Objectives. Drug List. Natural History of Type 2 Diabetes. Progression of Type 2 Diabetes. Presenter Disclosure Information.

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1 7:45 9 am Evolving Therapy: Optimizing Care Through Proper Selection & Use SPEAKERS Andrew Ahmann, MD, MS Guillermo E Umpierrez, MD, FACP, FACE Presenter Disclosure Infmation The following relationships exist related to this presentation: Andrew Ahmann, MD, MS: Research Suppt from Medtronic; Novo Ndisk Inc.; and sanofi-aventis U.S. Board and Advisy Panel Member f Janssen Pharmaceuticals, Inc. and Mannkind Cpation. Consultant f DexCom and Novo Ndisk Inc. Guillermo E Umpierrez, MD, FACP, FACE: No financial relationships to disclose. Off-Label/Investigational Discussion In accdance with pmicme policy, faculty have been asked to disclose discussion of unlabeled unapproved use(s) of drugs devices during the course of their presentations. Drug List Generic Drug Name US Trade Name insulin aspart Novolog, Novolog FlexPen, insulin detemir Levemir, Levemir Flexpen insulin glargine Lantus, Lantus SoloStar U-3 insulin glargine Toujeo insulin glulisine Apidra insulin human regular Humulin R, Novolin R insulin human isophane (NPH) Humulin N, Novolin N insulin lispro Humalog, Lispro-PFC metfmin Glucophage pioglitazone Actos sitagliptin Januvia Objectives Implement strategies f the timely initiation of insulin therapy to best achieve glycemic control in patients with type diabetes Design insulin regimens that are appropriate and tailed to a patient s needs Recognize the barriers to insulin-mediated glucose control and apply strategies to overcome them Outline the pharmacokinetic/ pharmacodynamics profiles and evidence f emerging basal insulin f the treatment of type diabetes Natural Histy of Type Diabetes Progression of Type Diabetes Duration of Diabetes Frank Diabetes Resistance Hepatic Glucose Production Endogenous Prediabetes Postprandial Blood Glucose Fasting Blood Glucose Microvascular Complications Macrovascular Complications Time Years to Decades Typical Diagnosis of Diabetes Ramlo-Halsted BA, Edelman SV. Clin Diabetes. ;18():8-85.

2 Stages of Type Diabetes By Beta Cell Function 1 Glycemic Control & Complications Microvascular Macrovascular Mtality DCCT/EDIC 1 -Cell Function (%) IGT Postprandial Type Hyperglycemia Diabetes Phase I Adapted from Lebovitz H. Diabetes Review. 1999;7: Type Diabetes Phase II Type Diabetes Phase III Years from Diagnosis Type Studies UKPDS,3 ACCORD 4,5 ADVANCE 6,7 VADT 8 Observational Follow-up 1. Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;35: Holman RR, et al. N Engl J Med. 8;359: Gerstein, et al. NEJM. 8;358: ACCORD Study Group. NEJM. 1; 363: Patel, et al. NEJM. 8;358: Zoungas S, et al. N Engl J Med. 14;371: Duckwth, et al, NEJM 9;36: Recommendations f Advancing Therapy in Type Diabetes Individualizing A1C Targets f Patients with TDM Most Intensive Less Intensive Least Intensive 6.% 7.% Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, & Comprehensive Suppt Systems 8.% Psychosocioeconomic Considerations Less motivated, Non-adherent, Limited Insight, Po Self-Care Capacities, & Weak Suppt Systems Low Moderate Hypoglycemia Risk High Patient Age Disease Duration Other Combidities Multiple/Severe None Few/Mild Established Vascular Complications None Cardiovascular Disease None Advanced Micro Early Micro Data from Ismail-Beigi F, et al. Ann Intern Med. 11;154(8): ADA/EASD 15 Guidelines Healthy eating, weight control, increased physical activity Initial drug monotherapy Efficacy ( HbA1c) Hypoglycemia Weight Side effects Costs Metfmin low risk neutral/loss GI / lactic acidosis low If needed to reach individualized HbA1c target after ~3 months, proceed to -drug combination (der not meant to denote specific preference) Dual Therapy ADA/EASD 15 Guidelines Cont d Efficacy ( HbA1c) Hypoglycemia Weight Maj side effect(s) Costs Triple Therapy SU moderate risk gain hypoglycemia low SU+ TZD DPP-4-i SGLT-i GLP-1-RA TZD low risk gain edema, HF, fx s DPP-4-i intermediate low risk neutral rare SGLT-i intermediate low risk neutral rare GLP-1 RA low risk loss GI If needed to reach individualized A1C target after ~3 months, proceed to 3-drug combination (der not meant to denote specific preference) TZD + SU DPP-4-i SGLT-i GLP-1-RA DPP-4-I + SU TZD SGLT-i SGLT-i + SU TZD DPP-4-i GLP-1 RA + SU TZD (basal) est risk gain hypoglycemia variable (basal) + TZD DPP-4-i SGLT-i GLP-1-RA If combination therapy that includes basal insulin has failed to achieve A1C target after 3-6 months, proceed to a me complex insulin strategy, usually in combination with 1- non-insulin agents Combination injectable therapy Basal + Mealtime insulin GLP-1 RA Adapted from American Diabetes Association. Diabetes Care. 15;38(suppl 1):S41-S48. SGLT-i = sodium-glucose cotranspter inhibit; GLP-1 RA = glucagon-like peptide-1 recept agonists. Adapted from American Diabetes Association. Diabetes Care. 15;38(suppl 1):S41-S48.

3 When to Consider in Type Diabetes as an Option Basal insulin may be second agent after metfmin When combination al/injectable agents become inadequate High FPG PPG Unacceptable side effects of other agents Patient with advanced hepatic renal disease Special circumstances (e.g., steroids, infection, pregnancy) Patient with hyperglycemia in the hospital Severely uncontrolled diabetes* FPG = fasting plasma glucose; PPG = postprandial glucose. *Defined as fasting glucose >5 mg/dl, random glucose > 3 mg/dl, A1C >1%, ketonuria, symptomatic (polyuria, polydipsia, and weight loss) by ADA 9 Consensus Statement. After glucose controlled, al agents can be added and insulin withdrawn if preferred. Nathan DM, et al. Diabetes Care. 9; volume 3, Inzucchi SE, et al. Diabetes Care. 1;35(6): ADA Diabetes Care. 14:37(Suppl 1):S14-S8. Why Consider Early? The Benefits of The most predictable glucose reduction Most effective Effective targeting of fasting glucose Also enhances post-prandial insulin response as well Potential f preservation of beta cell function Evidence of diabetes prevention in ORIGIN Trial Evidence of improved insulin secretion when added to al agents Evidence of beta cell preservation/ prolonged remission when used early in TDM Good safety recd other than hypoglycemia No evidence of increased cancer heart disease with glargine in ORIGIN Trial ADA. Diabetes Care. 15;38 (suppl 1):S41-S48; Weng J, et al. Lancet. 8;371:1753-6; Pennartz C, et al. Diabetes Care. 11; 34: ORIGIN Trial Investigats, Gerstein HC, et al. N Engl J Med. 1;367(4): Early Increased Remission in Newly Diagnosed TDM Percentage of Patients in Remission CSII (N=137) MDI (N=14) OHA (N=11) Treatment was stopped after nmoglycemia was maintained f weeks 51% 45% Days in Remission Target glycemic control was achieved in less time (4 & 5.6 days) and in me CSII and MDI pts (97.1% & 95.%) than OHA pts (9.3 days and 83.5%) CSII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections; OHA = al hypoglycemic agents. Weng J, et al. Lancet. 8;371: % p=.1 Barriers to Initiation and Adherence Impediments to the Potential Benefit of Therapy in Type Diabetes Provider inertia Delay in progression of therapy to reach target Wse with insulin than other agents Behavial barriers to initiating insulin Patients Providers Objective limitations once initiated Non-adherence Hypoglycemia Weight gain Adapted from Funnell MM. Clinical Diabetes. 7;5(1): Derr RL, et al. Diabetes Spectrum. 7; (3): Karter AJ, et al. Diabetes Care. 1;33(4):

4 Clinical Inertia Leads to Delayed Initiation Patients (%) % SOLVE: Baseline A1C Distribution at Initiation A1C (%) Data from Khunti K, et al. SOLVE Study Group. Diabetes. 11;6(Suppl 1):A36. Key Barriers to Therapy Patient Barriers Patient reluctance Sense of failure Loss of independence Belief that insulin is ineffective Fear of injections Fear of hypoglycemia Weight gain Provider Barriers Clinical inertia Lack of insulin training, time, and/ suppt Fear of hypoglycemia Weight gain Adapted from Funnell MM. Clinical Diabetes. 7;5(1): Polonsky WH, et al. Curr Med Res Opin. 11;7(6): Overcoming the Barriers to Therapy Avoid using insulin as a threat, but a solution and discuss it as an option early Use insulin pens and regimens that offer maximum flexibility Give a limited trial of insulin Tell patient injection is less painful than finger stick and give an injection in the office Teach patient to recognize and treat hypoglycemia, and use basal analog insulins to minimize hypoglycemia risk Meet with dietitian befe initiation of insulin Overcoming the Barrier of Hypoglycemia with Less hypoglycemia with basal only approach Analog insulins reduce hypoglycemia; new ultralong-acting basal insulins greater reduction Appropriate dosing reduces hypoglycemia Choose the right target and right insulin f each individual e.g., Higher targets f elderly those with renal insufficiency Proper patient education is crucial Learning to have consistent meals, adjust f exercise, monit glucose, etc. Kruger D, et al. Diabetes Educ. 1;36(suppl 3):44S-7S. Funnell MM. Clinical Diabetes. 7;5(1): Derr RL, et al. Diabetes Spectrum. 7; (3): Males J and Schneider D. Am J Med. 14;17:S17-4. American Diabetes Association. Diabetes Care. 15;38 (suppl 1):S41-S48. The Evolution of Products Products First Regular First Human s Rapid Acting Analogs Inhaled Human s s 15 Protamine Zinc (PZI) NPH Lente s Prolonged Basal Analogs Ultralong- Acting Basal s Tibaldi JM. Am J Med. 14;17:S5-S38.

5 Current Available s Type Onset Peak, h Duration of Action, h Rapid-acting analogs lispro, aspart, glulisine human inhaled Sht-acting Regular human (U-1) Regular human (U-5) 15 min 1-15 min 3-6 min 3-6 min ~ Intermediate-acting Human NPH insulin 1-3 h Long-acting (basal) glargine detemir Ultralong-acting (basal) glargine U-3 degludec (U-1/ U-) -4 h 1-3 h Develops over 6 h 3-9 min No pronounced peak 6-8 Nearly peakless Nearly peakless >4 Walia M and Molitch M. JAMA. 14;311: Accessed April 5, 15. Nasrallah SN, et al. Clin Med Insights Endocrinol Diabetes. 1:5: Plasma Levels PK Profile of Currently Available s Inhaled insulin Aspart, Lispro, Glulisine Regular Intermediate (NPH insulin) Long ( detemir) Long ( glargine) Ultralong (U3 glargine) Ultralong degludec Time (hours) PK = pharmacokinetic; NPH = neutral protamine Hagedn. Adapted from Hirsch IB. NEJM. 5;35: Flood TM. J Fam Pract. 7;56(suppl 1):S1-S1. Becker RH, et al. Diabetes Care. 15;38: Accessed April 5, 15. Hompesch M, et al. Clin Ther. 14;36(4): Current Available Premixed s Hypoglycemia Reduced with Basal Analogs No Difference in A1C but Reduced Hypoglycemia Type Onset Peak, h 7% NPH/ 3% Regular.5-1 h 75% NPL / 5% Lispro 5-15 min 5% NPL / 5% Lispro 5-15 min 7% NPA / 3% Aspart 5-15 min 3-1 (dual) 1-4 (dual) 1-4 (dual) 1-4 (dual) Duration of Action, h % Degludec / 3% Aspart 5-15 min 1-4 >4 Hypoglycemia (events pt-yr -1 ) A1C (%) Glargine NPH Hypoglycemia (events pt-yr -1 ) A1C (%) NPH Detemir Walia M and Molitch M. JAMA. 14;311: PL Detail-Document, Comparison of s and Injectable Diabetes Meds. Pharmacist s Letter/Prescriber s Letter. March 15. Little S, et al. Diabetes Technol Ther. 11:13(suppl 1):S53-S64. Preferential Glucose Effect of s Rapid-acting/sht-acting insulin (meal-time insulins) Reduces predominantly postprandial glucose (PPG) Ideal f controlling postprandial hyperglycemia Intermediate-acting (NPH) Reduces mostly fasting plasma glucose (FPG) Not an ideal basal insulin due to intermediate duration of action Long-acting/ultralong-acting (basal insulins) Reduces essentially only FPG, little effect on PPG Not useful in patients with well control FPG Monnier L, et al. Diabetes Care. 3;6: Walia M and Molitch M. JAMA. 14;311: Comparative Trials in TDM Summary of Key Findings Any insulin will lower glucose and A1C All insulins are associated with some weight gain and some risk of hypoglycemia The larger the doses and the me aggressive the titration, the lower the A1C, but often with a greater possibility of hypoglycemia Long-acting insulin analogs reduce the incidence of nocturnal hypos Rapid-acting insulin analogs reduce postprandial glucose excursions (compared with cresponding human insulins [NPH, Regular]) and tend to reduce hypoglycemia but they generally do not result in clinically significantly lower A1C Premixed insulin preparations are effective in reducing A1C but are associated with me hypoglycemia and weight gain than using individual sht and long-acting insulin Inzucchi SE, et al. Diabetologia. 1;55:

6 Options In Type Diabetes Regimens and Selection Basal only 1 injection Added to al agents Basal plus injections 1 injection + 1 inhalation Adding one rapid acting analog sequentially starting with largest meal Basal bolus 4 injections 1 injection + 3 inhalations Rapid acting analog befe each meal Pre-mixed injections ADA Recommendations f Advancing # INJECTIONS COMPLEXITY Basal 1 LOW (usually with metfmin ± other noninsulin agent) If not controlled after FBG target is reached ( if dose >.5 U/kg/dy), treat PPG excursions with mealtime insulin. (Consider initial GLP-1-RA trial) Add 1 rapid insulin injection Change to MOD befe largest meal premixed insulin twice daily Add rapid insulin 3+ If not controlled, If not controlled, Injections befe meals consider basal-bolus consider basal-bolus HIGH ( basal-bolus ) Benefits Start with Basal Added to Oral Agents Effective in reaching A1c goals f most Convenient once daily and easy titration Proven safe (particularly with glargine) Origin Trial showed no increased risk of CVD cancer Low risk of hypoglycemia, particularly with analog basal insulins Therefe, addresses several barriers to insulin use Dosing Start 1 units per day.1-. units per kg per day Adjust by 1-15% -4 U once twice weekly to reach target F Hypoglycemia Assess cause and crect dose 4 U 1-% FLEXIBILITY: MORE FLEXIBLE ADA. Diabetes Care. 15;38(suppl 1):S41-S48. LESS FLEXIBLE ORIGIN Investigats. N Engl J Med. 1; 367: American Diabetes Association. Diabetes Care. 15; 38(suppl 1)S41-S48. Adding to OADs Improves Glycemic Control (Results of Large RCTs) Study Treatment Baseline A1C Resulting A1C STEPWISE (11) DET + -3 ASP* weeks 1 DET + -3 ASP T (7) 5 weeks ASP TID a b BIASP BID a b DET QD a DURABLE (11) LM 75/5 BID weeks 3 GLAR QD *Measured PPG; Estimated meal size. a A second type of insulin could be added beginning at 4 weeks if HbA1C 8.% on consecutive readings > 1%; b p<.1 vs DET QD; c p<.5 vs BIASP; d p<.5 vs BIASP. 1. Meneghini L, et al. Endocr Pract. 11;17: Holman RR, et al. N Engl J Med. 7;357: Buse JB, et al. Diabetes Care. 11;34:49-55 When Basal Alone Is Not Enough When A1C values are still not at target AND Basal insulin dose titrated to.4-.6 units/kg/day Fasting BG levels at approaching target Post-prandial BG values remain above target Options: Advance insulin therapy with additional prandial insulin Add GLP-1 agonist therapy if tolerated, not contraindicated and is affdable f the patient BG = blood glucose. American Diabetes Association. Diabetes Care. 15;38(suppl 1):S41-S48.

7 Regimens Basal Plus Advantages Basal plus Two injections only, bolus typically targeted to largest meal of day Adherence is greater f twice daily than me frequent dosing Eliminates the barrier of lunch dosing Nearly as effective in lowering A1c as full basal bolus therapy in many Disadvantages Basal plus May not cover all prandial needs May not reach goal in some patients Plank J, et al. Arch Intern Med. 5;165: Hvath K, et al. Cochrane Database Syst Rev. 7;():CD5163. Davies M, et al. Diabetes Care. 5;8:18-8. Yki-Ja rvinen H, et al. Diabetes Care. 7;3: Crasto W, et al. Postgrad Med J. 9;85: How to Intensify Using the Basal Plus Approach Choose a target meal to initiate prandial insulin Breakfast the largest meal of the day Start rapid acting insulin analog 4 U,.1 U/kg 1% of basal dose 1-15 minutes befe meal If A1c is <8.% consider decreasing basal by 1% Adjust Increase dose 1- units 1-15% once twice weekly until SMBG following that meal is at target -h PPG -> target < 18 mg/dl Next pre-prandial HS BG -> target < 13 mg/dl F Hypoglycemia Determine cause and crect; cresponding dose by -4 units 1-% Once titrated to goal, if A1C remains above target add nd prandial dose American Diabetes Association. Diabetes Care. 15;38(suppl 1):S41-S48. Regimens Basal Bolus Regimens Pre-Mixed Advantages Disadvantages Advantages Disadvantages Basal bolus Basal bolus Pre-mixed Pre-mixed Flexible regimen, basal plus bolus whenever eating meal, allows f crection insulin use Appropriate f patients willing to do multiple injections daily with frequent BG moniting and capable of managing the complexity Many injections, adds complexity to daily insulin regimen May impact adherence Can minimize daily injection number Appropriate f patients that cannot use basal bolus, wanting only injections, and who have regular lifestyles, eat similar amounts at similar times each day (similar total calies and similar content f carbohydrate/fat/protein) Fixed ratio, does not allow flexibility in dosing, increased risk of hypoglycemia Plank J, et al. Arch Intern Med. 5;165: Hvath K, et al. Cochrane Database Syst Rev. 7;():CD5163. Davies M, et al. Diabetes Care. 5;8:18-8. Yki-Ja rvinen H, et al. Diabetes Care. 7;3: Crasto W, et al. Postgrad Med J. 9;85: Plank J, et al. Arch Intern Med. 5;165: Hvath K, et al. Cochrane Database Syst Rev. 7;():CD5163. Davies M, et al. Diabetes Care. 5;8:18-8. Yki-Ja rvinen H, et al. Diabetes Care. 7;3: Crasto W, et al. Postgrad Med J. 9;85: Strategies f Selection Convenience (once daily vs. twice three times daily) Proven safety Analogs ORIGIN study showed low hypoglycemic risk, no adverse CV effects, and no cancer risk 1 NPH a little me hypoglycemic risk than analogs Adverse Effects (Hypoglycemia, weight gain) Cost NPH $ Analogs $$-$$$ Insurance coverage Analogs coverage varies and may require pri authization New Ultralong-Acting Basal : U3 Glargine and Degludec 1. ORIGIN Trial Investigats. N Engl J Med. 1;367(4): Riddle M, et al. Diabetes Care. 3; 6:

8 Characteristics of the Ideal Basal Pharmacodynamic profile should be flat (peakless) Low risk of hypoglycemia Duration of action of 4 hours Low variability within individual patients Arnolds S, et al. Int J Clin Pract. 1;64(1): New Glargine U-3 U-3 insulin glargine offers a smaller depot surface area leading to a reduce rate of absption Provides a flatter and prolonged pharmacokinetic and pharmacodynamic profiles and me consistency Half-life is ~3 hours Steady state in 4 days Duration of action 36 hours Associated with less hypoglycemia especially nocturnal hypoglycemia FDA approved February 15 Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 13]. Owens DR, et al. Diabetes Metab Res Rev. 14;3(): Steinstraesser A, et al. Diabetes Obes Metab. 14 Feb 6. [Epub ahead of print]. Accessed March 11, Accessed January. Pharmacokinetic and Pharmacodynamics of U3 Glargine vs U1 Glargine INS [µu/ml -1 ] GIR [mg/kg -1 /min -1 ] LLOQ Gla-1.4 U/kg -1 Gla-3.4 U/kg -1 N= Time (h) U3 glargine displays a me even and prolonged PK/PD profile compared with U1 glargine, offering blood glucose control beyond 4 hours LLOQ = lower limit of quantification; GIR = glucose infusion rate; PK = pharmacokinetic; PD = pharmacodynamic. Becker RH, et al. Diabetes Care. 14;pii:DC_146. U3 Glargine vs U1 Glargine in TDM: Meta-Analysis of Phase III Trials EDITION 1,, & 3 Baseline to Month 6 Glar U3 (N=147) Glar U1 (N=149) RR (95% CI) A1C (%), LS mean NS Weight (kg), LS mean P=.58 Any hypo in 4 hr* ( ) Any nocturnal hypo* ( ) Confirmed BG <54 mg/dl severe hypo* (.7-.9) Confirmed nocturnal BG <54 mg/dl severe hypo* ( ) *% people 1 event. LS = least squares; RR = relative risk; BG = blood glucose; CI = confidence interval. Ritzel RA, et al. Presentation 963, 5th EASD Annual Meeting, September 15-19, 14, Vienna, Austria. Flexible vs Fixed Dosing U3 Glargine: Sub-Studies of Phase III Trials Percentage of Injections (%) Month Treatment Period (main study) U3 once daily every 4 h Edition 1 Sub-Study N=19 4 ± <1 h 6 Months (randomization, sub-study) 4 ± 1-3 h 4 ± >3 h Edition Sub-Study N=89 Flexible Dosing Fixed Dosing 4 ± <1 h 6 Month Extension Period (main study) U3 once daily every 4 ± 3h sub-study U3 once daily every 4 h No difference in A1C between flexible- vs fixed-dosing No difference in severe nocturnal hypoglycemia within each sub-study Ritzel R, et al. Presentation 919-P 74th ADA Scientific Sessions June 13-17, 14, San Francisco, CA. Accessed August 15, ± 1-3 h 9 Months (end of sub-study) 4 ± >3 h U-3 Glargine Only available in pens 3 U/mL, 1.5 ml Max dose per shot is 8 units with 1 unit increments using current pen New pen in development will allow a max dose of 4 units U-3 glargine pen is white and green with the concentration lighted in ange to distinguish it from U-1 glargine purple and gray 1. Accessed March 6, Accessed March 6, 15.

9 U-3 Glargine Dosing -Naive Patients: Type 1 Diabetes Start with 1/3 to 1/ of the total daily insulin dose calculated by using.-.4 U/kg/day; give the remainder of the total daily insulin dose as a sht-acting insulin and divide between each daily meal Type Diabetes Start with. U/kg/day Type 1 Type Diabetes: Changing from once daily long-acting intermediate-acting insulin: Initial dose can be the same as the once daily long-acting dose; f patients controlled on U-1 insulin glargine, expect that a er daily dose of U-3 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 Accessed March 8, 15. New Degludec desb3 insulin acylated (16 carbon fatty acid chain) at LysB9 Has a prolonged pharmacokinetic and pharmacodynamic profiles, offering me consistency Duration of action >4 hours Half-life ~5 hours Detectable f at least 5 days Steady state in -3 days FDA approved September 15 Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 13]. Owens DR, et al. Diabetes Metab Res Rev. 14;3(): Pharmacodynamics of Degludec Glucose Lowering Effect on Day 6 (mg/kg/min) Time since Injection (hours) Josse RG and Woo V. Diabetes Obes Metab. 13;15(1): Degludec.8 U/kg Degludec.6 U/kg Degludec.4 U/kg Degludec vs U1 Glargine In Type DM Equal Efficacy, Less Nocturnal Hypoglycemia and Less Overall Documented Hypoglycemia with Degludec Nocturnal Confirmed 1.6 Hypoglycemia 1.4 p = Time (weeks) Garber AJ, et al. Lancet. 1;379(985): A1C (%) Cumulative Events per Participant Cumulative Events per Participant A1C (mmol/mol) Degludec once-daily (N=744) Glargine once-daily (N=48) Cumulative Hypoglycemia per Participant per 4 hours p = Time (weeks) 5 Only available in pens Degludec 1 U/mL (3. ml), max dose per injection 8 units U/mL (3. ml), max dose per injection 16 units Degludec U-1 pen is yellow and blue while the U- is green and blue with the concentration lighted in blue When Might Ultralong-Acting Be Considered? Patient wanting basal insulin with the lowest risk of hypoglycemia Patient experiencing nocturnal hypoglycemia with current basal insulins Patient on current basal insulins not lasting throughout the day Individualize dose labelinfo. Accessed October 6, 15.

10 Basal s in Development PEGylated Lispro* Emerging Basal s Polyethylene glycol polymer covalently attached to lispro Half-life -3 days Steady state in 7-1 days Duration of action >36 hours Phase II-III clinical trials Not likely to be reviewed by FDA until 16 *Not FDA approved. Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 13]. Owens DR, et al. Diabetes Metab Res Rev. 14;3(): Accessed March 11, 14. Sinha VP, et al. Diabetes Obesity Metab. 14;16(4): Summary Summary Continued TDM is marked by progressive beta cell dysfunction requiring progressive pharmacological therapy to maintain glucose control Available guidelines promote stepwise advancement of therapy that includes basal insulin as an option after metfmin Early use of insulin appears to retard progression of beta cell loss and promotes improvement in 1 st and nd phase insulin secretion Clinical inertia particularly impacts insulin initiation and exposes patients to unnecessary glucose exposure and diabetes complications regimens should be tailed to the patient s preferences and needs taking into consideration the pros and cons of each regimen The real and the perceived threat of hypoglycemia are maj barriers among the multiple barriers to appropriately advancing therapy New ultralong-acting basal insulin U-3 glargine and those in development appear to offer further advantages in me consistent 4 hour coverage and reduced hypoglycemia risk