Session 5: Insulin: Tried and True - Update on Best Practices in Clinical Use and Patient Adherence Learning Objectives

Transcription

1 Session 5: Insulin: Tried and True - Update on Best Practices in Clinical Use and Patient Adherence Learning Objectives 1. Design strategies to help patients overcome cultural barriers to using insulin, and apply a team-based approach to initiating, switching, and intensifying insulin therapies. 2. Employ the tenets of physiologic insulin replacement, and select between various insulin formulations to help patients meet individualized treatment target goals.

2 Session 5 Insulin: Tried and True - Update on Best Practices in Clinical Use and Patient Adherence Faculty Javier Morales, MD Vice President Principal Clinical Trials Investigator Advanced Internal Medicine Group, P.C. New Hyde Park, New York Dr Morales is in private practice with the Advanced Internal Medicine Group in New Hyde Park, New York. After graduating from the University of Medicine and Dentistry of New Jersey, he completed residencies at Memorial Sloan-Kettering Cancer Center and North Shore University Hospital, where he served as chief medical resident. Dr Morales serves on multiple committees at St. Francis Hospital in Roslyn, New York. In addition to authoring several publications, he has served as principal investigator for several different studies and clinical trials. He is active in the educational sector and has been a presenter at many Pri-Med symposia. He also serves as a clinical instructor for several nurse practitioner, physician assistant, and internal medicine residency programs at North Shore University Hospital and Winthrop University Hospital. Dr Morales is an avid musician and percussionist, and he is fluent in Spanish, Italian, and Portuguese. Faculty Financial Disclosure Statement The presenting faculty reports the following: Dr Morales is consultant for Novo Nordisk Inc., Warner Chilcott, Eli Lilly and Company, Liposcience, and Boehringer Ingelheim. Suggested Reading List Handelsman Y, Mechanick JI, Blonde L, et al. AACE Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 211;17(suppl 2):1-53. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. April 19, 212. doi:1.2337/dc Peyrot M, Rubin RR, Khunti K. Addressing barriers to initiation of insulin in patients with type 2 diabetes. Primary Care Diabetes. 21;4(suppl 1):S11-S18. Unger J. Insulin initiation and intensification in patients with T2DM for the primary care physician. Diabetes Metab Syndr Obes. 211;4: Epub 211 Jun 28.

3 Faculty Disclosure Session 5 2: PM 3:3 PM Dr Morales is a consultant for Novo Nordisk Inc., Warner Chilcott, Eli Lilly and Company, Liposcience, and Boehringer Ingelheim. Insulin: Tried and True Update on Best Practices in Clinical Use and Patient Adherence Javier Morales, MD 2 Learning Objectives Question Pre-test #1 Design strategies to help patients overcome cultural barriers to using insulin, and apply a team-based approach to initiating, switching and intensifying insulin therapies Employ the tenets of physiologic insulin replacement, and select between various insulin formulations to help patients meet individualized treatment target goals. In patients on oral T2DM agents, at what A1C level should insulin therapy be initiated? 1. >7.5% 2. >8.% 3. >8.5% 4. >9.% 5. Any of the above 3 4 Question Pre-test #2 You seek to initiate insulin therapy in a poorly-controlled patient but she thinks this will be too complex for her to do. How will you address this? Check all that apply (press <<send>> after each selection) 1. Tell her that insulin is her only option at this point in time 2. Institute self-adjustment algorithms with glucose monitoring 3. Start with basal insulin twice daily 4. Address insulin myths that it causes complications, damages the pancreas 5. Institute a pre-mixed fixed-dose insulin regimen Pre-Test Question #3: A pre-/post- blood glucose delta value that s less than 5 mg/ml might indicate: 1. Concurrent illness, eg, flu 2. Missed previous insulin dose 3. Previous insulin dose is too high 4. Insulin solution has expired or is denatured 5 6 1

4 The History of Diabetes Survival Stepwise Treatment of T2DM: Role of Insulins Years year old 3 year old 5 year old Insulin Initiation Intensification Further Intensification Basal Plus Add insulin at main meal Basal Add basal insulin and titrate Additional OADs ± Incretins Basal-Bolus Information taken from: Bliss M. The Discovery of Insulin. University of Chicago Press Photographs courtesy of the National Library of Medicine Lifestyle Changes + Metformin Progressive deterioration of beta-cell function 8 A1C % A1C % A1C > 9.% Drug Naive Under Treatment 212 ADA/EASD Consensus Statement Recommendations Symptoms No Symptoms MET + GLP-1 or DPP4 Monotherapy MET DPP4 GLP-1 TZD AGI 2-3 Mos. Dual Therapy GLP-1 or DPP4 TZD MET + Glinide or SU TZD + GLP-1 or DPP4 MET + Triple Therapy + Colesevelam AGI 2-3 Mos. TZD Glinide or SU 2-3 Mos. INSULIN ± Other Agent(s) MET + MET + Dual Therapy GLP-1 or DPP4 or TZD SU or Glinide 2-3 Mos. Triple Therapy GLP-1 or DPP4 GLP-1 or DPP4 TZD 2-3 Mos. INSULIN ± Other Agent(s) + TZD + SU INSULIN ± Other Agent(s) ME T Dual or Triple Therapy + AGI DPP4 GLP-1 Met SU TZD GLP-1 or DPP4 TZD GLP-1 or DPP4 ±SU ±TZD α-glucosidase Inhibitor DPP-4 Inhibitor Incretin Mimetic Metformin Sulfonylurea Thiazolidinedione INSULIN ± Other Agent(s) Adapted and modified from: Rodbard H, Jellinger P, et al. Endocrine Practice, 29 Sept/Oct; 15 (6): Continue Current Management Sulfonylurea *pioglitazone TZD* Yes Diagnosis of Type 2 Diabetes Lifestyle Intervention + Metformin DPP 4 Inhibitor Inzucchi SE et al. Diabetes Care 212. doi: /dc A1C at Goal? No Add GLP 1 Receptor Agonist Insulin (basal) SOLVE: Baseline A1C Distribution at Insulin Initiation Patients (%) % A1C (%) The Insulin Paradox Many patients have high blood glucose levels, which puts them at risk for complications AND Insulin is the most powerful medication for lowering blood glucose BUT Many patients with poor glycemic control do not receive insulin treatment Khunti K et al, for the SOLVE Study Group. Diabetes. 211;6 (Suppl 1):A

5 Changes in A1C and Glycemic Burden (in months) A1C (%) Pre-Tx A1C Best Rx A1C Last Rx A1C Diet & Exercise N = 2319 SU N = 3394 MET N = 513 SU + MET N = 982 Insulin 9.5% PATIENTS WHO ARE NOT MANAGING THEIR DIABETES WELL.. ARE SIGNIFICANTLY MORE LIKELY TO PERCEIVE INSULIN THERAPY AS POTENTIALLY BENEFICIAL A1C > 8% (mo) A1C > 7% (mo) Brown JB et al. Diabetes Care. 24;27: Peyrot M et al. Diabetes Care. 25;28: Case: Douglas 52-Year-Old African-American Man Progression of Treatment Options for Type 2 Diabetes First MD visit after relocating for a new job - T2DM x 8 years, HTN and dyslipidemia x 15 years - 6 3, 223 lbs; BMI= A1C 6 mos ago 8.7% this visit, 8.9% Current medications (past 3 years) Metformin 1 mg BID Glipizide ER 2 mg QD Saxagliptin 5mg QD Simvastatin 4 mg HS Aspirin 81 mg QD 15 Beta-cell Function (%)* UKPDS: Beta-cell loss over time Douglas l l l l l l l l l Years From Diagnosis *Dashed line shows extrapolation forward and backward, years to 6 from diagnosis based on homeostasis model assessment (HOMA) data from UKPDS. The data points for the time of diagnosis () and the subsequent 6 years are taken from the obese subset of the UKPDS population and were determined by the HOMA model. UKPDS = United Kingdom Prospective Diabetes Study; OAD = oral antidiabetic drug. Lebovitz HE. Diabetes Rev. 1999;7: Post Hedonism Following a meal patients with poorly controlled diabetes will experience a significant rise in their post glucose values resulting in fatigue, lethargy, moodiness, irritability Overcoming Patients Resistance to Starting Insulin Replacement Therapy If baseline, pre-meal glucose levels are 24 mg/dl, post- glucose (PPG) levels can easily surpass 3 mg/dl Insulin can quickly suppress PPG excursions and improve post hedonism Unger, J. Diabetes Management In Primary Care. Lippincott

6 Common Reasons Why Patients May Resist Insulin Replacement Initiation Addressing Barriers to Insulin Initiation Fear of Needles Feeling of loss of health Insulin causes ill health Belief that insulin is unnecessary Ability to deal with insulin Fear of hypoglycemia Complexity of self-injection and pain Insulin seen as the beginning of the end Mourning related to loss of good health Observations of others (death or complications will follow introduction of insulin) Lack of understanding of disease process Not necessary with stricter dieting and increased exercise Whether the person will handle the equipment Adjust dosing Dealing with different situations Insulin Ignorance Observation of others experiences with insulin Barriers to Insulin Initiation Sense of failure Worsening disease severity Loss of control Perception of insulin ineffectiveness Fear of injections Addressing the Barriers Worsening beta-cell dysfunction is inevitable Insulin replacement expected over time Do not use insulin as threat, but as solution Control hyperglycemia to prevent damage from hyperglycemia Address insulin myths (causes complications, damages the pancreas, etc) Empower patient to take control of blood glucose Monitor glucose and provide self-adjustment algorithms Give limited trial with appropriate insulin doses Monitor for symptom improvement (nocturia, energy level, etc) Insulin pen is less threatening and more user-friendly 4-mm 32-G needles are painless Have patient inject in office Peyrot M et al. Primary Care Diabetes. 21;4(Suppl 1):S11-S18. 2 Addressing Barriers to Insulin Initiation ARS Question Barriers to Insulin Initiation Fear of hypoglycemia Insulin causes weight gain Burden of care and complexity Addressing the Barriers Low incidence, especially with basal analogs Teach patient to recognize and treat (Rule of 15) Start with basal insulin, which is associated with less weight gain More physiologic insulin delivery may minimize weight gain Metformin may offset Start basal insulin once daily Use disposable insulin pens Test once daily before breakfast, and provide simple instructions for insulin adjustment What type of insulin do you usually start with in your practice? 1. Detemir insulin 2. Glargine insulin 3. NPH insulin 4. Premixed insulin 5. Regular insulin 6. Rapid acting analog Peyrot M et al. Primary Care Diabetes. 21;4(Suppl 1):S11-S Physiologic Insulin Secretion Selecting an Insulin Regimen Plasma Insulin Breakfast Lunch Dinner Bolus, Mealtime, Prandial Insulin Start by assessing patient lifestyle, willingness to start insulin, blood glucose data, appropriate targets - Give the option of a 3-month trial - Any insulin will improve glucose control May start with a basal insulin regimen, optimize dose, and intensify with coverage if needed Basal Insulin 4: 8: 12: 16: 2: 24: 4: Time from Kruszynska Y, et al. Diabetologia. 1987; Adapted 3:

7 Insulin Delivery Devices: On-going Evolution 211 Insulin Absorption Variability (Mean Insulin Absorption) Pattern A Pattern B Both patients have identical A1C levels Which patient will most likely have the better longterm outcomes? Hypoglycemia 1945 Hyperglycemia Adapted from: Physiologic insulin replacement therapy. In: Unger Jeff. Diabetes Management in Primary Care. Lippincott, Williams and Wilkins. Philadelphia, PA. 27. P Glucose infusion rate (GIR) profiles following 4 nonconsecutive injections of identical doses (.4U/kg, thigh) in 3 patients Clamp 1 Clamp 2 Clamp 3 Clamp 4 GIR mg/(kg min) Variability in Time-action Profiles of Basal Insulins 8. NPH-insulin 8. Insulin glargine 8. Levemir Patient 1 Patient 2 Patient Time (hours) Time (hours) Time (hours) Insulins Used in Clinical Practice Rapid-acting analogs: Aspart Glulisine Lispro Short-acting insulin: Regular (soluble) Intermediate-acting insulin: NPH Human insulin 7/3: premix Reg/NPH Long-acting insulin: Detemir Glargine Reproduced with permission. T. Heise et al. Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in People With Type 1 Diabetes Diabetes 24;53: Premixed Analogs: Time (hours) Insulin lispro mix 75/25, 5/5 Biphasic insulin aspart 7/3 Adapted from Hirsch I. N Engl J Med. 25;352: Insulin Pharmacodynamics Type of Insulin Onset Peak Duration Appearance Fast-Acting Regular ½ -1 hr 2-4 hr 6-8 hr Clear Rapid-Acting Aspart/ Glulisine/ <15 min 1-2 hr 4-6 hr Clear Lispro Intermediate-Acting NPH 1-2 hr 6-1 hr 12+ hr Cloudy Long-Acting Detemir Glargine 1 hr 1.5 hr Relatively flat, max effect in 5 hr Flat, max effect in 5 hr hr Clear 24 hr Clear Advantages of Insulin Analogs Over Human Insulin: Basal Longer-acting (up to 24 hours) - Once-daily administration - Less variability from day to day Flatter biological activity (less peak) - Lower risk of nocturnal and overall hypoglycemia Less weight gain (insulin detemir) Hirsch IB. N Engl J Med. 25;352(2): Meneghini L et al. Diabetes Obes Metab. 27;9(6): Monami M et al. Diabetes Res Clin Pract. 28;81(2):

8 Advantages of Insulin Analogs Over Human Insulin: Rapid-Acting Starting Once-Daily Basal Insulin More rapid onset of action - Convenient mealtime administration - Better PPG control More rapid return to basal levels - Potentially less hypoglycemia Greater predictability For insulin-naïve patients, start basal insulin with u/kg/day, given once a day, and adjust to achieve goal Example: Douglas weighs 223 lbs Calculate his starting dose of basal insulin: 223 pounds 2.2 = 11 kg.2 units/kg x 11 kg = 2 units basal insulin Handelsman Y et al. Endocr Pract. 211;17(Suppl 2):1-53. Hirsch IB. N Engl J Med. 25;352(2): Meneghini L et al. Diabetes Obes Metab. 27;9(6): ADA. Standards of Medical Care in Diabetes 212. ADA. Diabetes Care 212; 35(1),:S4-S1 32 Monitoring Glycemic Control Insulin Detemir vs. Insulin Glargine Effect on Weight SMBG Treatment adjustment Identify glycemic burden, patterns, and variability Fasting, post, or both Allows for targeting of therapy Education Real-time feedback on glycemic response to diet, activity, and medications Detect hypoglycemia Use for real-time medication (insulin) adjustments A1C Level (%) Glycemic Control Treatment Time (weeks) No difference in hypoglycemia Weight Change (kg) Weight Gain Det QD * Det BID * Det All *P <.1; P =.12 Glarg QD 33 Rosenstock J et al. Diabetologia. 28;51(3): Self-Monitoring of Blood Glucose (SMBG) and Glycemic Control Basal Coverage Can help. Patients and their physicians better adjust therapy and assess responses to therapy Physicians and patients implement a treat-to-target approach Patients correct hyperglycemia and better adhere to treatment Detect and manage hypoglycemia Intermediate-acting insulin: NPH Long-acting insulin: Detemir Glargine Time (hours) 35 Adapted from Hirsch I. N Engl J Med. 25;352:

9 Observational, Open-Label, Treat-to-Target Study: Insulin Detemir vs NPH Insulin Added to Oral Therapy A1C Level (%) Detemir NPH *P <.1 A1C & Weight Changes Weeks +2.6 lb* +6.2 lb 7% of patients achieved A1C < 7% Hypoglycemic Events per Patient per Year Risk of Hypoglycemia P <.1 Overall Detemir + OAD NPH + OAD P <.1 Nocturnal Initiation and Adjustment of Insulin Regimens: Basal Insulin (Analog or NPH) Start once-a-day long-acting insulin analog or NPH bedtime or morning Starting dose: 1 units or.2 units/kg Titrate against FPG until in target range (7-13 mg/dl) Increase dose typically by 2 units every 3 days Can increase dose by 4 units every 3 days if BG > 18 mg/dl If hypoglycemia occurs or if BG < 7 mg/dl: Reduce dose by 4 units, or by 1% if dose > 6 units Yes A1C at goal after 2-3 months? No Hermansen K et al. Diabetologia. 24;47(Suppl 1):A273. Hermansen K et al. Diabetes Care. 26;29(6): Continue regimen, recheck A1C level every 3 months Premixed Intensify Basal-Bolus Adapted from Inzucchi SE et al. Diabetes Care April 19, 212. doi: /dc ARS Question Team Approach to Insulin Initiation Who usually is involved in insulin initiation in your practice? Physician Check all that apply (press <<send>> after each selection) 1. Physician 2. RN/PA/NP Pharmacist Patient Nurse/ Nurse Practitioner/ Physician Assistant 3. Certified diabetes educator (CDE) 4. Dietician 5. Pharmacist Dietitian Certified Diabetes Educator 39 ARS Question From your experience, patients who are provided guidance, eg, self-titration algorithms, can safely and effectively selftitrate insulin therapy. 1. Agree 2. Highly variable, depending on the patient 3. Disagree A1C Level (%) Insulin Glargine: Patient Self-Titration vs Physician Adjusted Frequent contacts with patients (12 in 24 weeks) Mixed-specialty and general medicine clinics Patients to adjust dose by 2 units Q3 days vs weekly adjustments by physicians A1C Level Baseline 24 Weeks Hypoglycemia Patient-Adjusted Physician-Adjusted Patient- Physician- Severe Symptomatic Nocturnal Adjusted Adjusted Increase graph size Davies M et al. Diabetes Care. 25;28(6): Incidence of Hypoglycemia (%)

10 Keys To Insulin Initiation In Primary Care Allow patients to self-titrate 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 utilize and interpret results of selfblood glucose monitoring values. Consider structured glucose testing rather than random glucose testing for all patients Prepare patients to recognize and treat hypoglycemia Insulin Intensification Unger J. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 211: Zisman A, et al. ADA Scientific Sessions. San Diego, CA P 4T: Insulin Initiation in Insulin-Naïve Patients With T2DM 78 patients: Type 2 diabetes A1C 7%-1% Maximum OAD dose Insulin naïve BMI 4 kg/m 2 Prandial insulin = aspart Basal insulin = detemir Premixed insulin = aspart 7/3 Prandial insulin TID Basal insulin OD Premix insulin BID Adapted from Holman RR et al. N Engl J Med. 29;361: Prandial TID + Basal OD Basal OD + TID Premix BID + mid-day Years Sulfonylurea therapy replaced by second insulin in the first year if: A1C 1%, or A1C 8% on 2 consecutive occasions, or A1C > 6.5% at end of year T: Results Most patients required and received intensification by 3 years Basal and insulin starts had more subjects at A1C 7.% at 3 years 1-year results: basal + OAD regimen was associated with less A1C reduction, but also with less hypoglycemia and weight gain - Sufficient intensification of basal dose 3-year results: intensification to basal + coverage achieved similar glycemic control, but maintained the weight and hypoglycemia advantages Holman RR et al. N Engl J Med. 29;361: The Study: Achievement of A1C Targets With Premixed Insulin Analog Therapy Premixed Insulin: Self-titration Algorithm Subjects (Cumulative %) ITT population* (n = 1) Mean baseline A1C level: 8.6% % (AACE) <7.% (ADA) 77 QD BID TID Pre-breakfast and Pre-dinner SMPG Adjustment <8 mg/dl 3 U 8 11 mg/dl No adjustment mg/dl + 3 U mg/dl + 6 U >18 mg/dl + 9 U Glycemic target: pre-breakfast and pre-supper self-monitored plasma glucose (SMBG) value of 8 to 11 mg/dl. *All patients enrolled in the trial. Garber AJ et al. Diabetes Obes Metab. 26;8(1): Oyer DS, INITIATEplus Study Group. Am J Med. 29;122(11):

11 Douglas Six Months Later Fasting vs Post Glucose: Relationship to A1C Level Glargine insulin 55 Units HS Wgt = 1 kg A1C: 7.8% FBG: mg/dl Oral regimen unchanged What is your next strategy? 1. Continue to increase basal dosage 2. Add a dose of premixed insulin 3. Add a dose of insulin prior to largest meal 4. Switch to basal-bolus regimen % Contribution % 7% 5% 5% 55% 45% < >1.2 A1C Range (%) Fasting plasma glucose (FPG) Post plasma glucose (PPG) 6% 4% 7% 3% 49 Monnier L et al. Diabetes Care. 23;26(3): Options When Patient Is Not at Goal With One Injection of Basal Insulin Prandial Coverage Add rapid-acting analog before meals 1% of the basal dose OR Switch to a premixed insulin analog Divide dose in half and give twice daily (before breakfast and dinner) OR Switch to basal-bolus regimen Rapid-acting analogs: Aspart Glulisine Lispro Short acting insulin: Regular (soluble) Time (hours) 51 Adapted from Hirsch I. N Engl J Med. 25;352: OPAL: Sequential Addition of Bolus Insulin at Mealtime: Change in A1C When and how do we get our patients to a basal-bolus regimen? Mean Change in A1C From Baseline to Endpoint Breakfast Group Main-Meal Group -.4 P = Lankisch MR et al. Diabetes Obes Metab. 28;1(12):

12 OPAL: Initial and Study-End Insulin Doses STEPwise: Two Intensification Strategies Insulin Amount (units) Breakfast Start Bolus Basal Breakfast End Main-Meal Start Main-Meal End Basal insulin optimization ExtraSTEP Add 1 st Add 1 st SimpleSTEP Add 2 nd Add 2 nd Add 3 rd Add 3 rd Period 1 Period 2 Period Week Prandial insulin = aspart Basal insulin = detemir s ExtraSTEP: Largest measured PPG increment; target PPG mg/dl SimpleSTEP: Largest perceived meal; target pre mg/dl Lankisch MR et al. Diabetes Obes Metab. 28;1(12): Meneghini L et al. Endocr Pract :1-26 STEPwise: Addition of First Bolus Injection STEPwise Study Conclusions Percentage of Patients (%) Breakfast Lunch Dinner Meneghini et al. Endocr Pract. 211 May 6:1-26 [Epub ahead of print]. ExtraSTEP SimpleSTEP ExtraSTEP group added insulin based on PPG measurement SimpleSTEP group added insulin based on patient assessment 58 Overall reduction in A1C of 1.2% was achieved with the addition of insulin Greatest A1C reductions were achieved with the first and second bolus injections Improvement in glycemic control was comparable in both groups Number of hypoglycemic episodes increased with increasing number of injections Basal-bolus treatment can be introduced in a more patient-friendly approach, using simple stepwise addition of insulin Meneghini, et al. Endocr Pract. 211;6: Question Do you use carbohydrate counting as a method of mealtime insulin adjustment? 1. Yes, it s my standard method for patients to self-titrate 2. Yes, but only with some patients 3. No, never use it Fixed vs Flexible Prandial Insulin Dosing T2DM (n=273) on 2 (36%) or more (64%) insulin injections daily - Baseline: A1C (8.1%-8.3%), BMI (36-37), mean DM duration (13 yr) Randomized to simple algorithm vs. carbohydrate counting Glulysine Adjustments Mean of Last 3-Day Fasting SMBG (mg/dl) Adjustments >18 Increase 8 units Increase 6 units Increase 4 units Increase 2 units 7-94 No change Decrease by the same number of units that insulin glulisine <7 was increased for that titration week, or decrease to 1% of the total insulin glargine dose 6 Bergenstal R et al. Diabetes Care. 28;31:

13 Simple Algorithm vs Carbohydrate Counting For Mealtime Insulin Adjustment A1C % BG (mg/dl) Baseline Week 25 BASELINE WEEK 24 Simple Algorithm Group Carb-Count Group Insulin dose: vs. 1.7 U/kg/d for simple vs. carb counting (P <.2) Weight gain: vs. 2.4 kg for simple vs. carb counting (P =.6) Question The result of the pre dinner finger-stick (FS) value determines the adjustment to make in: 1. Basal insulin 2. Breakfast insulin 3. Lunch insulin 4. Dinner insulin Bed Bergenstal R et al. Diabetes Care. 28;31: Suggested Basal-Bolus Adjustments: ± 2-Unit Changes Done Weekly Fix vs Flex Regimens Plasma Insulin (µu/ml) Prandial + correction Prandial + correction Prandial + correction Basal Bolus Basal daily Education Blood glucose measurement Insulin dose adjustment Fix Basic education.5 to 2 glucose profiles per week Only with the investigator during the visits Flex Basic education + carbohydrates + meal-dependent insulin dosing Daily glucose profile Self-adjustment every day FS FS FS FS 4: 8: 12: 16: 2: 24: 4: 8: Adjust basal insulin Adjust AM Adjust lunch Adjust dinner Carbohydrate-dependent dosing Insulin for blood glucose correction purposes Milek K et al. Diabetologia. 27;5(Suppl 1):S412. No No Yes, at every meal Yes, at every meal Paired Glucose Testing Can Provide Valuable Information to Patient Post-meal Delta Value >5 mg/dl >1 mg/dl Interpretation Not enough insulin used to cover carbs Insulin lag time not utilized Illness (flu) Snacking between the meal and 2-hour check time Forgot to give insulin (especially if delta >2 mg/dl) Insulin has expired or is denatured Insulin antibodies forming Insulin-to-carb mismatch Fasting Post- Pre- Post- Pre- Post- Brkfst Lunch Lunch Dinner Dinner -Investigational- Ultra Long-Acting Insulin <5 mg/dl Too much insulin (watch for hypoglycemia) Alcohol use (decreases gluconeogenesis) Insulin stacking: consider this option when the delta is NEGATIVE at 2 hours! 11

14 Ultra Long-Acting Insulin: Protracted Action Based on Formation of Multi-Hexamers Duration of Action Monomer Hexamer Molecular size Multi-hexamers Kurtzhals P, Heise T, Strauss HM, et al. American Diabetes Association 71 st Annual Scientific Sessions Abstract 42-LB. 68 Degludec Plus Metformin in T2DM versus Glargine HbA 1c (%) N= Zinman B, et al. Lancet. 211 Mar 12;377(9769): Weeks since randomization Degludec OD Degludec 3TW Glargine OD 7.4 (.1)% 7.3 (.1)% 7.2 (.1)% 69 Degludec Plus Metformin in T2DM vs. Insulin Glargine Patients With Confirmed Hypoglycemia* 25% 23% 23% Summary: Selecting Insulin Therapies Starting Strategy Basal Insulin + Oral Agent(s) Basal-Bolus Insulin Sensitizer(s) Starting Strategy Premixed Insulin Sensitizer(s) 2% 15% 1% 5% 8% % Degludec once daily Degludec three times Glargine once daily N= 236 weekly *Plasma glucose <56 mg/dl or Zinman B, et requiring assistance al. Lancet. 211 Mar 12;377(9769): Earlier stages of T2DM Elevated FPG Stable daytime BG Single daily injection Detemir Glargine NPH if cost an issue Gold standard but more complicated More flexible Long-acting: Detemir Glargine + Rapid-acting: Aspart Lispro Glulisine Elevated PPG 1-3 times per day Premixed : Human premix 7/3 Analogs Insulin lispro mix 75/25, 5/5 Biphasic insulin aspart 7/3 Self-mix: Rapid-acting analog or regular + NPH 71 Take Home Points Insulin therapy usually is needed if A1C level is > 8.% and blood glucose levels are not controlled on multiple OADs In most situations, first address the fasting blood sugars with basal insulin therapy - Monitor blood glucose and optimize insulin doses - Continue OADs or adjust dosages if necessary Start bolus insulin at the largest meal or the one with the highest post blood glucose levels (usually breakfast) Fixed insulin doses are effective and safe for basal/bolus therapy in type 2 diabetes Encourage and empower your patients! 72 Post-test Question #1 In patients on oral T2DM agents, at what A1C level should insulin therapy be initiated? 1. >7.5% 2. >8.% 3. >8.5% 4. >9.% 5. Any of the above 73 12

15 Post-Test Question #2 You seek to initiate insulin therapy in a poorly-controlled patient but she thinks this will be too complex for her to do. How will you address this? Check all that apply (press <<send>> after each selection) 1. Tell her that insulin is her only option at this point in time 2. Institute self-adjustment algorithms with glucose monitoring 3. Start with basal insulin twice daily 4. Address insulin myths that it causes complications, damages the pancreas 5. Institute a pre-mixed fixed-dose insulin regimen Post-Test Question #3: A pre-/post- blood glucose delta value that s less than 5 mg/ml might indicate: 1. Concurrent illness, eg, flu 2. Missed previous insulin dose 3. Previous insulin dose is too high 4. Insulin solution has expired or is denatured Questions 13