Emerging Challenges in Primary Care: Safely Achieving Goals in Type 2 Diabetes (T2D): The Role of Concentrated and Long-Acting Insulins

Transcription

1 Emerging Challenges in Primary Care: 2018 Safely Achieving Goals in Type 2 Diabetes (T2D): The Role of Concentrated and Long-Acting Insulins 1

2 Faculty Rodolfo J. Galindo, MD Assistant Professor of Medicine Emory University School of Medicine Principal Investigator, Center for Diabetes and Metabolism Research Division of Endocrinology, Diabetes and Metabolism Emory University Hospital Midtown Medical Chair, Hospital Diabetes Taskforce Emory Healthcare System Atlanta, GA Javier Morales, MD, FACP, FACE Clinical Associate Professor of Medicine Donald and Barbara Zucker School of Medicine At Hofstra/Northwell University Vice President Advanced Internal Medicine Group, P.C. East Hills, NY 2

3 Faculty Leann Olansky, MD, FACP, FACE Department of Endocrinology, Diabetes and Metabolism Endocrinology & Metabolism Institute Cleveland Clinic Cleveland, OH Mark Stolar, MD Associate Professor of Clinical Medicine Feinberg School of Medicine Northwestern University Chicago, IL Jeff Unger, MD, FAAFP, FACE Assistant Clinical Professor of Family Medicine, UC Riverside School of Medicine Director, Unger Concierge Primary Care Medical Group Rancho Cucamonga, CA 3

4 Disclosures Rodolfo J. Galindo, MD has no relevant financial relationships to disclose. Javier Morales, MD, FACP, FACE serves on the speakers bureau and as a consultant for Lilly, Novo Nordisk, Janssen, and Abbott. Leann Olansky, MD, FACP, FACE has no relevant financial relationships to disclose. Mark Stolar, MD serves on the speakers bureau for AstraZeneca. Jeff Unger, MD, FAAFP, FACE serves as a consultant, researcher and advisory board member for Novo Nordisk, Janssen, and Abbott Diabetes. 4

5 Learning Objectives Demonstrate greater awareness of clinician and patient barriers to initiation and intensification of insulin therapy Recognize the prevalence and clinical impact of hypoglycemia in special populations at risk Discuss the pharmacology and clinical differences between existing and new long-acting and concentrated insulins Incorporate new basal and concentrated insulins into clinical practice while minimizing the risk of adverse events 5

6 PRE-TEST QUESTIONS 6 6

7 Pre-test ARS Question 1 Please rate your confidence in your ability to utilize concentrated insulin therapy in patients with Type 2 Diabetes: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 7

8 Pre-test ARS Question 2 How often do you consider using concentrated insulin therapy in patients with Type 2 Diabetes who are not achieving treatment targets with standard insulin regimens? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 8

9 Pre-test ARS Question 3 Approximately how many patients with Type 2 Diabetes that require insulin therapy, do you see on a weekly basis, in any clinical setting? 1. None > 25 9

10 Diabetes Facts 9.4% of US population has diabetes 90% of patients with diabetes are managed by primary care In 2014, 51% of Americans achieved glycemic targets (A1C), despite availability of 18 classes of glucose-lowering agents In 2010, 52% of patients achieved glycemic targets Statistics about diabetes. American Diabetes Association. Accessed 11/18/2017; Edelman et al. Type 2 diabetes in the real world: The elusive nature of glycemic control. Diabetes Care :

11 Advancing Therapies with Stages of T2D Beta-Cell Function (%, HOMA) Metformin and lifestyle 20 Type 2 Type 2 Diabetes Diabetes Phase 0 Phase I Phase II III Years From Diagnosis HOMA = homeostasis model assessment. Based on data from UKPDS 16. Diabetes. 1995;4(11): Combination therapy (orals and injectables) Insulin intensive or in combination Criteria for Advancing to the Next Stage? A1C Level Not at Target 11

12 Evidence for Benefit of Glycemic Control Every 1% Decrease in HbA1c Resulted in 21% 14% 12% 37% Decrease in risk of any diabetes-related endpoint Decrease in risk of myocardial infarction Decrease in risk of stroke Decrease in risk of microvascular complications *According to the United Kingdom Prospective Diabetes Study (UKPDS) 35 *The study population was 82% White, 10% Asian Indian, and 8% Afro-Caribbean. Stratton IM, et al. BMJ. 2000;321:

13 Distribution of A1C at time of insulin initiation Basal Insulin Initiation in Patients with Very Elevated A1C 8.9% 41% 9.0% Clinical inertia exists despite: The benefits of timely glycaemic control Guidelines encourage earlier use of insulin Patients (%) At insulin initiation in SOLVE: Average A1C was 8.9% 41% had A1C 9.0% Khunti et al. Diabetes Obes Metab 2012;14:

14 Basal Insulin Initiation in Patients with Very Elevated A1C Distribution of A1C at time of insulin initiation % 41% 9.0% Clinical inertia exists despite: The benefits of timely glycaemic control Guidelines encourage earlier use of insulin Patients (%) 22% 10.0% At insulin initiation in SOLVE: Average A1C was 8.9% % had A1C 9.0% % had A1C 10.0% Khunti et al. Diabetes Obes Metab 2012;14:

15 Consequences of Delayed Intervention A1C, % Patients with A1C 7% not receiving IT within 1 year Patients with A1C <7% who received IT before 1 year of diagnosis At 5.3 years, significantly increased risk of: - MI 67% (CI ) - Stroke 51% (CI 25 83) - HF 64% (CI 40 91) - Composite CVE 62% (CI 46 80) 6.5 Bad glycemic legacy Drive risk for complications Months CVE, cardiovascular endpoint; HF, heart failure; TI, intensification of treatment; MI, myocardial infarction Paul S et al. Cardiovasc Diabetol 2015;14:100 doi: /s x 15

16 Barriers to Insulin Initiation Patient Barriers Sense of failure Insulin causes complications Loss of independence Perception of insulin ineffectiveness Fear of injections Fear of hypoglycemia Weight gain Cost Clinician Barriers Clinical inertia Suboptimal insulin knowledge Fear of hypoglycemia Weight gain Adapted from Funnell MM. Clinical Diabetes. 2007;25(1): Peyrot M, et al. Primary Care Diabetes. 2010;4(Suppl 1):S11-S18. 16

17 ARS Question 4 Which of the following is the leading health care provider concern about starting insulin therapy in a patient with T2D? 1. Patient age 2. Weight gain with insulin 3. Pain from insulin injections 4. Poor patient adherence to insulin 5. Risk of hypoglycemia 17

18 Health Care Provider: Barriers to Timely Insulin Initiation When Do HCP s Consider Using Insulin Therapy? Multiple medication failure 75% A1C >8.5% 41% Worsening of microvascular complications Unintentional weight loss Repeated fasting glucose >200 mg/dl 15% 12% 9% HCP Concerns Poor adherence 92% Hypoglycemia 80% Pain from glucose monitoring Pain from insulin injections 54% 48% Patient is too old 47% No experience with insulin 27% Weight gain 26% Diabetes is too severe 13% Nakar S, et al. J Diabetes Complications. 2007;21:

19 Barriers to Insulin Adherence Perceived decreasing efficacy with increasing doses Multiple injection regimens Cost of newer insulins Frustration with glycemic variability/dysglycemia Concern of hypoglycemia with higher doses 19

20 ARS Question 5 Which of the following can increase risk of hypoglycemia and reduce adherence to insulin therapy? 1. Weight gain associated with insulin therapy 2. Switching between basal insulin formulations 3. Delayed initiation or intensification of insulin therapy 4. Insulin formulations with high coefficient of variability 20

21 Improving Patient Adherence to Insulin Therapy Discussions between patients and clinicians related to risk:benefit of insulin therapy is critical Choose strategies that reduce risk of hypoglycemia (hypoglycemia risk increases with duration of disease and age of patient) Consider concomitant use use of drugs that may mitigate weight gain, but explain that weight gain is based on caloric intake not insulin Joint decisions that are patient-centered are likely to improve clinical outcomes, especially in the patient requiring high dose/multiple injection insulin therapy Garcia-Perez et al. Diabetes Ther. 2013;4:

22 Dysglycemia Insulins with high coefficient of variability can increase risk of hypoglycemia Hypoglycemia is likely to reduce adherence to prescribed insulin regimens Dysglycemia increases risk of oxidative stress which promotes long-term diabetes related complications Dysglycemia is frustrating for patients and clinicians Unger. Endocrinology, Diabetes, Metabolism Journal (1)

23 Meet Anna: Coping with Glycemic variability 59 y/o female with significant insulin resistance Current DM meds: metformin 1000 mg bid, empaglaflozin 10 mg qd, U100 basal insulin (70 units at breakfast, 45 units at bed), 20 units lispro at breakfast and dinner. Often reduces her basal insulin dose due to hypoglycemia and omits premeal insulin if glucose <100 or if she isn t eating much Hypoglycemia (BG mg/dl) 2-3 times per week HS = at bedtime; ---- = did not test. Breakfast Lunch Dinner HS Monday Tuesday Wednesday Thursday

24 Glycemic Variability Increases risk of hypoglycemia Drives long and short term complication rates Decreases adherence Reduces likelihood of patients successfully achieving their glycemic goals Confuses patients and clinicians 24

25 Glucose Variability Can Manifest as Fluctuating and Unpredictable Glucose Levels Glucose mg/dl Time (hours) Im age adapted from Penckofer et al. Diab Tech Ther 2012;14:

26 Glucose Variability Can Manifest as Fluctuating and Unpredictable Glucose Levels 400 Unpredictability 360 Glucose mg/dl Time (hours) Im age adapted from Penckofer et al. Diab Tech Ther 2012;14:

27 Glucose Variability Can Be Measured Between Individuals or Within One Person GIR (mg/kg/min) GIR (mg/kg/min) Inter-individual variability GIR curves from 2 subjects with T1D given insulin detemir 0.4U/kg on 4 occasions Responses are predictable, but vary between subjects Insulin doses must be individualised Intra-individual variability GIR curves from 1 subject with T1D given NPH insulin 0.4U/kg on 4 occasions Responses are unpredictable Patient will have difficulty titrating to glucose targets GIR, glucose infusion rate GIR curves adapted from Heise et al. Diabetes 2004;53:

28 Glucose Variability is Not Apparent from A1C Mean BG ( HbA1c) Glucose mg/dl Hyperglycemia Hypoglycemia Patient A (A1C 7.8%) Patient B (A1C 7.8%) Time (hrs) Im age adapted from Penckofer et al. Diab Tech Ther 2012;14:

29 Glucose Variability is Not Apparent from A1C Mean BG ( HbA1c) Glucose mg/dl Hyperglycemia Hypoglycemia Patient A (A1C 7.8%) Patient B (A1C 7.8%) Time (hrs) Im age adapted from Penckofer et al. Diab Tech Ther 2012;14:

30 Glucose Variability is Not Apparent from A1C Mean BG ( HbA1c) Glucose mg/dl Hyperglycemia Hypoglycemia Patient A (A1C 7.8%) Patient B (A1C 7.8%) Time (hrs) Im age adapted from Penckofer et al. Diab Tech Ther 2012;14:

31 Glucose Variability and Risk of Hypoglycemia FPG (mmol/l) Average FPG Target zone FPG (mg/dl) Hypoglycemia zone Day Vora, Heise. Diabetes Obes Metab 2013;15:

32 Glucose Variability and Risk of Hypoglycemia FPG (mmol/l) Average FPG Target zone FPG (mg/dl) Hypoglycemia zone Day Vora, Heise. Diabetes Obes Metab 2013;15:

33 Glucose Variability and Risk of Hypoglycemia FPG (mmol/l) Average FPG Target zone FPG (mg/dl) Hypoglycemia zone Day Vora, Heise. Diabetes Obes Metab 2013;15:

34 Basal Insulin Coefficient of Variability* Insulin Coefficient of Variability (%) NPH 68 Glargine U Detemir 27 Glargine U Degludec 20 *% within-subject variability based on glucose infusion rates and AUC Patients receive 4 single subcutaneous doses of 0.4 U/kg under euglycemic glucose clamp conditions on 4 study days Unger J. Concentrated and Fixed-Dose Insulin Formulations can Improve Outcomes in Patients with Type 2 Diabetes. Endocrinology, Diabetes, Metabolism Journal (1) Heise et Al (2012).diabetes obesity metabolism. 2012; 14(9):

35 3 Ultralong-acting Basal Insulins Have Minimal Glycemic Variability U300 glargine 1,a GIR, mg/kg/min Average Period 1 Period 2 glucose infusion rate (GIR) Time, h U Blood Glucose Level, mmol/l U100 degludec 2 Individual patient profiles Mean profile Time Since Injection, h a 2-period crossover study in T1D; n = 50. b 3-period crossover study in T2D. 1. Becker RH, et al. Diabetes Obes Metab. 2015;17: Haahr H, Heise T. Clin Pharmacokinet. 2014;53: Porcellati F, et al. Diabetes Care. 2011;34:

36 GIR, mg/kg/min Ultralong-acting Basal Insulins Have Minimal Glycemic Variability Average U300 glargine 1,a Period 1 Period 2 glucose infusion rate (GIR) Time, h U GIR, μmol/kg/min Older Basals 3,b 0 NPH Detemir Glargine Blood Glucose Level, mmol/l U100 degludec 2 Individual patient profiles Mean profile Time Since Injection, h Time, h a 2-period crossover study in T1D; n = 50. b 3-period crossover study in T2D. 1. Becker RH, et al. Diabetes Obes Metab. 2015;17: Haahr H, Heise T. Clin Pharmacokinet. 2014;53: Porcellati F, et al. Diabetes Care. 2011;34:

37 Dysglycemia is Often Patient Driven Patients usually adjust basal insulin rather than short-acting insulin for hypoglycemia (it s the bigger dose) Basal adjustments are reactive not proactive (PM dose needs to be lowered for AM hypoglycemia) Short-acting gets omitted, not reduced Patients don t understand the insulin/glucose/meal relationship 37

38 When to Consider Insulin in T2D When a combination of non-insulin antihyperglycemic medications unable to achieve A1C target High fasting or postprandial glycemia/adding basal not always the answer Unacceptable/concerning side effects of other medications Hyperglycemia in a hospitalized patient Severely uncontrolled diabetes* ie A1C >8.5% A1C >8.0% on 3 OAD meds * Random glucose >300 mg/dl, A1C >10%, ketonuria, polyuria/ polydipsia, weight loss Nathan et al. Diabetes Care. 2009; 32,193; Inzucchi Diabetes Care. 2012;35(6):1364; ADA Diabetes Care. 2014:37(Suppl 1):S14. 38

39 Keys to Insulin Initiation in Primary Care Allow patients to self-titrate when appropriate Customize insulin care plan for each patient and provide written instructions on protocol Use insulin pens for accurate insulin adjustment and delivery Teach patients how to interpret self-monitoring blood glucose (SMBG) values Consider structured glucose testing rather than random glucose testing for all patients Prepare patients to recognize and treat hypoglycemia Unger J. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2011;4: Zisman A, et al. ADA Scientific Sessions. San Diego, CA P 39

40 Insulin Therapy in T2D: Basic Facts Basal insulin alone brings A1C to target in 60% of patients Initial starting dose can be u/kg/d, but few require <20 units Can be prescribed with metformin + 1 or 2 additional noninsulin agents If basal insulin + OADs do not achieve targets, consider GLP-1 RA, SGLT-2 inhibitor, or prandial insulin If insulin added, consider eliminating ineffective OAD ADA. Diabetes Care S1. S

41 Questions to Consider 41

42 ARS Question 6 A 55-year-old obese man with 10-year history of T2D presents with A1C 8.8%. His fasting blood glucose levels are mg/dl. Current medications include metformin 1000 mg bid, pioglitazone 15 mg qd, linagliptin 5 mg qd, and insulin glargine U units bid. He often forgets to take his evening dose of basal insulin, but says blood glucose readings don t seem much different on the following mornings. Which of the following might improve his glycemic control? 1. Increase dose of glargine U Add rapid-acting prandial insulin 3. Switch from glargine U100 to insulin degludec U Add concentrated U500 regular insulin before largest meal 42

43 Types of Insulin Ultra-Rapid-acting: Inhaled human insulin Rapid-acting analogs: Aspart, Glulisine, Lispro Duration of action U300 glargine 36 hours Degludec 42 hours Short-acting Regular human insulin (soluble) Intermediate-acting NPH human insulin Long-acting basal insulin analogs: Detemir, Glargine; U300 Glargine, Degludec Premixed analogues Time (hours) Premixed Analogs: Adapted from Hirsch I. N Engl J Med. 2005;352: Insulin lispro mix 75/25, 50/50 Biphasic insulin aspart 70/30 43

44 Time-Action Profiles of Basal Insulins Name Form Time of Action* (h) Comments Generic Brand Onset Peak Duration Intermediate-acting ( Basal ) NPH Humulin N; Novolin N; Relion N Human Increased risk of hypoglycemia when compared to analog basal insulin. Pregnancy category B Long-acting ( Basal ) Detemir U-100 Glargine U-100 Glargine U-300 Degludec U-100, U-200 Levemir Analog 1-2 Relatively peakless Lantus, Basaglar Analog 1-2 Relatively peakless Toujeo Analog 6 Relatively peakless Tresiba Analog 1-2 Relatively peakless 24* Expect to need a higher daily dose of 24* glargine U-300 than glargine U-100 Pregnancy category: 24 Glargine - C Degludec - C 42 Detemir - B *Dose dependent (except glargine U-300, degludec) 44

45 Difficulties with U100 Insulin in High-dose Requiring Patients Absorption and action of insulin altered à Increased glycemic variability Time to peak delayed Peak effect diminished Longer duration Dose limitation based on device > 100 units via syringe > units via insulin pen Lipoatrophy at infusion site Pump cartridges units Pump bolus limits units Risk of lipohypertrophy/lipoatrophy at injection sites Pain/discomfort/leakage à impacting adherence 45

46 17% of Patients Use >100 U/d Insulin 2011 US Roper Diabetes Market Study, GfK Custom Research LLC. 46

47 ARS Question 7 Which of the following is an advantage of glargine U300 compared to glargine U100? 1. U300 available in pens and vials 2. Safety of U300 in pregnancy well established 3. Lower risk of nocturnal hypoglycemia with U Significantly greater A1C reductions with U300 in insulin-naïve patients with T2D 47

48 Potential Advantages of Concentrated Insulin Use in Patients with Severe IR Improved insulin absorption from smaller volume injection leads to more predictable insulin action and improved glycemic control Fewer injections and lower volume injections enhance patient comfort and adherence Concentration of insulin can prolong insulin action, depending on the method of protraction (U500R insulin and U300 glargine) Protracted PD profile of U300 glargine results in less hypoglycemia than U100 glargine Cost savings when used in CSII (fewer cartridge and battery changes) Sindelka et al. Diabetologia. 1994;37:

49 Rationale for Using Concentrated Insulins Condition Rationale Product of Choice Nocturnal hypoglycemia Patient needs peak-less profile Less variability, safer titration Glargine U-300 Degludec U-100/200 Severe insulin resistance ( 200 U/day) Patient needs >60 U basal Flexible dosing needed Patient needs >20 U prandial PBG and FBG coverage needed High-potency insulin can allow low-volume SQ depot U500 5x as potent as rapid-acting insulin 30% of patients need >60 U basal insulin per injection Degludec can be administered any time of day Lower cost; lower volume reduces # pens used monthly Fixed-dose insulin/glp-1 RA can reduce daily insulin dose Insulin R U-500 Degludec U-200 Glargine U-300 Degludec U-100 Degludec U-200 Lispro U-200 Degludec+ liraglutide Glargine + lixisenatide 49 49

50 Concentrated Insulin Preparations Insulin Concentration Duration of Action (Hours) Degludec U100 U Glargine U Lispro U200 6 Insulin R U hours 50

51 Glargine U100 vs U300 Insulin Strength Limitation U100 Available in vials and pens More nocturnal hypoglycemia than U300 Studied in pregnancy, Category C Higher insulin dosing = weight gain and risk of hypoglycemia U300 16% lower risk of nocturnal hypoglycemia vs. U kg less weight gain Slightly greater A1C reduction with U300 in insulin-experienced patients with T2D using basal-bolus insulin 18% higher dose than U100 in trials More expensive Not studied in pregnancy Despite equivalent glycemic control, U300 in T1D produced no difference in hypoglycemia risk Riddle et al. Diabetes Care 2014 Oct; 37(10): 2755; Home et al. Diabetes Care. 2015; 38(12):2217; Pollex et al. Annal Pharmacotherapy. 2011;45(1):1. 51

52 Degludec: Strengths and Limitations Insulin Strengths Limitations Degludec Less glycemic variability Lower risk of hypoglycemia vs. glargine U100/U200 doses bioequivalent U200 dosed up to 160 U/injection U100 dosed up to 100 U/injection 30% T2D patients need >60 U/day basal insulin Long duration of action allows for flexible dosing regimens May be beneficial for shift workers and travelers U200 has dose increments of 2 U per click on pen Unavailable in vials Glargine U300 Lower variability than glargine U100 14% less variability at 0.4 U/kg Less weight gain than glargine Can dose up to 80 U per injection 52

53 Strengths and Limitations: Rapid-acting Insulins Insulin Strength Limitations Lispro U200 Costs similar to Lispro U100 Available in pens only, no vials Insulin R U500 Available in vials and pens Variable PK Used for patients requiring >200 units of insulin/d Weight gain Off label can be used in insulin pumps for patients with severe insulin resistance Expensive Should inject or bolus 45 minutes prior to eating due to 60 minute onset of action Insulin pumping and use of continuous glucose sensors in primary care. In Unger Jeff. Diabetes Management in Primary Care- Second Edition. Lippincott, Williams and Wilkins Philadelphia, PA

54 Concentrated Insulin U200/U300 Reduction of volume by 2/3 Reduction of depot surface by 1/2 Same amount of units U100 U300 U100 U300 Ø Contains the same molecule as U200/U300 but in a lower volume ØThe decrease in volume decreases depot surface area, which can be predicted to slow down the rate of insulin release Heise T, et al. Diabetes Obes Metab. 2012;14(10):

55 Our Patient Would Benefit From Concentrated, Ultra Long-lasting Basal 55 y/o male T2D for 10 years, A1C >7% Current DM meds: metformin 1000 mg bid; pioglitazone 15 mg qd; linagliptin 5mg qd; glargine U units bid Most recent visit: BMI 33.7 kg/m 2 A1C 8.8% SMBG once daily (AM) mg/dl Often forgets to take his pm dose of insulin, but BG readings don t seem much different to him on the following mornings. 55

56 Our Patient Would Benefit From Concentrated, Ultra Long-lasting Basal T2D for 10 years, A1C >7% Current DM meds: metformin 1000 mg bid; pioglitazone 15 mg qd; linagliptin 5mg qd; glargine U units bid Most recent visit: BMI 33.7 kg/m 2 A1C 8.8% SMBG once daily (AM) mg/dl Often forgets to take his pm dose of insulin, but BG readings don t seem much different to him on the following mornings. 56

57 Our Patient Would Benefit From Concentrated, Ultra Long-lasting Basal Current DM meds: metformin 1000 mg bid; pioglitazone 15 mg qd; linagliptin 5mg qd; glargine U units bid Often forgets to take his pm dose of insulin, but BG readings don t seem much different to him on the following mornings. 57

58 Our Patient Would Benefit From Concentrated, Ultra Long-lasting Basal Current DM meds: metformin 1000 mg bid; pioglitazone 15 mg qd; linagliptin 5mg qd; glargine U units bid Replace with degludec U200, 140 units once daily Often forgets to take his pm dose of insulin, but BG readings don t seem much different to him on the following mornings. 58

59 Meet Michael: Long-acting Basal Not Acting Long Enough 59 y/o male Current DM meds: metformin 1000 mg bid, empagliflozin 10 mg qd, U100 basal insulin, 70 units at bedtime Prior to initiating insulin, A1C was 9.0%, currently 7.9% despite increasing doses of insulin Hypoglycemia (BG mg/dl) once weekly BG elevated after dinner, even if he has no carbohydrate in that meal. HS = at bedtime; ---- = did not test Breakfast Lunch Dinner HS Monday Tuesday Wednesday Thursday

60 Ultralong-Acting Insulins: Mechanisms of Action Insulin degludec injected Phenol from the vehicle diffuses quickly, and insulin degludec links up via single side-chain contacts U300 Insulin Glargine 1,2 Same amino acid substitutions as glargine U100 Forms microprecipitates after injection Higher concentration (x3) = smaller injection volume (1/3) Unexpected differences in exposure and activity for U300 vs U100 glargine Long multihexamer chains assemble U100 and U200 Insulin Degludec 3,4 Dihexamers form soluble multihexamers after injection Multihexamers (> 5000 kda) disassemble slowly Monomers released rapidly after hexamers disassemble Exposure and activity similar for U100 vs U200 degludec Drugs@FDA Jonassen 60 et al. Pharm Res. 2012;29:2104; 4. Haahr et al. Clin Pharmacokinet. 2014;53:787.

61 Pharmacodynamics of U300 Glargine vs U100 Glargine GIR (mg/kg -1 min -1 )* SC Injection U U/kg -1 U U/kg U U/kg -1 U U/kg Time (hours) U300 glargine has a flatter more prolonged effect The time it takes for 50% of the effect of a single injection U100 = 12.1 hours; U300 = 16.7 hours *GIR = glucose infusion rate Tillner J, et al. Poster 920P 73 rd ADA Scientific Sessions June 21-25, 2013, Chicago, IL. Accessed March 21,

62 U300 vs U100 Glargine: Safety and Efficacy A1C (%) Mean SE Baseline U100 U300 Week 12 LS mean difference (95% CI) between groups: 000 (-0.08 to 0.07)% 6 Mon Nocturnal Hypo-Events* per Participant-Year U100 RR 31% p= U300 Weight Change (Kg) Mean SE Base line W2 U100 U300 W4 W8 W12 M4 M6 p=0.039 LOV Confirmed ( 70 mg/dl) or severe hypoglycemia from 00:00 05:59 h. SE = standard deviation; LOV = last on-treatment value. Ritzel R, et al. Presentation 90-LB 74 th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA. Accessed August 15,

63 Insulin Degludec (IDeg) Ultra-long basal insulin with duration of action 42 hours and half-life ~24-27 hours Can be injected at any time of day Reaches steady-state in 3 days Available in U100 pen and concentrated U200 pen Heise T, et al. Diabetes Obes Metab. 2012;14(10):

64 A1C (%) Cumulative Events per Participant Degludec vs U100 Glargine in T2D Equal efficacy, less nocturnal hypoglycemia, and less overall documented hypoglycemia with degludec Nocturnal Confirmed Hypoglycemia p = Time (weeks) Garber AJ, et al. Lancet. 2012;379(9825): Cumulative Events A1C (mmol/mol) per Participant Insulin Degludec once-daily (N = 744) Insulin Glargine U100 once-daily (N = 248) Cumulative Hypoglycemia per Participant per 24 h p = Time (weeks) 64

65 Glycemic Variability: Glargine U100 vs. Degludec SWITCH pts with T2D randomized to glargine U100 or degludec Two 32-week trial periods; crossover design Compared with glargine, degludec resulted in: 30% confirmed hypoglycemia 42% nocturnal hypoglycemia 51% in severe hypoglycemia Glargine and degludec patients achieved similar A1C reductions and had similar insulin dose requirements Wysham et al. Presented at: 76th Scientific Sessions of the American Diabetes Association; June 10-14, 2016; New Orleans, LA. 65

66 Dosing Glargine U300 and Degludec Initiate therapy with 10 units Degludec given any time of day Glargine U300 given same time each day Increase by 4 units every 4 days until targeted FBG is achieved Note: These are concentrated insulins 20 units of glargine U300 = 20 units of glargine U100 insulin, but with 1/3 the volume injected 20 units of degludec U200 = 20 units of degludec U100, but with 1/2 the volume injected Degludec available in U100 or U200 pen formulations 66

67 Suggested Titration Schedule for Glargine U300 and Degludec Average glucose value over 3 days (mg/dl) U300 Glargine (Units) Degludec (units) Titration driven by average SBGM for 3 days prior to dose adjustment consideration 67

68 Michael Would Benefit from an Ultralong-acting Basal Michael 59 year-old male Current DM mgmt: metformin 1000 mg BID, empagliflozin 10 mg and U100 basal insulin, 70 units at bedtime. Before insulin, A1C was 9.0%, now 7.9% Hypoglycemia (BG mg/dl) once weekly BG elevated after dinner even if he has no carbohydrate in that meal. HS = at bedtime; ---- = did not test. Breakfast Lunch Dinner HS Monday Tuesday Wednesday Thursday

69 Michael Would Benefit from an Ultralong-acting Basal Current DM mgmt: metformin 1000 mg BID, empagliflozin 10 mg and U100 basal insulin, 70 units at bedtime. BG elevated after dinner even if he has no carbohydrate in that meal. HS = at bedtime; ---- = did not test. Breakfast Lunch Dinner HS Monday Tuesday Wednesday Thursday

70 Michael Would Benefit from an Ultralong-acting Basal Current DM mgmt: metformin 1000 mg BID, empagliflozin 10 mg and U100 basal insulin, 70 units at bedtime. à replace with U200 degludec or U300 glargine 70 units once daily (1:1 unit conversion) BG elevated after dinner even if he has no carbohydrate in that meal. HS = at bedtime; ---- = did not test. Breakfast Lunch Dinner HS Monday Tuesday Wednesday Thursday

71 Meet Lavergne: On High-dose Prandial Insulin Lavergne: 45 y/o African American woman T2D for 7 years Struggled with morbid obesity her entire life but not willing to consider bariatric surgery Current DM meds: U100 glargine, 100 units/day; aspart units before meals; metformin ER 1000 mg qam Most recent A1C 9.0% Endocrinologist recommended U500 pens for intensifying her regimen, but she is confused about what that means and is afraid she will take too much insulin 71 71

72 Dosing Guidelines for U500 Use either pre-filled insulin pens or must prescribe U500 syringes when using vials to reduce dosing errors No calculation required, 1:1 unit conversion Volume is 1/5 of the equivalent dose of U100 Recommend doses in multiples of 5 to simplify patient education Administer minutes before meals (slow onset of action) Dose adjustments when converting from U100 10% 20% reduction if A1C <8% 10% 20% increase if A1C >10% Segal et al. Am J Health-Syst Pharm. 2010;67: Unger J. Diabetes Management in Diabetes Care. Lippincott

73 Concentrated Insulins: Take Home Lessons U100 basal insulins exhibit variability in PD and duration of action not true basal Glycemic variability and dysglycemia due to inconsistent insulin action are barriers to patient adherence and glycemic control U200, U300 insulin are equal to the same dose as U100 insulin, but in less volume (1/2, 1/3) U200 and U300 basal insulin have a duration of action >24 hours and dosed once daily, with more consistent pharmacokinetic profile Concentrated insulin may be cost-effective means of delivering higher doses of insulin with fewer daily injections and are useful tool in the management of the insulinresistant patient 73

74 POST-TEST QUESTIONS 74

75 Post-test ARS Question 1 After completing this activity, please rate your confidence in your ability to utilize concentrated insulin therapy in patients with Type 2 Diabetes: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 75

76 Post-test ARS Question 2 After completing this activity, how often do you intend to consider using concentrated insulin therapy in patients with Type 2 Diabetes who are not achieving treatment targets with standard insulin regimens? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 76

77 Post-test ARS Question 3 Which of the following is the leading health care provider concern about starting insulin therapy in a patient with Type 2 Diabetes? 1. Patient age 2. Weight gain with insulin 3. Pain from insulin injections 4. Poor patient adherence to insulin 5. Risk of hypoglycemia 77

78 Post-test ARS Question 4 Which of the following can increase risk of hypoglycemia and reduce adherence to insulin therapy? 1. Weight gain associated with insulin therapy 2. Switching between basal insulin formulations 3. Delayed initiation or intensification of insulin therapy 4. Insulin formulations with high coefficient of variability 78

79 Post-test ARS Question 5 A 55-year-old obese man with 10-year history of T2D presents with A1C 8.8%. His fasting blood glucose levels are mg/dl. Current medications include metformin 1000 mg bid, pioglitazone 15 mg qd, linagliptin 5 mg qd, and insulin glargine U units bid. He often forgets to take his evening dose of basal insulin, but says blood glucose readings don t seem much different on the following mornings. Which of the following might improve his glycemic control? 1. Increase dose of glargine U Add rapid-acting prandial insulin 3. Switch from glargine U100 to insulin degludec U Add concentrated U500 regular insulin before largest meal 79

80 Post-test ARS Question 6 Which of the following is an advantage of glargine U300 compared to glargine U100? 1. U300 available in pens and vials 2. Safety of U300 in pregnancy well established 3. Lower risk of nocturnal hypoglycemia with U Significantly greater A1C reductions with U300 in insulin-naïve patients with T2D 80

81 Questions? 81