6/5/18. Emerging Challenges in Primary Care: Safely Achieving Goals in Type 2 Diabetes (T2D): The Role of Concentrated and Long- Acting Insulins

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1 Emerging Challenges in Primary Care: 218 Safely Achieving Goals in Type 2 Diabetes (T2D): The Role of Concentrated and Long- Acting Insulins 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 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 1

2 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 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 PRE-TEST QUESTIONS 6 2

3 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 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 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 >

4 Diabetes Facts 9.4% of US population has diabetes 9% of patients with diabetes are managed by primary care In 214, 51% of Americans achieved glycemic targets (A1C), despite availability of 18 classes of glucose-lowering agents In 21, 52% of patients achieved glycemic targets Statistics about diabetes. American Diabetes Association. Accessed 11/18/217; Edelman et al. Type 2 diabetes in the real world: The elusive nature of glycemic control. Diabetes Care : Advancing Therapies with Stages of T2D Beta-Cell Function (%, HOMA) Metformin and lifestyle 2 Type 2 Type 2 Diabetes Diabetes Phase Phase I Phase II III Years From Diagnosis Criteria for Advancing to the Next Stage? A1C Level Not at Target HOMA = homeostasis model assessment. Based on data from UKPDS 16. Diabetes. 1995;4(11): Combination therapy (orals and injectables) Insulin intensive or in combination 11 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, 1% Asian Indian, and 8% Afro-Caribbean. Stratton IM, et al. BMJ. 2;321:

5 Distribution of A1C at time of insulin initiation Basal Insulin Initiation in Patients with Very Elevated A1C Patients (%) 8.9% 41% 9.% 22% 1.% Clinical inertia exists despite: The benefits of timely glycaemic control Guidelines encourage earlier use of insulin At insulin initiation in SOLVE: Average A1C was 8.9% % had A1C 9.% 22% had A1C 1.% Khunti et al. Diabetes Obes Metab 212;14: A1C, % Consequences of Delayed Intervention 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 39 11) - Stroke 51% (CI 25 83) - HF 64% (CI 4 91) - Composite CVE 62% (CI 46 8) 6.5 Bad glycemic legacy Drive risk for complications Months 54 6 CVE, cardiovascular endpoint; HF, heart failure; TI, intensification of treatment; MI, myocardial infarction Paul S et al. Cardiovasc Diabetol 215;14:1 doi:1.1186/s x 14 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. 27;25(1): Peyrot M, et al. Primary Care Diabetes. 21;4(Suppl 1):S11-S

6 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 16 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 >2 mg/dl 15% 12% 9% Nakar S, et al. J Diabetes Complications. 27;21: HCP Concerns Poor adherence 92% Hypoglycemia 8% 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% 17 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 18 6

7 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 19 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. 213;4: 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)

8 Meet Anna: Coping with Glycemic variability ² 59 y/o female with significant insulin resistance ² Current DM meds: metformin 1 mg bid, empaglaflozin 1 mg qd, U1 basal insulin (7 units at breakfast, 45 units at bed), 2 units lispro at breakfast and dinner. ² Often reduces her basal insulin dose due to hypoglycemia and omits premeal insulin if glucose <1 or if she isn t eating much ² Hypoglycemia (BG mg/dl) 2-3 times per week HS = at bedtime; ---- = did not test. Breakfast Lunch Dinner HS Monday Tuesday Wednesday Thursday 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 23 Glucose Variability Can Manifest as Fluctuating and Unpredictable Glucose Levels 4 Unpredictability 36 Glucose mg/dl Time (hours) 24 Image adapted from Penckofer et al. Diab Tech Ther 212;14:33 1 8

9 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.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.4u/kg on 4 occasions Responses are unpredictable Patient will have difficulty titrating to glucose targets GIR, glucose infusion rate 25 GIR curves adapted from Heise et al. Diabetes 24;53: Glucose Variability is Not Apparent from A1C Glucose mg/dl Hyperglycemia Hypoglycemia Mean BG ( HbA 1c ) Patient A (A1C 7.8%) Patient B (A1C 7.8%) Time (hrs) 26 Image adapted from Penckofer et al. Diab Tech Ther 212;14:33 1 Glucose Variability and Risk of Hypoglycemia FPG (mmol/l) Average FPG Target zone Hypoglycemia zone FPG (mg/dl) Vora, Heise. Diabetes Obes Metab 213;15:71 12 Day 27 9

10 Basal Insulin Coefficient of Variability* Insulin Coefficient of Variability (%) NPH 68 Glargine U1 48 Detemir 27 Glargine U Degludec 2 *% within-subject variability based on glucose infusion rates and AUC Patients receive 4 single subcutaneous doses of.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 (212).diabetes obesity metabolism. 212; 14(9): GIR, mg/kg/min 3 2 U3 glargine 1,a Period 1 Period 2 1 Average glucose infusion rate (GIR) Time, h U Blood Glucose Level, mmol/l Ultralong-acting Basal Insulins Have Minimal Glycemic Variability U1 degludec 2 GIR, μmol/kg/min Individual patient profiles Mean profile Time Since Injection, h Older Basals 3,b Time, h NPH Detemir Glargine a 2-period crossover study in T1D; n = 5. b 3-period crossover study in T2D. 1. Becker RH, et al. Diabetes Obes Metab. 215;17: Haahr H, Heise T. Clin Pharmacokinet. 214;53: Porcellati F, et al. Diabetes Care. 211;34: 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 3 1

11 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/concering side effects of other medications Hyperglycemia in a hospitalized patient Severely uncontrolled diabetes* ie A1C >8.5% A1C >8.% on 3 OAD meds Nathan et al. Diabetes Care. 29; 32,193; Inzucchi Diabetes Care. 212;35(6):1364; ADA Diabetes Care. 214:37(Suppl 1):S14. * Random glucose >3 mg/dl, A1C >1%, ketonuria, polyuria/ polydipsia, weight loss 31 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. 211;4: Zisman A, et al. ADA Scientific Sessions. San Diego, CA P 32 Insulin Therapy in T2D: Basic Facts Basal insulin alone brings A1C to target in 6% of patients Initial starting dose can be.1-.2 u/kg/d, but few require <2 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

12 Questions to Consider 34 ARS Question 6 A 55-year-old obese man with 1-year history of T2D presents with A1C 8.8%. His fasting blood glucose levels are mg/dl. Current medications include metformin 1 mg bid, pioglitazone 15 mg qd, linagliptin 5 mg qd, and insulin glargine U1 7 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 U1 2. Add rapid-acting prandial insulin 3. Switch from glargine U1 to insulin degludec U2 4. Add concentrated U5 regular insulin before largest meal 35 Ultra-Rapid-acting: Inhaled human insulin Rapid-acting analogs: Aspart, Glulisine, Lispro Types of Insulin Short-acting Regular human insulin (soluble) Duration of action U3 glargine 36 hours Degludec 42 hours Intermediate-acting NPH human insulin Long-acting basal insulin analogs: Detemir, Glargine; U3 Glargine, Degludec Premixed analogues Time (hours) Premixed Analogs: Insulin lispro mix 75/25, 5/5 Biphasic insulin aspart 7/3 Adapted from Hirsch I. N Engl J Med. 25;352:

13 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 Long-acting ( Basal ) Detemir U-1 Glargine U-1 Glargine U-3 Degludec U-1, U-2 Human Increased risk of hypoglycemia when compared to analog basal insulin. Pregnancy category B 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-3 than glargine U-1 Pregnancy category: 24 Glargine - C Degludec - C 42 Detemir - B *Dose dependent (except glargine U-3, degludec) 37 Difficulties with U1 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 > 1 units via syringe > 6 8 units via insulin pen Pump cartridges 18 3 units Pump bolus limits 25 3 units Risk of lipohypertrophy/lipoatrophy at injection sites Pain/discomfort/leakage à impacting adherence Lipoatrophy at infusion site 38 17% of Patients Use >1 U/d Insulin 211 US Roper Diabetes Market Study, GfK Custom Research LLC

14 ARS Question 7 Which of the following is an advantage of glargine U3 compared to glargine U1? 1. U3 available in pens and vials 2. Safety of U3 in pregnancy well established 3. Lower risk of nocturnal hypoglycemia with U3 4. Significantly greater A1C reductions with U3 in insulin-naïve patients with T2D 4 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 (U5R insulin and U3 glargine) Protracted PD profile of U3 glargine results in less hypoglycemia than U1 glargine Cost savings when used in CSII (fewer cartridge and battery changes) Sindelka et al. Diabetologia. 1994;37: Rationale for Using Concentrated Insulins Condition Rationale Product of Choice Nocturnal hypoglycemia Severe insulin resistance ( 2 U/day) Patient needs >6 U basal Patient needs peak-less profile Less variability, safer titration High-potency insulin can allow low-volume SQ depot U5 5x as potent as rapid-acting insulin 3% of patients need >6 U basal insulin per injection Glargine U-3 Degludec U-1/2 Humulin R U5 Degludec U-2 Glargine U-3 Flexible dosing needed Degludec can be administered any time of day Degludec U-1 Degludec U-2 Patient needs >2 U prandial Lower cost; lower volume reduces # pens used monthly Lispro U-2 PBG and FBG coverage needed Fixed-dose insulin/glp-1 RA can reduce daily insulin dose Degludec+ liraglutide Glargine + lixisenatide 42 14

15 Concentrated Insulin Preparations Insulin Concentration Duration of Action (Hours) Degludec U1 U2 42 Glargine U3 36 Humalog U2 6 Humulin R U5 4-6 hours 43 Glargine U1 vs U3 Insulin Strength Limitation U1 Available in vials and pens More nocturnal hypoglycemia than U3 Studied in pregnancy, Category C Higher insulin dosing = weight gain and risk of hypoglycemia U3 16% lower risk of nocturnal hypoglycemia vs. U1.5 kg less weight gain Slightly greater A1C reduction with U3 in insulin-experienced patients with T2D using basal-bolus insulin 18% higher dose than U1 in trials More expensive Not studied in pregnancy Despite equivalent glycemic control, U3 in T1D produced no difference in hypoglycemia risk 44 Riddle et al. Diabetes Care 214 Oct; 37(1): 2755; Home et al. Diabetes Care. 215; 38(12):2217; Pollex et al. Annal Pharmacotherapy. 211;45(1):1. Degludec: Strengths and Limitations Insulin Strengths Limitations Degludec Less glycemic variability Lower risk of hypoglycemia vs. glargine U1/U2 doses bioequivalent U2 dosed up to 16 U/injection U1 dosed up to 1 U/injection 3% T2D patients need >6 U/day U2 has dose increments of 2 U per click on pen Unavailable in vials basal insulin Long duration of action allows for flexible dosing regimens May be beneficial for shift workers and travelers Glargine U3 Lower variability than glargine U1 14% less variability at.4 U/kg Less weight gain than glargine Can dose up to 8 U per injection 45 15

16 Strengths and Limitations: Rapid-acting Insulins Insulin Strength Limitations Humalog U2 Humulin R U5 Costs similar to Humalog U1 Available in vials and pens Variable PK Used for patients requiring >2 units of insulin/d Weight gain Off label can be used in insulin pumps for patients with severe insulin resistance Available in pens only, no vials Expensive Should inject or bolus 45 minutes prior to eating due to 6 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 Concentrated Insulin U2/U3 Reduction of volume by 2/3 Reduction of depot surface by 1/2 Same amount of units U1 U3 U1 U3 Ø Contains the same molecule as U2/U3 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 47 Heise T, et al. Diabetes Obes Metab. 212;14(1): Our Patient Would Benefit From Concentrated, Ultra Long-lasting Basal 55 y/o male T2D for 1 years, A1C >7% Current DM meds: metformin 1 mg bid; pioglitazone 15 mg qd; linagliptin 5mg qd; glargine U1 7 units bid Most recent visit: BMI 33.7 kg/m 2 A1C 8.8% Replace with degludec U2, 14 units once daily 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

17 Meet Michael: Long-acting Basal Not Acting Long Enough ² 59 y/o male ² Current DM meds: metformin 1 mg bid, empagliflozin 1 mg qd, U1 basal insulin, 7 units at bedtime ² Prior to initiating insulin, A1C was 9.%, currently 7.9% despite increasing doses of insulin ² Hypoglycemia (BG mg/dl) once weekly ² 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 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 U3 Insulin Glargine 1,2 Same amino acid substitutions as glargine U1 Forms microprecipitates after injection Higher concentration (x3) = smaller injection volume (1/3) Unexpected differences in exposure and activity for U3 vs U1 glargine Long multihexamer chains assemble U1 and U2 Insulin Degludec 3,4 Dihexamers form soluble multihexamers after injection Multihexamers (> 5 kda) disassemble slowly Monomers released rapidly after hexamers disassemble Exposure and activity similar for U1 vs U2 degludec Drugs@FDA Jonassen et al. Pharm Res. 212;29:214; 4. Haahr et al. Clin Pharmacokinet. 214;53:787. GIR (mg/kg -1 min -1 )* Pharmacodynamics of U3 Glargine vs U1 Glargine SC Injection U1.4 U/kg -1 U3.4 U/kg Time (hours) U3.6 U/kg -1 U3.9 U/kg -1 U3 glargine has a flatter more prolonged effect The time it takes for 5% of the effect of a single injection U1 = 12.1 hours; U3 = 16.7 hours *GIR = glucose infusion rate Tillner J, et al. Poster 92P 73 rd ADA Scientific Sessions June 21-25, 213, Chicago, IL. Accessed March 21,

18 U3 vs U1 Glargine: Safety and Efficacy A1C (%) Mean SE Baseline U1 U3 Week 12 LS mean difference (95% CI) between groups: (-.8 to.7)% 6 Mon Nocturnal Hypo-Events* per Participant-Year U1 RR 31% p= U3 Weight Change (Kg) Mean SE 1.5 U1 U Base W2 W4 line W8 W12 M4 M6 p=.39 LOV Confirmed ( 7 mg/dl) or severe hypoglycemia from : 5:59 h. SE = standard deviation; LOV = last on-treatment value. Ritzel R, et al. Presentation 9-LB 74 th ADA Scientific Sessions June 13-17, 214, San Francisco, CA. Accessed August 15, 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 U1 pen and concentrated U2 pen Heise T, et al. Diabetes Obes Metab. 212;14(1): A1C (%) Cumulative Events per Participant Degludec vs U1 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. 212;379(9825): A1C (mmol/mol) Cumulative Events per Participant Insulin Degludec once-daily (N = 744) Insulin Glargine U1 once-daily (N = 248) Cumulative Hypoglycemia per Participant per 24 h p = Time (weeks) 52 18

19 Glycemic Variability: Glargine U1 vs. Degludec SWITCH pts with T2D randomized to glargine U1 or degludec Two 32-week trial periods; crossover design Compared with glargine, degludec resulted in: 3% 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 1-14, 216; New Orleans, LA. 55 Dosing Glargine U3 and Degludec Initiate therapy with 1 units Degludec given any time of day Glargine U3 given same time each day Increase by 4 units every 4 days until targeted FBG is achieved Note: These are concentrated insulins 2 units of glargine U3 = 2 units of glargine U1 insulin, but with 1/3 the volume injected 2 units of degludec U2 = 2 units of degludec U1, but with 1/2 the volume injected Degludec available in U1 or U2 pen formulations 56 Suggested Titration Schedule for Glargine U3 and Degludec Average glucose value over 3 days (mg/dl) U3 Glargine (Units) Degludec (units) Titration driven by average SBGM for 3 days prior to dose adjustment consideration 57 19

20 Michael Would Benefit from an Ultralongacting Basal ² Michael 59 year-old male ² Current DM mgmt: metformin 1 mg BID, empagliflozin 1 mg and U1 basal insulin, 7 units at bedtime. à replace with U2 degludec ² Before insulin, A1C was 9.%, now 7.9% or U3 glargine 7 units once daily (1:1 unit conversion) ² Hypoglycemia (BG mg/dl) once weekly ² 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 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: U1 glargine, 1 units/day; aspart units before meals; metformin ER 1 mg qam Most recent A1C 9.% Endocrinologist recommended U5 pens for intensifying her regimen, but she is confused about what that means and is afraid she will take too much insulin Dosing Guidelines for U5 Use either pre-filled insulin pens or must prescribe U5 syringes when using vials to reduce dosing errors No calculation required, 1:1 unit conversion Volume is 1/5 of the equivalent dose of U1 Recommend doses in multiples of 5 to simplify patient education Administer 3 45 minutes before meals (slow onset of action) Dose adjustments when converting from U1 1% 2% reduction if A1C <8% 1% 2% increase if A1C >1% Segal et al. Am J Health-Syst Pharm. 21;67: Unger J. Diabetes Management in Diabetes Care. Lippincott

21 Concentrated Insulins: Take Home Lessons U1 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 U2, U3 insulin are equal to the same dose as U1 insulin, but in less volume (1/2, 1/3) U2 and U3 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 61 patient POST-TEST QUESTIONS 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 63 21

22 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 64 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 65 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 66 22

23 Post-test ARS Question 5 A 55-year-old obese man with 1-year history of T2D presents with A1C 8.8%. His fasting blood glucose levels are mg/dl. Current medications include metformin 1 mg bid, pioglitazone 15 mg qd, linagliptin 5 mg qd, and insulin glargine U1 7 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 U1 2. Add rapid-acting prandial insulin 3. Switch from glargine U1 to insulin degludec U2 4. Add concentrated U5 regular insulin before largest meal 67 Post-test ARS Question 6 Which of the following is an advantage of glargine U3 compared to glargine U1? 1. U3 available in pens and vials 2. Safety of U3 in pregnancy well established 3. Lower risk of nocturnal hypoglycemia with U3 4. Significantly greater A1C reductions with U3 in insulin-naïve patients with T2D 68 23