5/16/2018. Insulin Workshop. Disclosures to Participants. Learning Objectives. This presentation will cover the following learning objectives:

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1 Insulin Workshop Joshua J. Neumiller, PharmD, CDE, FASCP Vice Chair & Associate Professor, Department of Pharmacotherapy Washington State University Spokane, WA Holly Divine, PharmD, BCACP, BCGP, CDE, FAPhA Associate Professor College of Pharmacy University of Kentucky Lexington, KY Disclosures to Participants Conflicts of Interest and Financial Relationship Disclosures: Presenters: Joshua J. Neumiller, PharmD, CDE, FASCP ADA Editorial Board/Committee Membership: Editor for the ADA journal Diabetes Spectrum Member of ADA Professional Practice Committee (PPC) Holly Divine, PharmD, BCACP, BCGP, CDE, FAPhA No Disclosures Learning Objectives This presentation will cover the following learning objectives: 1. Review current ADA recommendations for the initiation and titration of insulin in people with type 2 diabetes; 2. Discuss key challenges related to the initiation and optimization of insulin therapy in people with type 2 diabetes; 3. Utilize clinical case scenarios to discuss potential strategies for successful insulin use to meet patient centered treatment goals. 1

2 Glucose Lowering Comparison Monotherapy Route of Administration Targets Insulin Resistance Target Glucose: FPG or PPG Approximate A1C Reduction (%) Sulfonylurea Oral No Both Metformin Oral Yes FPG 1.5 Glitazones Oral Yes Both Meglitinides Oral No PPG AGIs Oral No PPG DDP 4 inhibitors Oral No PPG SGLT 2 inhibitors Oral glucose toxicity Both GLP 1 agonists Injectable No Short acting PPG Long acting FPG Amylin analogs Injectable No PPG 0.6 Insulin Injectable glucose toxicity Basal FPG as much as Bolus PPG needed Unger J, et al. Postgrad Med. 2010;122(3): Cornell S, et al. Postgrad Med. 2012;124(4): Insulin PK/PD Comparison Insulin Time to Onset Duration of Time to Peak Action (hr) of Action (hr) Action (hr) Lispro (U 100, U 200) within Aspart within Glulisine within Insulin human (inhaled) within Insulin human regular (U 100) Insulin human regular (U 500) Human insulin isophane (NPH) Detemir (though relatively flat) Up to 24 Glargine (U 100) 2 4 flat Glargine (U 300) 6 flat up to 36 Degludec (U 100, U 200) 1 flat >42 Lispro mix 50/50 within Up to 24 Lispro mix 75/25 within Aspart mix 70/30 within Up to 24 Degludec/aspart mix 70/30 within >24 Patient specific onset, peak, and duration may vary from times listed in table. Peak and duration are dose dependent with shorter durations of action seen for smaller doses and longer durations of action with larger doses. Hirsch IB. N Engl J Med. 2005; 352:174 83; Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16 38; Dansinger M. Types of insulin. June 21, types insulin (accessed 2016 Sep 29); Bennett JA. Insulin chart. July 17, chart (accessed 2016 Sep 29); Individual product prescribing information. Pharmacokinetic Profile of Currently Available Single Insulin Products Plasma Insulin Levels Rapid (aspart, lispro, glulisine, inhaled human insulin) Short (regular U 100) Mixed short/intermediate (regular U 500) Intermediate (NPH) Long (detemir) Long (U 100 glargine) Ultra long (glargine U 300) Ultra long (degludec) Time (hr) Hirsch IB. N Engl J Med. 2005; 352: Flood TM. J Fam Pract. 2007; 56(suppl 1):S1 S12. Becker RH et al. Diabetes Care. 2015; 38:

3 Antihyperglycemic Therapy in Adults with T2DM Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Antihyperglycemic Therapy in Adults with T2DM Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Antihyperglycemic Therapy in Adults with T2DM From the Standards: If the A1C target is not achieved after approximately 3 months and patient does not have ASCVD, consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP 4 inhibitor, SGLT2 inhibitor, GLP 1 receptor agonist, or basal insulin; the choice of which agent to add is based on drug specific and patient factors (Table 8.1). Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 3

4 See page S77 in: Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Hypoglycemic Risk of Antihyperglycemic Agents Added to Metformin 25 Increased Risk vs. Placebo Odds Ratio vs. Placebo Biphasic Insulin TZD SU Glinide Basal Insulin No Increased Risk vs. Placebo DPP 4i AGi GLP 1 RA SGLT 2i Liu S et al. Diabetes Obes Metab 2012; 14: Antihyperglycemic Therapy in Adults with T2DM Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 4

5 Case #1: GD GD is a 64 year old woman with T2DM of 7 years duration Past medical history Type 2 diabetes mellitus Hypertension Hyperlipidemia Peripheral neuropathy Chief complaint My blood sugar readings aren t as good as they once were. Case #1: GD Current medications Metformin 1000 mg PO BID Sitagliptin 100 mg daily Glimepiride 4 mg daily Lisinopril 20 mg PO once daily Amlodipine 10 mg daily Rosuvastatin 20 mg PO once daily Duloxetine 60 mg PO once daily Case #1: GD Vital signs BP: 132/90 mmhg Pulse: 70 bpm, regular Weight: 198 lb (90 kg) Height: 5 6 BMI: 32.0 Labs (fasting) Glucose: 170 mg/dl A1C: 8.1% SCr: 1.2 mg/dl UACR: 120 mg/g egfr (MDRD): 45 ml/min/1.73m 2 Na: 142 meq/l K: 4.5 meq/l LDL: 90 mg/dl HDL: 52 mg/dl TG: 130 mg/dl 5

6 Case #1: GD Social and Family History GD is retired and lives with her husband of 40 years Weight has been relatively stable for the past year GD has never smoked or used illicit drugs Drinks 1 2 glasses of wine with dinner 2 3 times per week Works in the yard on occasion, but is otherwise sedentary Mother and father both had T2D Private insurance plan with low co pays Case #1: GD s Blood Glucose Log GD currently checks her blood glucose twice daily once in the morning before breakfast and at bedtime Day Morning (Fasting) Bedtime Monday 185 mg/dl 180 mg/dl Tuesday 170 mg/dl 192 mg/dl Wednesday 198 mg/dl 210 mg/dl Thursday 176 mg/dl 205 mg/dl Friday 192 mg/dl 121 mg/dl Saturday 205 mg/dl 230 mg/dl Sunday 173 mg/dl 202 mg/dl Additional meter download data: 14 day average: 186 mg/dl 30 day average: 198 mg/dl Case #1: GD Questions 1. What would be an appropriate A1C goal for GD? 2. What medication changes would you recommend (if any)? 6

7 ADA 2018: Summary of Glycemic Recommendations Glycemic Targets: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S55 S64. Determining an Appropriate A1C Target Patient/Disease Features Risk of hypoglycemia/drug adverse effects Disease Duration Life expectancy Important comorbidities Established vascular complications more stringent low newly diagnosed long absent absent A1C 7% Few/mild Few/mild less stringent high long-standing short severe severe Patient attitude & expected treatment efforts Resources & support system highly motivated, adherent, excellent self-care capabilities readily available less motivated, nonadherent, poor self-care capabilities limited Glycemic Targets: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S55-S64 Case #1: GD Basal Insulin Initiation GD s primary care provider (PCP) would like to start her on U 100 insulin glargine. 3. What would you recommend as a starting dose? 4. What titration schedule/approach would you recommend? 7

8 Basal Insulin Initiation in T2DM: Start with 10 units/day or units/kg/day Adjust 10 15% or 2 4 units once or twice weekly to reach FBG target Assess and adjust for hypoglycemia American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care Standards 2017; 40 (Suppl. of Medical 1): S64-S74 Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Treat to Target Strategy for Basal Insulin Titration Start with 10 units/day bedtime basal and adjust weekly Mean of FPG from preceding 2 days 180 mg/dl Increase insulin dose (units/day) 8 units mg/dl 6 units mg/dl 4 units mg/dl 2 units <100 0 units *No increase in dosage if BG <72 mg/dl in preceding week; dose decreases of 2 4 units/day allowed if BG <56 mg/dl in preceding week. Riddle JC. Diabetes Care. 2003;26: Insulin Glargine Titration: Physician vs. Patient Directed Titration Mean of FBBG from previous 3 consecutive days Increase in insulin glargine dose (units/day) Algorithm 1: Physician Directed (at each visit) Algorithm 2: Patient Driven (every 3 days) 180 mg/dl 6 8 units 2 units mg/dl 4 units 2 units mg/dl 2 units 2 units mg/dl 0 2 units 0 2 units Davies M, et al. Diabetes Care. 2005;28:

9 Insulin Glargine Titration: Physician vs. Patient Directed Titration Davies M, et al. Diabetes Care. 2005;28: Strategy for Basal Insulin Self Titration *Self adjust basal insulin every 3 days Mean of FPG from preceding 3 days Change in insulin dose (units/day) <80 mg/dl by 3 units mg/dl No Change >110 mg/dl by 3 units Meneghini L. Diabetes Obes Metab. 2007;9: Case #1: GD Basal Insulin Initiation 5. What counseling/support would you recommend for GD at this time? 6. When starting basal insulin in this scenario, would you discontinue any of her current antihyperglycemic agents? 9

10 Barriers to Effective Insulin Use Common Barriers for People with Diabetes Psychological Insulin represents failure Lack of perceived benefit Pain/fear of injections Belief that insulin is complicated Loss of independence/change in lifestyle Stigma related to needle use Harmful effects Hypoglycemia Weight gain Financial Common Barriers for Providers Negative feelings about insulin Time constraints Lack of support/resources Concern about adverse effects Hypoglycemia Weight gain Fear of patient response/lack of adherence Minze MG, et al. J Fam Pract 2011;60(10): Therapeutic Inertia: Barriers and Solutions to Insulin Therapy DSME; Mobile Apps Improved Therapies Side Effects Burdensome Regimens Fear of Injection Therapeutic Inertia Improved Devices Nurse Management; Specialist Feedback Poor Negative Communication Appraisals of Insulin Barriers Support from a Psychologist Solutions Russell Jones D, et al. Diabetes Obes Metab 2018;20: Overcoming Barriers to Insulin Therapy: Potential Strategies Motivational interviewing Avoid using insulin as a threat Use insulin as a solution Discuss it as an option early Use insulin pens and regimens that offer maximum flexibility Give a limited trial of insulin Give an injection in the office/clinic Teach patient to recognize and treat hypoglycemia 10

11 Hypoglycemia Treatment: Rule of If blood glucose <70 mg/dl, consume 15 grams of quick acting carbohydrate; 2. Wait 15 minutes; 3. Re check blood glucose; 4. If still <70 mg/dl consume another 15 grams of carbohydrate; 5. If >70 mg/dl, consume a snack or meal within 60 minutes Continuation of Non Insulin Agents with Insulin? Continued use of metformin, SGLT 2 inhibitors and GLP 1 receptor agonists may mitigate weight gain Thiazolidinediones plus insulin can result in significant weight gain/edema Must consider medication burden and cost May consider elimination of sulfonylureas, DPP 4 inhibitors, TZDs and meglitinides Riddle MC. Diabetes Care 2008;31(Suppl 2):S125 S130. Vos RC, et al. Cochrane Database of Systematic Reviews 2016;9:CD Case #1: GD Case Debrief 11

12 Case #2: RL RL is a 66 year old man with T2DM of 14 years duration Past Medical History Type 2 diabetes mellitus Hypertension Hyperlipidemia Hypothyroidism History of MI 6 years ago Chief complaint My blood sugars are high at night before I go to bed. Case #2: RL Current Medications Metformin 1000 mg PO BID Insulin detemir 42 units once daily QHS Fosinopril 20 mg PO once daily Hydrochlorothiazide 25 mg PO once daily Atorvastatin 40 mg PO once daily Levothyroxine 100 mcg PO once daily Aspirin 81 mg once daily Ibuprofen 400 mg QID PRN Case #2: RL Social and Family History RL lives with his wife of 28 years RL works part time (20 hours per week) as a grocery store clerk He is adherent to his current medication regimen RL engages in minimal physical activity Golf on Saturdays Father died from an MI at the age of 65 12

13 Case #2: RL Vital signs BP: 152/92 mmhg Pulse: 72 bpm, regular Weight: 225 lbs (102 kg) Height: 6 0 BMI: 30.5 Labs (fasting) Glucose: 125 mg/dl A1C: 8.4% SCr: 1.1 mg/dl UACR: 40 mg/g egfr (CKD EPI): 70 ml/min/1.73m 2 Na: 136 meq/l K: 4.6 meq/l LDL: 82 mg/dl HDL: 42 mg/dl TG: 156 mg/dl Case #2: RL s Blood Glucose Log RL checks his blood glucose once to twice daily Day Morning (Fasting) Bedtime* Monday 132 mg/dl Tuesday 112 mg/dl 195 mg/dl Wednesday 141 mg/dl Thursday 115 mg/dl Friday 132 mg/dl 230 mg/dl Saturday 152 mg/dl 202 mg/dl Sunday 123 mg/dl *RL explains that he only checks his blood glucose at bedtime if he doesn t feel right. Case #2: RL Questions 1. What additional questions would you have for RL? 2. What medication changes would you recommend (if any) at this time? 13

14 Case #2: RL s Follow Up Blood Glucose Log RL was asked to check his blood glucose more frequently and provide some additional data as shown below: Day Breakfast Lunch Pre Dinner Bedtime Before After Before After Monday 115 mg/dl 140 mg/dl 132 mg/dl 183 mg/dl 221 mg/dl Tuesday 141 mg/dl 170 mg/dl 154 mg/dl 192 mg/dl 170 mg/dl 189 mg/dl Wednesday 108 mg/dl 153 mg/dl 172 mg/dl 202 mg/dl 263 mg/dl Case #2: RL Basal Insulin Switch RL s PCP believes his insulin detemir may be wearing off late in the day and would like to switch him to a longer acting basal insulin analog. 3. Which insulin product would you recommend? 4. How would you recommend converting RL to the new insulin product? Reasons for Insulin Product Switching Medical Switching Regimen complexity considerations Adherence Hypoglycemia Glycemic control Weight considerations Dosing limitations (large insulin doses/injection) Non Medical Switching Formulary restrictions/changes Cost Care transitions Nguyen E, et al. Curr Med Res Opin 2016;32: Parkin C, Meece J. AADE in Practice 2017;

15 Case #2: RL RL was switched to U 100 insulin degludec and has been titrated to achieve his fasting blood glucose target. His PCP would now like to add an agent to target postprandial glucose because his A1C is still elevated at 7.9%. 5. What would you recommend to add at this time? Postprandial vs. Fasting Hyperglycemia on A1C Fasting PPG Monnier L, et al. Diabetes Care. 2003;26: Once FBG optimized target PPG excursions: Add 1 rapid acting insulin injection to largest meal, or Add GLP 1 RA, or Change to premixed insulin twice daily American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care Standards 2017; 40 (Suppl. of Medical 1): S64-S74 Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 15

16 Once FBG optimized target PPG excursions: Add 1 rapid acting insulin injection to largest meal, or Add GLP 1 RA, or Change to premixed insulin twice daily American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care Standards 2017; 40 (Suppl. of Medical 1): S64-S74 Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 A1C Change From Baseline to Week 24 Following 14-week run-in with insulin glargine Mean A1C decreased from >10.0% to ~8.0% 288 patients achieved A1C 7.0% Final dose was 0.55 U/kg regardless of reaching target Davidson MB et al. Endocr Pract 2011;17(3): Once FBG optimized target PPG excursions: Add 1 rapid acting insulin injection to largest meal, or Add GLP 1 RA, or Change to premixed insulin twice daily American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care Standards 2017; 40 (Suppl. of Medical 1): S64-S74 Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 16

17 Pharmacologic Therapy For T2DM: Recommendations In patients with T2DM and established ASCVD, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse CV events and CV mortality (currently empagliflozin and liraglutide), after considering drugspecific and patient factors (Table 8.1). A In patients with T2DM and established ASCVD, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse CV events, based on drug specific and patient factors (Table 8.1). C Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Start with basal insulin Titration If A1c 7 7.5%,* despite titration *or an individualized target Add GLP 1 receptor agonist CONSIDERATIONS Weight loss Reduced risk of hypoglycemia Similar efficacy to prandial insulin GI adverse effects Pancreatitis avoid Intensify insulin Multiple Daily Inj. Additional prandial injections CONSIDERATIONS Weight gain Hypoglycemia risk Large doses of insulin often needed Basal Plus Treat to target Good efficacy GLP 1 Receptor Agonist vs. Bolus Insulin in T2DM Patients with Optimized Basal Insulin A1c, % Lispro Exenatide BID FPG, mmol/l Weeks Since Randomization Weeks Since Randomization a a a a a a a a Blood Glucose, mmol/l Pre Post Pre Post Pre Post 3AM Breakfast Lunch Dinner Body Weight, kg a p<0.01 for exenatide BID vs. insulin lispro b p<0.001 for exenatide BID vs. insulin lispro b -1 b b b b -2 b b b Weeks Since Randomization Compared with lispro, exenatide caused more GI issues (47% vs. 13%), but fewer non nocturnal hypoglycemic episodes (15% vs. 34%) Diamant M et al. Diabetes Care. 2014; 37:

18 Insulin Glargine/Lixisenatide Fixed Dose Combination Fixed dose combination product Insulin glargine U 100 Lixisenatide (short acting GLP 1RA) 33 mcg/ml Initiation: For patients on < 30 units basal insulin: 15 units insulin glargine U 100 (5 mcg lixisenatide) For patients on units basal insulin: 30 units insulin glargine U 100 (10 mcg lixisenatide) Administration: within 1 hour before the first meal of the day Titration: 2 4 units (insulin glargine U 100 component) once weekly on the basis of FPG Max dose: 60 units insulin glargine U 100/20 mcg lixisenatide Pen device delivers units of insulin glargine Insulin glargine/lixisenatide Prescribing Information. Available at: 33/Soliqua pdf Insulin Degludec/Liraglutide Fixed Dose Combination Fixed dose combination product Insulin degludec U100 Liraglutide (once daily GLP 1RA) 3.6 mg/ml Initiation: 16 units insulin degludec (0.58 mg liraglutide) once daily Administration: same time once daily (with or without food) Titration: Titrate by 2 units (insulin degludec) every 3 4 days on the basis of FPG (or hypoglycemia) Max dose: 50 units insulin degludec/1.8 mg liraglutide Pen device delivers units of insulin degludec Insulin degludec/liraglutide Prescribing Information. Available at: pi.com/xultophy10036.pdf Once FBG optimized target PPG excursions: Add 1 rapid acting insulin injection to largest meal, or Add GLP 1 RA, or Change to premixed insulin twice daily American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care Standards 2017; 40 (Suppl. of Medical 1): S64-S74 Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 18

19 Premixed Insulin Administration Aspart 70/30 Insulin Effect B L S HS B If additional intensification is needed: Basal bolus ( 2 rapid acting injections with meals) Premixed analog 3 times daily American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment. Diabetes Care Standards 2017; 40 (Suppl. of Medical 1): S64-S74 Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Case #2: RL Case Debrief 19

20 Standards of Care Potentially Useful Resources Full version available Abridged version for PCPs SOC slide deck Free app Pocket cards with key figures Free webcast for continuing education credit Professional.Diabetes.org/SOC Thank you 20