Session 3: Insulin Strategies for Primary Care Providers: Addressing a Core Defect in Diabetes Learning Objectives

Transcription

1 Session 3: Insulin Strategies for Primary Care Providers: Addressing a Core Defect in Diabetes 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 targets.

2 Session 3 Insulin Strategies for Primary Care Providers: Addressing a Core Defect in Diabetes Faculty Luigi Meneghini, MD, MBA Professor of Clinical Medicine Director, Kosow Diabetes Treatment Center Diabetes Research Institute University of Miami Leonard M. Miller School of Medicine Miami, Florida Luigi Meneghini is professor of clinical medicine and director of the Kosow Diabetes Treatment Center at the University of Miami Miller School of Medicine in Miami, Florida. He has also serves as director of the Southeastern Florida Regional Diabetes Program, a state grant that supports diabetes patient education programs at the University of Miami. Dr Meneghini s primary interests lie in improving the metabolic control of patients with diabetes through the application of cutting edge drug therapies and technologies, and the implementation of these management strategies through patient and professional education activities. He has been actively involved in testing new therapies and better defining their role within the treatment paradigm for patients with type 1 and type 2 diabetes. Recognizing the importance of patient education, Dr Meneghini has been a strong advocate and promoter of the state-of-the-art diabetes education center at the Kosow Center at the Diabetes Research Institute. Over a decade ago, he was instrumental in adapting an innovative European educational approach to intensive insulin management, which places expertise and problem solving skills in the hands of the patient with diabetes. The program, renamed Mastering Your Diabetes (MYD), has since been translated and exported to several collaborative institutions in Italy, with the ultimate goal of expanding its worldwide reach and accessibility through interactive web-based technologies. Dr Meneghini is a frequent lecturer, and has published multiple articles on diabetes and insulin management in peer-reviewed medical journals. He is actively involved in clinical research, much of which revolves around the application of insulin formulations and algorithms in both the outpatient and hospital setting. He has presented numerous projects at the Scientific Sessions of the American Diabetes Association, many of which involved mentoring of physicians in training and junior faculty. He is a native of Italy, grew up in Liberia (West Africa) and speaks Italian, French, English, and Spanish fluently. Faculty Financial Disclosure Statement The presenting faculty report the following: Dr Meneghini serves on the advisory panel and is a consultant for Novo Nordisk Inc., and receives research support from MannKind Corporation, Pfizer Inc., and Boehringer Ingelheim Pharmaceuticals, Inc.

3 Session 3 Suggested Reading List Bergenstal R et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm to carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care. 2;31: Davies M et al. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2 ;2: Meneghini L et al. Comparison of 2 intensification regimens with rapid-acting insulin aspart in type 2 diabetes mellitus inadequately controlled by once-daily insulin detemir and oral antidiabetes drugs: the step-wise randomized study. Endocr Pract. 211; May :1-2. Peyrot M et al. Addressing barriers to initiation of insulin in patients with type 2 diabetes. Primary Care Diabetes. 21;(Suppl 1):S11-S1. Wagner JA et al. Beliefs about Racism and Health among African American Women with Diabetes: A Qualitative Study. J Natl Med Assoc. 211;13(3):

4 Faculty Disclosure Session 3 1: AM 12:1 PM Insulin Strategies for Primary Care Providers: Tools to Address a Core Defect in Diabetes Dr Meneghini serves on the advisory panel and is a consultant for Novo Nordisk Inc., and receives research support from MannKind Corporation, Pfizer Inc., and Boehringer Ingelheim Pharmaceuticals, Inc. Luigi Meneghini, MD, MBA Professor of Clinical Medicine Director, Kosow Diabetes Treatment Center Diabetes Research Institute University of Miami Leonard M. Miller School of Medicine Miami, Florida 2 Learning Objectives Drug List 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 targets. Generic name Metformin Glimepiride Simvastatin Aspirin Colesevelam Insulin detemir Insulin aspart Insulin lispro Insulin glulisine Insulin injection regular Trade name(s) Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet Amaryl Zocor various Welchol Levemir NovoLog Humalog Apidra Humulin R, Humulin R U-, Novolin R Humulin N, Novolin N Insulin isophane suspension (NPH) Insulin lispro mix 7/2 Humalog Mix 7/2 Insulin lispro mix / Humalog Mix / Biphasic insulin aspart 7/3 NovoLog Mix 7/3 3 Case Study: Doug 2-Year-Old African-American Man Cultural Insights: African Americans and Diabetes Doug came to establish his care at the office - -year history of type 2 diabetes - Grocery store clerk; children ranging in age from -1 years in the home, including 1 grandchild - Does not follow any meal plan - Obese; no regular physical activity Current medications (unchanged x 3 years) - Metformin 1 mg BID - Glimepiride mg QD - Simvastatin mg/day - Aspirin 1 mg/day Etiology: - Belief that sugar or sweet blood is caused by imbalance in eating (too much sugar and starchy foods) - Belief that legacy of slavery and segregation may play a role in onset of diabetes Severity: - Continuum of intensity A diagnosis of sugar being less serious than one of diabetes - Stress or worry may worsen sugar Common treatments: - Prayer, trusting in God - Use of bitter foods and herbs (lemon juice, garlic, juniper berries) to neutralize blood BID = twice daily; QD = once daily. Tripp-Reimer T. Diabetes Spectr. 21;1: Wagner JA et al. J Natl Med Assoc. 211;13:

5 Barriers to Physical Activity for African Americans Unsafe walking areas Transportation problems Lack of child care Peripheral neuropathy Degenerative joint disease 2 Age-Adjusted Estimates of the Percentage of Adults Who Are Physically Inactive Dutton GR et al. Diabetes Care. 2;2(): Pre-Test Question #1: If following the ADA/EASD recommendations, which well-validated medication should be added when the combination of lifestyle management and metformin therapy no longer achieves the desired glycemic control? 1. Basal insulin 2. DPP- inhibitor 3. GLP-1 agonist. TZD ADA/EASD Consensus Statement Recommendations Continue Current Management Add Sulfonylurea Hypoglycemia if not dosed near meal No Diagnosis of Type 2 Diabetes Lifestyle Intervention + Metformin A1C 7% Tier 1 Yes Tier 2 Add Basal Insulin Add Glitazone (TZD) Contraindicated in patients with heart failure or heart disease Renal function Relative contraindication in very elderly Add GLP-1 Agonist ADA = American Diabetes Association EASD = European Association for the Study of Diabetes. 9 Adapted from Nathan DM et al. Diabetes Care. 29;32(1): Stepwise Treatment of T2DM Pre-Test Question #2: Insulin Initiation Intensification Basal Add basal insulin and titrate Additional OADs ± Incretins Lifestyle Changes + Metformin Further Intensification Basal-Bolus Basal Plus Add insulin at main meal In patients on oral antidiabetic agents, at what A1C level should insulin therapy be initiated? 1. 7.% 2..% 3..%. 9.%. Over 9.% Progressive deterioration of beta-cell function

6 A1C. 7.% Monotherapy MET DPP GLP-1 TZD AGI A1C 7. 9.% Dual Therapy GLP-1 or DPP Drug Naive A1C > 9.% This is a really bad slide to read and understand. Way Symptoms No Symptoms Too much information. For next iteration, needs to be redone Dual or Triple Therapy Under Treatment A1C Goal.% SOLVE: Baseline A1C Distribution at Insulin Initiation 1 1.9% 2-3 Mos. MET + or TZD SU or Glinide INSULIN ± Other Agent(s) GLP-1 or DPP ± SU INSULIN ± Other Agent(s) 1 MET + Dual Therapy 2-3 Mos. Triple Therapy MET + TZD GLP-1 or + DPP Glinide or SU INSULIN ± Other Agent(s) GLP-1 or DPP TZD Glinide or SU TZD + GLP-1 or DPP MET + Colesevelam AGI 2-3 Mos. MET Mos. Triple Therapy GLP-1 or DPP GLP-1 or DPP TZD INSULIN ± Other Agent(s) + TZD + SU 2-3 Mos. MET + Adapted and modified from: TZD GLP-1 or DPP ± TZD AGI α-glucosidase Inhibitor DPP DPP- Inhibitor GLP-1 Incretin Mimetic Met Metformin SU Sulfonylurea TZD Thiazolidinedione Rodbard H, Jellinger P et al. Endocrine Practice, 29 Sept/Oct; 1 (): Patients (%) A1C (%) Khunti K et al, for the SOLVE Study Group. Diabetes. 211; (Suppl 1):A3. 1 The Insulin Paradox Insulin Many patients have high blood glucose levels, which put them at risk for complications AND Insulin is the most powerful medication for lowering blood glucose BUT Most potent agent to lower glucose (dose is limited only by hypoglycemia) Addresses core defect of T2DM Increasingly needed as patients with T2DM live longer - Increased beta-cell failure with increasing duration of disease No longer reserved for last-line use Many patients with poor glycemic control do not receive insulin treatment 1 1 Pre-Test Question #3: Which of the following is NOT true about the need for timely initiation of insulin therapy in patients with type 2 diabetes? 1. Insulin therapy can reduce the risk of diabetes-related complications 2. Insulin therapy is likely to be needed by a majority of patients with type 2 diabetes over the course of their lifetime 3. Type 2 diabetes is characterized by insulin resistance and insulin deficiency, with insulin deficiency increasing over time. Patients should be told that the need for insulin therapy indicates that they have not taken the appropriate steps (eg, sufficient weight loss and exercise, compliance to OAD therapy) to control their diabetes 17 Changes in A1C and Glycemic Burden (in months) A1C (%) Brown JB et al. Diabetes Care. 2;27:13-1. Pre-Tx A1C Best Rx A1C Last Rx A1C Diet & Exercise N = 2319 SU N = 339 MET N = 13 SU + MET N = 92 A1C > % (mo) A1C > 7% (mo) Insulin 9.% 1 3

7 Are Patients With T2DM Reluctant to Start Insulin Therapy? Anxiety About Starting Insulin Is Associated With Self-Blame Percentage Willingness to Start Insulin/ Psychological Insulin Resistance Unwilling Ambivalent Willing Factors Related to Psychological Insulin Resistance Among Ambivalent or Unwilling Patients More negative and fewer positive beliefs about starting insulin More negative feelings about their current medications More diabetes-related distress Percentage of patients worried about starting insulin 1 2 Patients with low self-blame 1 2 Patients with high self-blame 73 N = 1. Polonsky WH et al. Curr Med Res Opin. 211;27(): Peyrot M et al. Diabetes Care. 2;2: Identify Patient Barriers Patient Barriers Ask patient, listen to response, and confirm answer What is the hardest thing about taking care of your diabetes? What concerns or worries do you have about using insulin to treat your diabetes? Sense of personal failure Worsening disease severity Loss of control Perception of insulin ineffectiveness Injection-related anxiety Fear of hypoglycemia or weight gain Burden of care and complexity (injecting, testing) 21 Peyrot M et al. Primary Care Diabetes. 21;(Suppl 1):S11-S1. 22 Addressing Barriers to Insulin Initiation PATIENTS WHO ARE NOT MANAGING THEIR DIABETES WELL ARE SIGNIFICANTLY MORE LIKELY TO SEE INSULIN THERAPY AS POTENTIALLY BENEFICIAL 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 -mm 32-G needles are painless Have patient inject in office Peyrot M et al. Diabetes Care. 2;2: Peyrot M et al. Primary Care Diabetes. 21;(Suppl 1):S11-S1. 2

8 Addressing Barriers to Insulin Initiation Selecting an Insulin Regimen 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 1) Starting with basal insulin, especially detemir, 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 Start by assessing patient lifestyle, willingness to start insulin, blood glucose data, appropriate targets - Give the option of a 3-month trial - Remember: Any insulin will improve glucose control May start with a basal insulin regimen, optimize dose, and intensify with coverage if needed Peyrot M et al. Primary Care Diabetes. 21;(Suppl 1):S11-S Selecting Insulin Therapies Starting Strategy Basal Insulin + Oral Agent(s) Basal-Bolus Insulin ± Sensitizer(s) Starting Strategy Premixed Insulin ± Sensitizer(s) 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 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 May be used 1, 2, or 3 times a day Premixed : Human premix 7/3 Analogs Insulin lispro mix 7/2, / Biphasic insulin aspart 7/3 Self-mix: Rapid-acting analog or regular + NPH Titrate against FPG until in target range (7-13 mg/dl) Increase dose typically by 2 units every 3 days Can increase dose by units every 3 days if BG > 1 mg/dl If hypoglycemia occurs or if BG < 7 mg/dl: Reduce dose by units, or by 1% if dose > units Yes Continue regimen, recheck A1C level every 3 months A1C level < 7% after 2-3 months? Premixed No Intensify Basal-Bolus T2DM = type 2 diabetes mellitus; FPG = fasting plasma glucose; BG = blood glucose; PPG = post glucose. 27 Adapted from Nathan DM et al. Diabetes Care. 29;32(1): Insulin Pharmacodynamics Type of Insulin Fast-Acting Onset Peak Duration Appearance Regular ½-1 hr 2- hr - hr Clear Rapid-Acting Aspart/ Glulisine/ Lispro Intermediate-Acting <1 min 1-2 hr - hr Clear NPH 1-2 hr -1 hr 12+ hr Cloudy Insulins Used in Clinical Practice: Prandial Coverage Rapid-acting analogs: Aspart Glulisine Lispro Shortacting insulin: Regular (soluble) Long-Acting Detemir Glargine 1 hr 1. hr Relatively flat, max effect in hr Flat, max effect in hr 12-2 hr Clear 2 hr Clear 29 Adapted from Hirsch I. N Engl J Med. 2;32: Time (hours) 3

9 Advantages of Insulin Analogs Over Human Insulin: Rapid-Acting Insulins Used in Clinical Practice: Basal Coverage More rapid onset of action - Convenient mealtime administration - Better PPG control More rapid return to basal levels - Potentially less hypoglycemia Greater predictability Rapid-acting analogs: Aspart Glulisine Lispro Shortacting insulin: Regular (soluble) Intermediate-acting insulin: NPH Long-acting insulin: Glargine Detemir PPG = post glucose. Hirsch IB. N Engl J Med. 2;32(2): Meneghini L et al. Diabetes Obes Metab. 27;9(): Time (hours) Adapted from Hirsch I. N Engl J Med. 2;32: Advantages of Insulin Analogs Over Human Insulin: Basal Insulins Used in Clinical Practice: Mixed Coverage Longer-acting (up to 2 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) Rapid-acting analogs: Aspart Glulisine Lispro Short-acting insulin: Regular (soluble) Intermediate-acting insulin: NPH Human insulin (HI) 7/3 premix Long-acting insulin: Glargine Detemir Premixed Analogs Insulin lispro mix 7/2, / Biphasic insulin aspart 7/3 Hirsch IB. N Engl J Med. 2;32(2): Meneghini L et al. Diabetes Obes Metab. 27;9(): Monami M et al. Diabetes Res Clin Pract. 2;1(2): Time (hours) Adapted from Hirsch I. N Engl J Med. 2;32: Delayed Biologic Action of Rapid-Acting Analogs in Obese Patients With T2DM ARS Question Glucose Infusion Rate (mg/kg/min) 1 2 1u Controls u T2DM 3u T2DM 1u T2DM Time (minutes) What type of insulin do you usually initiate in your practice? 1. Detemir insulin 2. Glargine insulin 3. NPH insulin. Premixed insulin Gagnon-Auger M et al. Diabetes Care. 21;33:

10 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. lb* +.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 A1C Level (%) 2-Week Treat-to-Target Trial: Insulin Detemir vs. Insulin Glargine 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 Hermansen K et al. Diabetologia. 2;7(Suppl 1):A273. Hermansen K et al. Diabetes Care. 2;29(): Rosenstock J et al. Diabetologia. 2;1(3):-1. 3 Starting Once-Daily Basal Insulin Monitoring Glycemic Control For insulin-naïve patients, start basal insulin with 1 U/day or.2 u/kg/day, given once a day, and adjust to achieve goal Example: DS weighs 23 lbs Calculate her starting dose of basal insulin: 23 pounds 2.2 = 12 kg.2 units/kg x 12 kg = 2 units basal insulin Adapted from Starting and Adjusting Insulin, International Diabetes Center, 2. Riddle MC, et al. Diabetes Care. 23;2: A1C Risk assessment - Overall glycemic exposure for previous 2-3 months - Best assessment of vascular (especially microvascular) risk 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 SMBG = self-monitoring of blood glucose SMBG and Glycemic Control ARS Question 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 Who usually is involved in insulin initiation in your office? 1. Just myself 2. Myself, plus nurse 3. Myself, plus certified diabetes educator. Myself, plus referral to dietitian. All of the above 1 2 7

11 Team Approach to Insulin Initiation Pharmacist Physician Patient Nurse/ Nurse Practitioner/ Physician Assistant Project Dulce: Peer-Led Diabetes Education Programs in High-Risk Mexican Americans A1C (%) P =.1 P <.1 P =. P <.1 Project Dulce Peer Education Control -2. Dietitian Certified Diabetes Educator -3 Baseline Month Month 1 3 Philis-Tsimikas A et al. Diabetes Care. 211;3: Project Dulce: Adding Basal Insulin Results in Additional Improvement in Diabetes Control A1C (%) * Baseline 7.9 Community-Based Diabetes Program ** 7.3 Community-Based Diabetes Program + Basal Insulin Pre-Test Question #: Patients who are provided guidance can safely and effectively self-titrate insulin therapy. 1. True 2. False *P <.1 vs. baseline **P <.1 vs. pre-glargine Philis-Tsimikas A et al. Am J Ther. 2;13():-72. ARS Question Do you provide patients with self-titration algorithms so they can adjust their own basal insulin dose? 1. Yes 2. No 3. Sometimes A1C Level (%) Patients Can Safely and Effectively Self-Titrate Insulin Glargine Frequent contacts with patients (12 in 2 weeks) Mixed-specialty and general medicine clinics Patients to adjust dose by 2 units Q3 days vs weekly adjustments by physicians A1C Level Patient- Adjusted 7.9 Physician- Adjusted Baseline 2 Weeks Incidence of Hypoglycemia (%) Hypoglycemia Patient-Adjusted Physician-Adjusted Severe Symptomatic Nocturnal 7 Davies M et al. Diabetes Care. 2;2():

12 Self-Titration of Insulin Detemir: PREDICTIVE 33 Study Design: randomized 2-week study comparing physician-directed vs. patient-directed dose adjustment of basal insulin Subjects: type 2 diabetes Outcomes: safety and efficacy FPG (mg/dl) Dose adjustments every third day Response < Reduce dose by 3 units 3-11 No change >11 Increase dose by 3 units 3 FPG = fasting plasma glucose. Meneghini L et al. Diabetes Obes Metab. 27;9: Patient Self-Titration vs. Physician-Adjusted: A1C and Fasting Glucose in T2DM Treated With Long-Acting Insulin Detemir A1C Level (%) *P =.1 **P <.1 A1C * ** ** 19 ** ** Self-Adjusted N = 21 Physician-Adjusted N = 27 Baseline FPG = fasting plasma glucose. Meneghini L et al. Diabetes Obes Metab. 27;9: FBG (mg/dl) Months Self-Adjusted N = 2392 FBG ** Physician-Adjusted N = 29 Insulin-Naïve Subset of the PREDICTIVE 33 Study Final Basal Insulin Doses in Treat-to-Target Trials A1C (%) * * * * 33 Algorithm Standard of Care Day 1 Week 12 Week 2 Trial Riddle et al, 23 Mean Weight -Adjusted Insulin Dose (U/kg) Insulin glargine. NPH insulin.2 Philis-Tsimikas et al, 2 Insulin detemir PM. NPH insulin PM. AT.LANTUS Davies et al, 2 Insulin glargine (patient-directed). Insulin glargine (physician-directed). TITRATE Blonde et al, 29 Insulin detemir (FPG target 3.9-.).7 Insulin detemir (FPG target.-.1).1 Selam JL et al. Curr Med Res Opin. 2;2: Basal Insulin Initiation and Optimization Start 1-2 units of glargine or detemir at HS - Use NPH if cost is an issue Continue OADs unless a specific contraindication exists Titrate dose based on fasting BG target - ADA: < 13 mg/dl If A1C is still not at goal with.-. U/kg/day, consider adding coverage What regimen should we use for insulin intensification? Adapted from Nathan DM et al. Diabetes Care. 29;32(1):

13 At 12-Month follow-up visit with Doug, A1C is 7.% on NPH, 3 Units before dinner A1C Level Reflects PPG and FPG What is your next strategy? 1. Continue to increase the dinner dosage 2. Add a second dosage of premixed insulin 3. Switch to basal insulin analog. Add a dose of insulin prior to largest meal. Switch to basal-bolus regimen Glucose Concentration (mg/dl) Breakfast A1C 9% A1C.%.9% A1C 7.% 7.9% A1C.%.9% A1C <.% Time (hours) Monnier L. Diabetes Care. 27;3(2): Fasting vs. Post Glucose: Relationship to A1C Level Options When Patient Is Not at Goal With One Injection of Basal Insulin % Contribution 1 2 3% 7% % % % % A1C Range (%) Fasting plasma glucose (FPG) Post plasma glucose (PPG) % % 7% 3% < >1.2 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 Monnier L et al. Diabetes Care. 23;2(3):1-. 7 Optimizing and Intensifying Single dose OPAL study Optimize basal insulin dose Sequential doses STEPwise study Full coverage Fixed vs. flexible doses T study Fix vs. Flex B/B Premixed insulin therapy PREFER study study INITIATE study INITIATE plus study T: Insulin Initiation in Insulin-Naïve Patients With T2DM 7 patients: Type 2 diabetes A1C 7%-1% Maximum OAD dose Insulin naïve BMI kg/m 2 Prandial insulin = aspart Basal insulin = detemir Premixed insulin = aspart 7/3 Prandial insulin TID Basal insulin OD Premix insulin BID Prandial TID + Basal OD Basal OD + TID Premix BID + mid-day Years SU therapy replaced by second insulin in the first year if: A1C 1%, or A1C % on 2 consecutive occasions, or A1C >.% at end of year 1 9 TID = three times daily; OD = once daily; BID = twice daily. Adapted from Holman RR et al. N Engl J Med. 29;31:

14 T: Most Patients Required and Received Intensification by 3 Years T: At 3 Years, A1C Reduction Was Similar in All 3 Insulin Groups Patients (%) Subjects eligible for a second type of insulin per protocol P =.7 1 P =.7 P = Premix Prandial Basal Start Group Start Group Start Group Patients (%) Subjects taking 2 types of insulin Premix + Prandial P =.1 P <.1 Prandial + Basal P =.37 Basal + Prandial Glycated Hemoglobin (%) 9 7 Median ± 9% confidence interval Years Premix ± Prandial Prandial ± Basal Basal ± Prandial Overall.9% (.-7.1) Adapted from Holman RR et al. N Engl J Med. 29;31: Adapted from Holman RR et al. N Engl J Med. 27;37: Adapted from Holman RR et al. N Engl J Med. 29;31: T: Basal and Prandial Insulin Starts Had More Subjects at A1C 7.% at 3 Years T: Basal Insulin Starts Resulted in Less Hypoglycemia After 1 Year and Cumulatively Year 1 Year 3 2 Basal ± Prandial Prandial ± Basal Premix ± Prandial Patients (%) Reaching A1C 7% 2 *P <.1 vs. basal at year 1 P <. vs. premix at year 3 * * Premix ± Prandial Prandial ± Basal Basal ± Prandial Patients with Hypoglycemia (%) Years Holman RR et al. N Engl J Med. 27;37: Holman RR et al. N Engl J Med. 29;31: Holman RR et al. N Engl J Med. 27;37: Holman RR et al. N Engl J Med. 29;31: T: Basal Insulin Starts Resulted in Less Weight Gain Over 3 Years T: Conclusions Weight Change From Baseline (kg) *.7 **.7 *.7 **. Premix ± Prandial Prandial ± Basal Basal ± Prandial 1.9 Year 1 Year 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 *P <. vs. basal ± P =. vs. ± ID Holman RR et al. N Engl J Med. 27;37: Holman RR et al. N Engl J Med. 29;31:

15 PREFER: A1C Reduction in Insulin-Naïve vs. Insulin-Treated Patients PREFER: Total Daily Doses Change in A1C (%) Insulin naïve Premix BID Basal/Prandial TID.%.1% 7.7%.92% P = Previous insulin Premix BID Basal/Prandial TID.17% 7.7% P =.129.2% 7.% Baseline-corrected treatment difference Mean Daily Insulin Dose (U/kg) Premix Basal Prandial Randomization weeks weeks weeks weeks Total at end of trial:.31. Prandial dose split: 1/3-1/3-1/3 Premix dose split: 1/2 1/2 Liebl A et al. Diabetes Obes Metab. 29;11:-2. 7 Liebl A et al. Diabetes Obes Metab. 29;11:-2. PREFER Sub-Analysis: Hypoglycemia Rate in Patients Previously Treated With Insulin PREFER: Conclusions Hypoglycemia Premix Basal/ Prandial Major (n) 1 Incidence of minor* (events/subject/year) Incidence of nocturnal minor (events/subject/year) Between-treatment differences not significant. *Confirmed by plasma glucose <3.1 mmol/l. Calculated for the final 2 weeks of the study Both insulin analog regimens enabled patients with type 2 diabetes to achieve A1C < 7.% Rates of hypoglycemia were low and comparable between analog regimens Insulin-naïve patients achieved equal glycemic control with a premixed analog regimen or a basal-bolus regimen Patients who did not reach target A1C on NPH or glargine (+OADs) benefited more from intensification to basalbolus than to premix insulin Liebl A et al. Diabetes. 21;9(Suppl 1):A12. 9 Liebl A et al. Diabetes Obes Metab. 29;11:-2. 7 A1C Level (%) INITIATE: Basal Analog vs. Premixed Analog Change in A1C Level From Baseline to Study End Baseline Endpoint P < % 7.% Insulin Glargine + OADs 2.% 9.7% Raskin P et al. Diabetes Care. 2;2(2):2-2..9% Biphasic Insulin Aspart 7/3 2.% Episodes per Patient Year Documented Hypoglycemic Episodes (< mg/dl) P <..7 Insulin Glargine + OADs 3. Biphasic Insulin Aspart 7/3 Total units = 1.3 ± 2.7 with glargine plus OADs vs. 7. ± 39. with premixed insulin 71 The Study: Achievement of A1C Targets With Premixed Insulin Analog Therapy Subjects (Cumulative %) *All patients enrolled in the trial. Garber AJ et al. Diabetes Obes Metab. 2;(1):-. ITT population* (n = 1) Mean baseline A1C level:.%.% (AACE) <7.% (ADA) 72 12

16 A1C Level Control in a Primary Care Setting: Self-Titrating an Insulin Analog Premix (INITIATEplus trial) Initiated twice-daily biphasic insulin aspart 7/3 with units pre-breakfast and units pre-supper, self-titrating according to self-measured blood glucose values. Subjects were randomized (1:1:1) to telephone counseling provided by a registered dietitian. A1C Reduction Patients Achieving A1C Goal (<7%) Premixed Insulin: Self-titration Algorithm Pre-breakfast and Predinner SMPG < mg/dl 3 U Adjustment 11 mg/dl No adjustment mg/dl + 3 U 11 1 mg/dl + U >1 mg/dl + 9 U Gylcemic target: pre-breakfast and pre-supper self-monitored plasma glucose (SMPG) value of to 11 mg/dl. Hypoglycemia was experienced by 1.2% to 11.% of the subjects in each group. Rates of minor and major hypoglycemia were low, but decreased as dietary counseling increased. Oyer DS, INITIATEplusStudy Group. Am J Med. 29;122(11): Oyer DS, INITIATEplusStudy Group. Am J Med. 29;122(11): Premixed vs. Basal-Bolus Patients to Target A1C < 7. (%) Premix Basal-bolus When and how do we get our patients to a basal-bolus regimen? Liebl et al, 29 Hirao et al, 27 Rosenstock et al, OPAL: Sequential Addition of Bolus Insulin at Mealtime: Change in A1C OPAL: Initial and Study-End Insulin Doses Mean Change in A1C From Baseline to Endpoint P =. Breakfast Group Main-Meal Group Insulin Amount (units) Breakfast Start Bolus Basal Breakfast End Main-Meal Start Main-Meal End Lankisch MR et al. Diabetes Obes Metab. 2;1(12): Lankisch MR et al. Diabetes Obes Metab. 2;1(12):

17 STEPwise: Change in A1C STEPwise: Change in A1C A1C (%) Change to Week Change to Week 23 Change to Week 3.9%.7% ExtraSTEP SimpleSTEP Basal insulin optimization EXTRA STEP Add 1 st Add 1 st SIMPLE STEP Add 2 nd Add 2 nd Period 1 Period 2 Add 3 rd Largest measured PPG increment; target PPG 72-1 mg/dl ( mmol/l) Largest perceived meal; target pre 72-1 mg/dl ( mmol/l) Add 3 rd Period Change was adjusted for baseline A1C P = NS Weeks Inclusion criteria: Type 2 diabetes > months with A1C 7.-1.%on basal insulin 3 months +1 3 OADs Prandial insulin = aspart Basal insulin = detemir Meneghini L et al. Endocr Pract. 211; May :1-2 [Epub ahead of print]. 79 Meneghini L et al. Endocr Pract. 211; May :1-2 [Epub ahead of print]. STEPwise: Overall Hypoglycemia Rates STEPwise: Addition of First Bolus Injection Hypoglycemia Rate (episodes/year) P = NS.1. P = NS.7.9 Major Minor Nocturnal Week 3 P = NS ExtraSTEP SimpleSTEP Nocturnal diurnal rates include all hypoglycemia (including unclassified and symptoms only). Percentage of Patients (%) Breakfast Lunch Dinner ExtraSTEP SimpleSTEP ExtraSTEP group added insulin based on PPG measurement SimpleSTEP group added insulin based on patient assessment During the trial, only major hypoglycemic episodes were reported (for 2 patients in the SimpleSTEP group, and 1 episode in 1 patient in the ExtraSTEP group). Meneghini L et al. Endocr Pract. 211; May :1-2 [Epub ahead of print]. 1 Meneghini et al. Endocr Pract. 211 May :1-2 [Epub ahead of print]. 2 STEPwise Study Conclusions An overall reduction in A1C of 1.2% was achieved with the addition of insulin The greatest A1C reductions were achieved with the first and second bolus injections Improvement in glycemic control was comparable in both groups Can basal-bolus regimens be simplified? The 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 May :1-2 [Epub ahead of print]. 3 1

18 Restaurant ARS Question Do you teach carbohydrate counting to patients with T2DM? 1. Yes 2. No 3. I have other team members teach carbohydrate counting (eg, dietitian) Fixed vs. Flexible Prandial Insulin Dosing T2DM (n=273) on 2 (3%) or more (%) insulin injections daily - Baseline: A1C (.1%-.3%), BMI (3-37), mean DM duration (13 yr) Randomized to simple algorithm vs. carbohydrate counting Glargine Adjustments Mean of Last 3-Day Fasting SMBG (mg/dl) Adjustments >1 Increase units 1-1 Increase units Increase units Increase 2 units 7-9 No change <7 Decrease by the same number of units that insulin glulisine was increased for that titration week, or decrease to 1% of the total insulin glargine dose Bergenstal R et al. Diabetes Care. 2;31: A1C % BG (mg/dl) Fixed vs. Flexible Prandial Insulin Dosing Baseline Week BASELINE WEEK Bergenstal R et al. Diabetes Care. 2;31: Fasting Post- Brkfst Pre- Lunch Post- Lunch Pre- Dinner Post- Dinner Bed.7 Simple Algorithm Group Carb-Count Group Insulin dose: 1.9 vs. 1.7 U/kg/d for simple vs. carb counting (P <.2) Weight gain: 3. vs. 2. kg (P =.) for simple vs. carb counting 7 Fix vs. Flex: Study Regimens Education Blood glucose measurement Insulin dose adjustment Carbohydrate-dependent dosing Insulin for blood glucose correction purposes Fix Basic education. to 2 glucose profiles per week Only with the investigator during the visits No No Flex Basic education + carbohydrates + meal-dependent insulin dosing Daily glucose profile Self-adjustment every day Yes, at every meal Yes, at every meal Milek K et al. Diabetologia. 27;(Suppl 1):S12. Data on file Novo Nordisk. Fix vs. Flex: Duration of Education Fix vs. Flex: SMBG Data FIX 1 12 P = Fix Flex 1 Hours.7 FLEX 2 Number of documented hours during 12-week education and titration period Milek K et al. Diabetologia. 27;(Suppl1):S

19 Suggested Basal-Bolus Adjustments: ± 2-Unit Changes Done Weekly Fix vs. Flex: Change in A1C Plasma Insulin (µu/ml) FS Prandial + correction Prandial + correction FS Prandial + correction FS FS Basal Bolus Basal daily : : 12: 1: 2: 2: : : A1C (%) Baseline 2 Weeks Baseline 2 Weeks Fix Flex Adjust basal insulin Adjust AM Adjust lunch Adjust dinner 91 Analysis of the per-protocol group P =.191 Milek K et al. Diabetologia. 27;(Suppl1):S Fix vs. Flex: Percentage of Patients Who Achieved A1C Target Fix vs. Flex: Change in Total Insulin Dose Total daily insulin (U) Total daily basal insulin (U) Percentage of Patients P = NS P = NS P = NS Fix Flex Fix Flex A1C Target No significant differences. Milek K et al. Diabetologia. 27;(Suppl 1):S12. Data on file Novo Nordisk. 93 Milek K et al. Diabetologia. 27;(Suppl 1):S12. Data on file Novo Nordisk. 9 Fix vs. Flex: Rate of Hypoglycemia ARS Question Patients With Hypoglycemic Events (%) Fix Flex 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. Dinner insulin Only one case of major hypoglycemia occurred in each treatment group Milek K et al. Diabetologia. 27;(Suppl 1):S

20 Fix vs. Flex: Conclusions Patients in both treatment arms achieved good glycemic control No significant between-group difference in the proportion of patients achieving target Both regimens reduced plasma glucose profiles below target No significant differences in PPG or FPG reductions Rates of hypoglycemia did not differ between approaches 97 Addressing Healthcare System Barriers Locating services within the targeted community to maximize access Offering a broad array of health and social services to increase efficiency and continuity Maintaining a consistent staff Expanding hours of operation Emphasizing family and community involvement Hiring and retaining bilingual, bicultural staff Using educational materials that are multicultural Identifying and working with/through the key social institutions (eg, African-American churches and barber shops) 9 Improving Adherence in Patients With Diabetes Praise every patient at every visit Understand that achieving perfect glycemic control is extremely challenging Challenge patients to take control of their diabetes rather than having diabetes control them Refer to CDEs for patients who present with difficult issues (eg, eating disorders, shift workers, mental illness, pregnancy, adolescents) Intensification of therapy for your patients will likely bring more patients to your practice! Consider group visits for your practice 99 Summary Insulin therapy usually is needed if A1C level is >.% 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! 1 Post-Test Question #1: If following the ADA/EASD recommendations, which well-validated medication should be added when the combination of lifestyle management and metformin therapy no longer achieves the desired glycemic control? 1. Basal insulin 2. DPP- inhibitor 3. GLP-1 agonist. TZD Post-Test Question #2: In patients on oral antidiabetic agents, at what A1C level should insulin therapy be initiated? 1. 7.% 2..% 3..%. 9.%. Over 9.% EASD = European Association for the Study of Diabetes

21 Post-Test Question #3: Which of the following is NOT true about the need for timely initiation of insulin therapy in patients with type 2 diabetes? Post-Test Question #: Patients who are provided guidance can safely and effectively self-titrate insulin therapy. 1. Insulin therapy can reduce the risk of diabetes-related complications 2. Insulin therapy is likely to be needed by a majority of patients with type 2 diabetes over the course of their lifetime 3. Type 2 diabetes is characterized by insulin resistance and insulin deficiency, with insulin deficiency increasing over time. Patients should be told that the need for insulin therapy indicates that they have not taken the appropriate steps (eg, sufficient weight loss and exercise, compliance to OAD therapy) to control their diabetes True 2. False 1 1