9/18/18. Faculty. Disclosures

Transcription

1 Clinical Updates for Nurse Practitioners and Physician Assistants: 2018 Advances in Insulin Therapy: Another Step Closer to a More Physiological Strategy Faculty Robert S. Busch, MD, FACE Director of Clinical Research Albany Medical Faculty: Community Endocrine Group Albany, NY Davida F. Kruger, MSN, APN-BC, BC-ADM Certified Nurse Practitioner Henry Ford Health System Division of Endocrinology, Diabetes, Bone and Mineral Disease Detroit, MI Donna L. Jornsay, MS, BSN, RN, CPNP, CDE, CDTC, BC-ADM Diabetes Educator and Nurse Consultant San Bruno, CA Lucia M. Novak, MSN, ANP-BC, BC-ADM, CDTC Director, Riverside Diabetes Center Riverside Medical Associates Adjunct Assistant Professor Uniformed Services University of the Health Sciences Bethesda, MD Ashlyn Smith, MMS PA-C Endocrinology Associates, P.A. Secretary, American Society of Endocrine Physician Assistants Adjunct Assistant Professor, Midwestern University Scottsdale, AZ Mark Stolar, MD Associate Professor of Clinical Medicine Northwestern University Medical School Chicago, IL Jeff Unger, MD, ABFM, FACE Director, Unger Primary Care Medical Group Rancho Cucamonga, CA 2 Disclosures Dr. Busch serves as a speaker for Novo Nordisk, Sanofi, AstraZeneca and Lilly. He also serves as a researcher for Novo Nordisk, Sanofi and AstraZeneca. Ms. Jornsay is a Speaker for AstraZeneza, and Insulet, and a stock holder for Medtronic. She is also a member of the advisory board for Glooko, and a consultant for BD (Becton, Dickinson and Company). Ms. Kruger serves as a member of the advisory board for Novo Nordisk, Abbott, Eli Lilly and Company, Sanofi Aventis, Janssen, Dexcom, and Intarcia. She also serves on the Speakers Bureau for Janssen, Valeritas, AstraZeneca, BI/Lilly, Novo Nordisk, Dexcom, Lilly, Abbott, and Insulet. She has received grants/research support to Henry Ford Health System from AstraZeneca, Eli Lilly, Novo Nordisk, Hemsley Foundation, Dexcom, Lexicon, Abbott. Ms. Kruger has stocks from Dexcom. Ms. Novak serves as a speaker for Novo Nordisk, AstraZeneca and Janssen. She is also a member of the advisory board and is a consultant for Novo Nordisk and Sanofi. Ms. Smith is a member of the speaker s bureau and advisory board for Abbott Nutrition. Dr. Stolar serves as a speaker for AstraZeneca. Dr. Unger is on the advisory board for Abbott Diabetes. He is also a consultant for Novo Nordisk and a speaker for Janssen

2 Learning Objectives 1. Discuss clinician and patient barriers to initiation and intensification of insulin therapy 2. Recognize the prevalence and clinical impact of hypoglycemia in special populations at risk 3. Discuss the pharmacology and clinical differences between existing and new long-acting and concentrated insulins 4. Discuss how to incorporate new basal and concentrated insulins into clinical practice while minimizing the risk of adverse events 4 PRE-TEST QUESTIONS 5 Pre-test ARS Question 1 Please rate your confidence in your ability to identify patients with T2D who may benefit from concentrated insulins: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 6 2

3 Pre-test ARS Question 2 How often do you consider using concentrated insulin therapy in patients with T2D who are not achieving treatment targets with standard insulin regimens? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 7 Progressive β-cell Dysfunction Is a Key Driver of Progressive Dysglycemia in T2D By diabetes onset, up to 80% of β-cell function may be lost 1,2 Insulin Resistance Decreasing β-cell function partially driven by incretin defect PPG FPG Normal Impaired Glucose Glucose Tolerance Tolerance Insulin Secretion β-cell Function Diagnosis Severity of Glucose Intolerance Time in Years PPG=postprandial plasma glucose; FPG=fasting plasma glucose. 1. Defronzo RA. Diabetes. 2009;58: Fehse F, et al. J Clin Endocrinol Metab. 2005;90: Figure adapted from Kendall DM, et al. Am J Med. 2009;122(6 Supp):S37-S50. 8 Basal Insulin Replacement Initiated in Patients with Very Elevated A1C Distribution of A1C at time of insulin initiation Patients (%) 8.9% 41(%) 9.0% 22(%) 10.0% Clinical inertia exists despite: The benefits of timely glycaemic control Guidelines encouraging earlier use of insulin At insulin initiation in SOLVE: The average A1C was 8.9% 41% had A1C 9.0% 22% had A1C 10.0% Khunti et al. Diabetes Obes Metab 2012;14:

4 Consequences of Delayed Intervention A1C, % Bad glycemic legacy 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%) 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 10 Pre-test ARS Question 3 Which of the following is both a leading healthcare provider barrier and a common patient barrier to insulin initiation? 1. Clinical inertia 2. Sense of failure 3. Medication cost 4. Fear of hypoglycemia 11 Barriers to Insulin Initiation Patient Barriers Clinician Barriers Sense of failure Insulin causes complications Loss of independence Perception of Insulin ineffectiveness Fear of injections Fear of hypoglycemia Weight gain Cost Adapted from Funnell MM. Clinical Diabetes. 2007;25(1): Peyrot M, et al. Primary Care Diabetes. 2010;4(Suppl 1):S11-S18. Clinical inertia Suboptimal insulin knowledge Fear of hypoglycemia Weight gain 12 4

5 Health Care Provider: Roadblocks to Timely Insulin Initiation When Do HCP s Consider Using Insulin Therapy? Multiple medication failure 75% A1C > 8.5% 41% Worsening of microvascular complications 15% Unintentional weight loss 12% Repeated fasting glucose > 200 mg/dl 9% HCP: Concerns About Starting Insulin Therapy Poor patient adherence 92% Hypoglycemia 80% Pain from glucose monitoring 54% Pain from insulin injections 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: 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 of drugs that may mitigate weight gain, but explain that weight gain is caloric intake based not insulin based 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 LE, Alvarez M, Dilla T, Gil-Guillen V, Orozco-Beltran D. Adherence to therapies in with type 2 diabetes. Diabetes Ther. 2013;4: Hypoglycemia- So What? 15 5

6 Hypoglycemia Unawareness is a Dangerous Complication of Insulin Therapy Each episode of hypoglycemia reduces counterregulatory response to low glucose even after one episode Reduction in catecholamine response decreases awareness/symptoms even after a single episode Nocturnal hypoglycemia is most pathogenic and unrecognized Hypoglycemic awareness decreases significantly in the elderly Can be significant in patients with liver or renal impairment or with high glycemic variability Ahren Vasc Health Risk Manag. 2013;9: Pre-test ARS Question 4 Approximately what proportion of patients with diabetes experience unrecognized hypoglycemia? 1. 5% 2. 20% 3. 35% 4. 50% 17 Patients, % Asymptomatic Episodes of Hypoglycemia n=70 n=40 n=30 All patients with diabetes Type 1 diabetes Type 2 diabetes Patients With 1 Unrecognized Hypoglycemic Event, % In a cohort of patients with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by continuous glucose monitoring 1 Other researchers have reported similar findings 2,3 1. Copyright 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4): Reprinted with permission from The American Diabetes Association. 2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007; 115(8): Zick R et al. Diab Technol Ther. 2007;9(6):

7 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 Confuses patients and clinicians Decreases adherence Unger J. Concentrated and Fixed-Dose Insulin Formulations can Improve Outcomes in Patients with Type 2 Diabetes. Endocrinology, Diabetes, Metabolism Journal (1) Glucose Variability can Manifest as Both Fluctuating and Unpredictable Glucose Levels Unpredictability Glucose mg/dl Time (hours) Image adapted from Penckofer et al. Diab Tech Ther 2012;14: Glucose Variability can be Measured Between Individuals or Within the Same Person GIR (mg/kg/min) GIR (mg/kg/min) Inter-individual variability GIR curves from 2 subjects with type 1 diabetes each administered insulin detemir 0.4U/kg on 4 occasions Responses are predictable, but vary between subjects Insulin doses must be individualised GIR, glucose infusion rate GIR curves adapted from Heise et al. Diabetes 2004;53: Intra-individual variability GIR curves from 1 subject with type 1 diabetes administered NPH insulin 0.4U/kg on 4 occasions Responses are unpredictable This patient will have difficulty titrating to glucose targets 21 7

8 Glucose variability is not apparent from A1C Mean BG ( HbA1c) Patient A (A1C = 7.8%) Hyperglycemia Patient B (A1C = 7.8%) 280 Glucose mg/dl Hypoglycemia Time (hrs) Image adapted from Penckofer et al. Diab Tech Ther 2012;14: 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 Note: Lower CV results in more predictable insulin profile and less hypoglycemia 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): Dysglycemia is Often Patient-driven Patients usually adjust basal insulin rather than short acting for hypoglycemia (it s the bigger dose) Basal adjustments are reactive not proactive (PM dose needs to be lowered for AM hypo) Short acting gets omitted not reduced. Patients don t understand the insulin/glucose/ meal relationship. 24 8

9 9/18/18 Stevie: Introduction 47 y/o T2D x 10 years Comorbidities: HTN, dyslipidemia, sleep apnea Current OAD meds: Metformin 1000 mg bid with food Dulaglutide 1.5 mg weekly Empagliflozin 25 mg/d Glipizide 20 mg with dinner A1C has been > 8.5 % x 2 years A1C today is 9.2 %. He is experiencing distal paresthesias and increased fatigue over past month. CGM demonstrates persistent hyperglycemia over a 2 week period 25 More on Stevie Family history: Mother: 74, witht2dm, CKD, dyslipidemia Father: Died at 71 Acute MI Social history Work: Entrepreneur. CEO of Electronic Banking Firm Exercise: None except for ATV riding on holidays No cigs, ETOH, drugs 26 Stevie: Concerns Doesn t want insulin Might interfere with lifestyle and business travel Believes that needing insulin is a sign of personal failure and loss of control over diabetes self-management Wants a bit more time to attempt to get his A1C to his prescribed target of < 7 % 27 9

10 When to Consider Insulin in a Person with T2D When a combination of non-insulin antihyperglycemic medications are unable to achieve A1C target High fasting or postprandial glycemia/ adding basal not always the answer Unacceptable/ worry about side effects of other medications Hyperglycemia in a hospitalized patient Poorly controlled, symptomatic hyperglycemia or in the presence of DKA A1C above 8.0% on 3 OAD meds Nathan DM, et al. Diabetes Care. 2009; volume 32, Inzucchi SE, et al. Diabetes Care. 2012;35(6): ADA Diabetes Care. 2014:37(Suppl 1):S14-S80. * Random Glucose > 300 mg/dl, A1C > 10%, Ketonuria, Symptomatic polyuria/polydipsia, weight loss 28 Keys to Insulin Initiation in Primary Care Teach patients to self-titrate where appropriate. Customize insulin care plan for each patient and provide written instructions on adjustment protocol. Use insulin pens for accurate insulin adjustment and delivery. Teach patients how to utilize and interpret results of Selfmonitoring of blood glucose (SMBG) values. Consider structured glucose testing rather than random glucose testing for all patients. Prepare patients to recognize and treat hypoglycemia. Refer for diabetes education when available Unger J. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2011;4: Zisman A, et al. ADA Scientific Sessions. San Diego, CA P 29 Insulin Therapy in T2D: Basic Facts Basal insulin alone is able to achieve targeted A1C in 60% of all patients Initial starting dose can be u/kg/d but few require less than 20units Consider initiating basal insulin at 10 units/d taken at the same time daily Can be prescribed with metformin + one/two additional noninsulin agents. If basal insulin + OADs are unable to achieve targeted therapy in a patient, consider initiating GLP-1 RA, SGLT2 inhibitor or prandial insulin Consider reducing or eliminating doses of SUs, TZDs, GLP- RAs if A1C is < 8 % when starting insulin ADA. Diabetes Care S1. S

11 Individualizing A1C Targets for People with T2D Most 6.0% Intensive Less 7.0% Intensive Least Intensive 8.0% Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, & Comprehensive Support Systems Low Moderate Psychosocioeconomic Considerations Less motivated, Non-adherent, Limited Insight, Poor Self-Care Capacities, & Weak Support Systems Hypoglycemia Risk High Patient Age Disease Duration Other Comorbidities None Few/Mild Multiple/Severe None None Established Vascular Complications Cardiovascular Disease Early Micro Advanced Micro Data from Ismail-Beigi F, et al. Ann Intern Med. 2011;154(8): , also published in ADA Standards of Care 2015 Diabetes Care 2015;38(Suppl 1) Pre-test ARS Question 5 All of the following statements about basal insulin are true, EXCEPT: 1. Dosing of newer insulins can be adjusted every 3-4 days 2. Glargine U300 and degludec have a duration of action of >24 hours 3. Newer concentrated basal insulins have a longer duration of action but the same risk of nocturnal hypoglycemia as older basal insulins 4. The disadvantage of existing basal insulins detemir and glargine U100, compared to newer basal insulins, is that they both have peaks and troughs that impact control 32 Selecting Basal Insulin

12 Questions to Consider 34 Ultra-Rapid-acting: Inhaled human insulin Types of Insulin Rapid-acting analogs: Aspart, Glulisine, Lispro Short-acting Regular human insulin (soluble) Duration of action U-300 glargine 36 hours Degludec 42 hours Intermediate-acting NPH human insulin Long-acting basal insulin analogs: Detemir, Glargine U-300 Glargine, Degludec Human insulin 70/30: premix NPH/regular Time (hours) Premixed Analogs: Insulin lispro mix 75/25, 50/50 Biphasic insulin aspart 70/30 Adapted from Hirsch I. N Engl J Med. 2005;352: 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-100 Levemir Analog 1-2 Relatively peakless Glargine U-100 Lantus, Basaglar Human Increased risk of hypoglycemia when compared to analog basal insulin. Pregnancy (category B)- safe. Analog 1-2 Relatively peakless Glargine U-300 Toujeo Analog 6 Relatively peakless 24* Expect that a higher daily dose of glargine U-300 than glargine U- 24* 100 will be needed. (Glargine- C; Degludec- C; 24 Detemir- B) Degludec U- 100, U-200 Tresiba Analog 1-2 Relatively peakless 42 *Dose dependent (except glargine U-300, degludec) 36 12

13 Pre-test ARS Question 6 A 51-year-old man with a 13-year history of T2D has had A1C ~7.5% for 2 years. His clinician recommended CGM, which identified occasional nocturnal hypoglycemia. He notes that the basal insulin often leaks out after he injects it. Antidiabetic medications include metformin 1000 mg bid and insulin glargine U units qhs. What might be appropriate at this time? 1. Initiate lispro U Switch from glargine U100 to glargine U Switch from glargine U100 to human insulin R U Increase glargine U100 dose and split between morning and evening injections 37 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 administration device > 100 units via syringe > units via many insulin pen 1.2" Risk of lipohypertrophy/lipoatrophy at injection sites Pain/discomfort/leakage à impacting adherence Lipoatrophy at infusion site Lipodystrophy with NPH 38 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 enhance adherence Concentration of the insulin can prolong the insulin action, depending on the method of protraction 1 (U500R insulin and U300 glargine) Protracted PD profile of U300 glargine results in less confirmed and nocturnal hypoglycemia than U100 glargine Flexible dose times with degludec but timing must be consistent Cost savings when used in CSII (fewer cartridge and battery changes) 1 Sindelka G, et al. Diabetologia. 1994;37:

14 Rationale for Using Concentrated Insulins Condition Rationale Product of Choice Nocturnal Patient needs peak-less (flat) Glargine U300 hypoglycemia basal insulin profile Insulin with lower variability allows for safer titration to Degludec U100 or U200 FBG lowering risk of hypoglycemia Severe insulin resistance requiring > 200 units of insulin/day Patient requires > 60 units of basal insulin High-potency concentrated insulin can result in a low volume SQ depot U500 is 5x as potent as rapid acting meal time insulin 30 % of patients require > 60 units of basal insulin/injection Insulin R U500 Degludec U200 (160 u/dose max) Glargine U300 (160 units/dose max) 40 Rationale for Using Concentrated Insulins and GLP-1 RA + Insulin Formulations Condition Rationale Product of Choice Flexible dosing required due to work or travel Due to protracted duration of action, degludec can be administered any time of day without compromising glycemic control or safety Degludec U100 Degludec U200 Patient requires > 20 units of prandial insulin Postprandial and fasting glucose coverage is needed Lower cost; lower volume Lispro U200 insulin reduces the number of pens used monthly Fixed dose combination therapy with insulin + GLP- 1 RA can reduce total daily dose of insulin and reduce postprandial glucose excursions Insulin degludec+ liraglutide (100/3.6) Insulin glargine + lixisenatide (100/33) 41 Concentrated Insulins Strengths and Limitations (Rapid Acting Insulins) Insulin Strength Limitations Lispro U200 Insulin R U500 Costs similar to Lispro U100 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 (1) Available in pens only, no vials Expensive Should administer 30 minutes prior to eating due to 60 minute onset of action 1)Unger, J. (2012). Insulin pumping and use of continuous glucose sensors in primary care. In Diabetes Management in Primary Care (2 nd Ed.), (pp ). Philadelphia, PA. Lippincott, Williams and Wilkins

15 Concentrated Insulins Strengths and Limitations (Glargine U100 vs U300) Insulin Strength Limitations Glargine U100 Available in vials and pens More nocturnal hypoglycemia than U300 Studied in pregnancy. Risk appears to be similar to NPH Higher insulin dosing results in weight gain and increase risk of hypoglycemia Glargine U % lower risk of nocturnal hypoglycemia (< 70 mg/dl) vs. glargine U kg less wt gain vs U100 mall but significant difference in HbA 1c reduction at 12 months favoring Gla-300 in insulinexperienced patients with T2DM using basal plus mealtime insulin 18 % higher insulin dose than U100 in clinical trials Cost $290 for 3 pens vs $270 for 5 pens (equivalent amounts of insulin) Not studied in pregnancy Despite equivalent efficacy in terms of glycemic control, the use of Gla-300 in patients with T1D resulted in no difference in the incidence of nocturnal or hypoglycemia at any time of day (24 hours) Riddle, M, et al. EDITION 4. Diabetes Care 2014 Oct; 37(10): Home PD, et al. Diabetes Care Dec; 38(12): Pollex, E, et al. The Annals of Pharmacotherapy. 2011;45(1): Ultralong-acting Basal Insulins have Minimal Glycemic Variability GIR, mg/kg/min 3 2 U-300 glargine 1,a Period 1 Period 2 1 Average glucose 0 infusion rate Time, h (GIR) U Blood Glucose Level, mmol/l U-100 degludec 2 Individual patient profiles Mean profile Time Since Injection, h GIR, μmol/kg/min Older Basals 3,b Time, h NPH Detemir Glargine 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: a 2-period crossover study in T1DM; n = 50. b 3-period crossover study in T2DM. 44 Pharmacodynamics of U-300 Glargine vs U-100 Glargine GIR (mg/kg -1 min -1 )* SC Injection U U/kg -1 U U/kg Time (hours) U U/kg -1 U U/kg -1 The U-300 glargine has a flatter more prolonged effect The time it takes for 50% of the effect of a single injection U-100 = 12.1 hours U-300 = 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,

16 Meta-analysis: U300 Glargine 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 U100 Nocturnal Hypo-Events* per Participant-Year U100 RR 31% p= U300 Weight Change (Kg) Mean SE U Base W2 W4 line 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, 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 HbA1c reductions and had similar insulin dose requirements Wysham C, et al. Paper presented at: 76th Scientific Sessions of the American Diabetes Association; June 10-14, 2016; New Orleans, LA. 47 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 3-4 days until targeted FBG is achieved Clinical trials have confirmed the safety of targeting FBG of 70 mg/dl in patients using concentrated insulins (degludec) Lower risk of hypoglycemia is due to reduced glycemic variability 48 16

17 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 3-4 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 49 Stevie: Subsequent Events Recall: Saw diabetes educators Started on basal insulin, given at bedtime Glipizide stopped, other meds continued Placed on CGM Subsequently: Basal insulin titrated from 10 to 40 units/d over 2 months A1C: 7.2% Now complains of occasional hypoglycemia in late morning, late afternoon, & nocturnal; often associated with increased activity 50 SMBG: What Would You Do Now? Brkfst Post- Brkfst Lunch Post- Lunch Supper Post- Supper Bedtime Sunday Monday Tuesday Wednesday Thursday Friday Saturday Make no changes to therapy 2. Change to fixed-mixture insulin BID 3. Change to ultrabasal insulin at same dose 4. Add premeal insulin at suppertime, reduce basal 5. Reduce basal insulin to reduce risk of hypoglycemia Meds: Metformin ER 1000 mg bid, GLP-1 RA, SGLT2 inhibitor basal insulin 40 units daily at bedtime A1C: 7.2% 51 17

18 CGM: What Would You Do Now? 1. Make no changes to therapy 2. Change to fixed-mixture insulin BID 3. Change to concentrated basal insulin at same dose 4. Add premeal insulin at suppertime, reduce basal 5. Reduce basal insulin to reduce risk of hypoglycemia Meds: Metformin 1000 mg bid, GLP-1RA, SGLT2-I, basal insulin 40 u/d 52 Available Glucose Sensors Type of CGM Abbott Freestyle Libre Medtronic Enlite Guardian Sensor 3 ipro2 Dexcom 4, 5, 6 Calibration necessary? No Yes Yes. Not for Dexcom 6 (2 hour warmup) Sensor duration Audible alerts for high and low glucose 10 days (14 day with 1 hour warmup FDA approved 6 days 7-10 days No Yes Yes Trend arrow displayed? Yes Yes Yes Connectivity to insulin pump No Yes Yes 53 BeAM Factor : Avoiding Overbasalization BeAM factor = the difference between bedtime and AM blood glucose levels Example: Bedtime BG = 165 mg/dl; AM glucose = 100 mg/dl; BeAM = mg/dl = 65 mg/dl Patients with a BeAM factor >55 mg/dl are less likely to achieve an HbA1c 7% without experiencing hypoglycemia if BASAL INSULIN DOSE 60 units Thus, patient with BeAM factor >55 mg/dl should be placed on either prandial insulin, GLP 1RA, or an SGLT2i Zisman A, et al.. ADA Scientific Sessions. San Diego, CA. 2011;#1121-P 54 18

19 Pattern of Prolonged Nocturnal Hypoglycemia From 12 3 AM! Bedtime BG = 130 mg/dl Fasting BG = 70 mg/dl BeAM= 60 mg/dl HbA1c= 7.8% Basal insulin dose = 65 units Patient case supplied by Jeff Unger, MD, with permission. 55 Concentrated Insulins: Take Home Lessons U100 basal insulins exhibit variability in pharmacodynamics and duration of action 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) Both U200 and U300 basal insulin have a duration of action >24 hours and therefore once daily dosed with a more consistent pharmacokinetic profile U500 can be used in highly insulin resistant patients, especially if requiring > 200 units/day. Use pens only to minimize errors Concentrated insulin may be a cost effective means of delivering higher doses of insulin with fewer daily injections and is a useful tool in the management of patients with diabetes 56 POST-TEST QUESTIONS 57 19

20 Post-test ARS Question 1 After completing this activity, how confident are you now in your ability to identify patients with T2D who may benefit from concentrated insulins: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 58 Post-test ARS Question 2 After completing this activity, how often do you intend to consider using concentrated insulin therapy in patients with T2D who are not achieving treatment targets with standard insulin regimens? 1. Never 2. Rarely 3. Sometimes 4. Often 5. Always 59 Post-test ARS Question 3 Which of the following is both a leading healthcare provider barrier and a common patient barrier to insulin initiation? 1. Clinical inertia 2. Sense of failure 3. Medication cost 4. Fear of hypoglycemia 60 20

21 Post-test ARS Question 4 Approximately what proportion of patients with diabetes experience unrecognized hypoglycemia? 1. 5% 2. 20% 3. 35% 4. 50% 61 Post-test ARS Question 5 All of the following statements about basal insulin are true, EXCEPT: 1. Dosing of newer insulins can be adjusted every 3-4 days 2. Glargine U300 and degludec have a duration of action of >24 hours 3. Newer concentrated basal insulins have a longer duration of action but the same risk of nocturnal hypoglycemia as older basal insulins 4. The disadvantage of existing basal insulins detemir and glargine U100, compared to newer basal insulins, is that they both have peaks and troughs that impact control 62 Post-test ARS Question 6 A 51-year-old man with a 13-year history of T2D has had A1C ~7.5% for 2 years. His clinician recommended CGM, which identified occasional nocturnal hypoglycemia. He notes that the basal insulin often leaks out after he injects it. Antidiabetic medications include metformin 1000 mg bid and insulin glargine U units qhs. What might be appropriate at this time? 1. Initiate lispro U Switch from glargine U100 to glargine U Switch from glargine U100 to human insulin R U Increase glargine U100 dose and split between morning and evening injections 63 21