et al. Lancet Diabetes Endocrinol. ;: Rosenstock J, et al. Diabetologia. ;(suppl ):S8 [abstract ] Prandial Insulins Improve glycemic control Greatest flexibility Stepwise initiation minimizes risks of and weight Premixed insulin may be an appropriate alternative for some patients Summary GLP- Receptor Agonists Improve glycemic control Potentially fewer daily injections than prandial insulin Low risks of or weight Prescribing limitations in some patients