1. AHRQ’s Effective Health Care Program: Applying Existing Evidence to Diabetes Care Tuesday, December 14, 2010 CALL-IN TELEPHONE NUMBER: (888) 632-5065 ACCESS CODE: 25848872#

2. Questions To submit a question: – Press the “Ask Question” button located at the bottom of the screen. – When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. – Once completed, press the “Submit” button. 2 22 2 CALL-IN NUMBER: (888) 632-5065 ACCESS CODE: 25848872# CALL-IN NUMBER: (888) 632-5065 ACCESS CODE: 25848872 #

3. Agenda Brief Overview of Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program- Sonia Nagda, moderator Brief Overview of Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program- Sonia Nagda, moderator Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults With Type 2 Diabetes- Rehan Qayyum, M.D., M.H.S. Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults With Type 2 Diabetes- Rehan Qayyum, M.D., M.H.S. Q&A from Audience Q&A from Audience 3 33 3 CALL-IN NUMBER: (888) 632-5065 ACCESS CODE: 25848872# CALL-IN NUMBER: (888) 632-5065 ACCESS CODE: 25848872 #

4. Questions To submit a question: – Press the “Ask Question” button located at the bottom of the screen. – When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. – Once completed, press the “Submit” button. 4 44 4

5. Patient-Centered Outcomes Research and AHRQ’s Effective Health Care Program Sonia Nagda, M.D., M.P.H. AHRQ’s Office of Communications and Knowledge Transfer 5 55 5

6. Patient-Centered Outcomes Research Benefits Harms Also known as comparative effectiveness research Also known as comparative effectiveness research Unbiased and practical, evidence-based information Unbiased and practical, evidence-based information Compares drugs, devices, tests and surgeries, and approaches to health care Compares drugs, devices, tests and surgeries, and approaches to health care – Benefits and harms – What is known and what isn’t Descriptive, not prescriptive Descriptive, not prescriptive 6 66 6

7. HorizonScanning Evidence Need Need Identification Identification EvidenceSynthesis Evidence Generation GenerationStrategiesInterventionsConditionsPopulations DisseminationTranslation Improvements in in Health Care Health Care Research Platform Infrastructure – Methods Development – Training A Framework for Patient-Centered Outcomes Research 7 77 7

8. Research Focus: 14 Priority Conditions Arthritis and nontraumatic joint disorders Arthritis and nontraumatic joint disorders Cancer Cancer Cardiovascular disease, including stroke and hypertension Cardiovascular disease, including stroke and hypertension Dementia, including Alzheimer’s disease Dementia, including Alzheimer’s disease Depression and other mental health disorders Depression and other mental health disorders Developmental delays, ADHD and autism Developmental delays, ADHD and autism Diabetes mellitus Diabetes mellitus Functional limitations and disability Functional limitations and disability Infectious diseases, including HIV/AIDS Infectious diseases, including HIV/AIDS Obesity Obesity Peptic ulcer disease and dyspepsia Peptic ulcer disease and dyspepsia Pregnancy including preterm birth Pregnancy including preterm birth Pulmonary disease/asthma Pulmonary disease/asthma Substance abuse Substance abuse 8

9. Effective Health Care Program Translation Products 9 Executive Summary Web Site Clinician Guide Consumer Guide Policymaker Summary Interactive Case Study CE Modules Faculty Slides Patient Decision Aid (available soon) Systematic Review Report

10. Diabetes Resources 10

11. Public Involvement Topic Generation Topic Development Topic Refinement Research Review Research Needs Development Report Translation & Dissemination During the Research Process Web links Newsletter blurbs Articles or commentaries Web conferences Continuing Education Disseminating the Findings Nominate topics using the online Nominate topics using the online form form Participate in key question Participate in key question refinement refinement Comment via the web on draft key Comment via the web on draft key questions and reports questions and reports 11

12. Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults with Type 2 Diabetes Rehan Qayyum, M.D., M.H.S. Prepared for: Agency for Healthcare Research and Quality and Quality Contract No. #290-02-0018 Prepared by: Evidence-based Practice Center, The Johns Hopkins University The Johns Hopkins University 12

13. Insulin Analogues Insulin analogues are altered forms of human insulin with minor structural changes without affecting glycemic control Insulin analogues are altered forms of human insulin with minor structural changes without affecting glycemic control These structural changes impart pharmacokinetic properties that allow better control of the onset and duration of insulinlike activity. These structural changes impart pharmacokinetic properties that allow better control of the onset and duration of insulinlike activity. These analogues are produced using recombinant DNA technology. These analogues are produced using recombinant DNA technology. 13

14. Insulin Analogues 14

15. Premixed Insulin Analogues Mixture of rapid-acting and intermediate- acting insulin analogues Mixture of rapid-acting and intermediate- acting insulin analogues Intermediate-acting insulin is prepared by mixing insulin analogues with protamine sulfate Intermediate-acting insulin is prepared by mixing insulin analogues with protamine sulfate 15

16. Key Questions 1. In adults (age ≥ 18 years) with type 2 diabetes, what is the effectiveness of premixed insulin analogues (insulin aspart 70/30, insulin lispro 75/25, insulin lispro 50/50) in achieving optimal glycemic control, as compared to insulin regimens including, but not necessarily limited to, the following preparations?  Premixed human insulin preparations (neutral protamine Hagedorn [NPH]/regular 70/30, NPH/regular 50/50)  Long-acting insulin analogues (insulin detemir, insulin glargine) administered alone  Intermediate-acting human insulin (NPH insulin) administered alone  Short-acting human insulin (regular insulin) administered prandially  Rapid-acting insulin analogues (insulin aspart, insulin glulisine, insulin lispro) administered separately (prandially) with a long-acting insulin analogue (insulin detemir, insulin glargine) 2. For adults with type 2 diabetes, do premixed insulin analogues differ from other commonly used insulin preparations with regard to safety, adverse effects, or adherence? The adverse effects of interest include, but are not limited to, hypoglycemia (nocturnal and daytime), weight gain, and interactions with other medications. 16

17. Key Questions (cont.) 3. Does the effectiveness or safety of the new premixed insulin analogue regimens vary across the following subpopulations of patients with type 2 diabetes  The elderly (≥ 65 years), very elderly (≥ 85 years)  Other demographic groups (ethnic or racial groups, genders)  Individuals with comorbid medical conditions  Individuals with limited life expectancy  Individuals with disabilities 4. What is the effectiveness and safety of the new premixed insulin analogue regimens in individuals on oral antidiabetic agents and individuals with different blood glucose patterns (such as fasting hyperglycemia or postprandial hyperglycemia) or types of control (such as tight control, usual control, good fasting or postprandial control)? 17

18. Methods Search Strategy Search Strategy – Electronic database (February 2008) – Hand search of literature and Web sites – Scientific information submitted by the pharmacy industry Study Inclusion Criteria Study Inclusion Criteria – Clinical trials and observational studies Two reviewers independently selected studies Two reviewers independently selected studies Data Abstraction Data Abstraction – For relevant outcomes – Crossover studies excluded from progressive outcomes 18

19. Statistical Methods Intermediate outcomes (Fasting and postprandial glucose, A1c) Intermediate outcomes (Fasting and postprandial glucose, A1c) – Random effects model Adverse Effects (Hypoglycemia, weight change) Adverse Effects (Hypoglycemia, weight change) – Random effects model Clinical Outcomes (rare-event data) Clinical Outcomes (rare-event data) – Fixed effects model (Mantel-Haenszel) – Sensitivity analysis with Peto’s method and Bayesian random-effects model 19

20. Results Qayyum et al. Ann Intern Med. 2008; 21:549-559 20

21. Results - Fasting Glucose - Qayyum et al. Ann Intern Med. 2008; 21:549-559 21

22. Results - Postprandial Glucose - Qayyum et al. Ann Intern Med. 2008; 21:549-559 22

23. Results - Hemoglobin A1C - Qayyum et al. Ann Intern Med. 2008; 21:549-559 23

24. Results - Hypoglycemia - Qayyum et al. Ann Intern Med. 2008; 21:549-559 24

25. Results - Weight Change - Mean95%CIP-value Long-acting insulin analogues vs. All premixed insulin analogues 1.971.22 to 2.73< 0.001 Insulin Aspart 70/302.51.6 to 3.4< 0.001 Insulin Lispro 75/25No data Insulin Lispro 50/501.580.99 to 2.18< 0.001 Non-insulin antidiabetic agents vs. All premixed insulin analogues 2.350.84 to 3.860.002 Insulin Aspart 70/302.820.61 to 5.020.012 Insulin Lispro 75/251.881.35 to 2.41< 0.001 Insulin Lispro 50/50No data Premixed Human insulin vs. All premixed insulin analogues Not enough data 25

26. Results - Other Comparisons - No or scant data for other comparisons 26

27. Results - Clinical Outcomes - Qayyum et al. Ann Intern Med. 2008; 21:549-559 27

28. Results - Quality of Life - Six studies evaluated this outcome. Six studies evaluated this outcome. In four studies using validated measurement tools, only one of six quality of life outcomes (psychological distress) showed a statistically significant difference, in favor of premixed insulin analogues over other antidiabetic agents. In four studies using validated measurement tools, only one of six quality of life outcomes (psychological distress) showed a statistically significant difference, in favor of premixed insulin analogues over other antidiabetic agents. 28

29. Results - in combination with oral agents - Fasting glucose, Postprandial glucose, and Hypoglycemia Fasting glucose, Postprandial glucose, and Hypoglycemia – 3 studies; no significant difference Hemoglobin A1c Hemoglobin A1c – 3 studies, combination better than premixed analogues alone Weight change and Clinical outcomes Weight change and Clinical outcomes – 2 studies, no significant difference 29

30. Results No evidence for No evidence for – adherence to treatment regimen – effectiveness and safety in subpopulations of interest – different intensity of glucose control – targeting fasting versus postprandial glucose control 30

31. Case Study 1 50-year-old obese diabetic male comes in for his regular clinic visit 50-year-old obese diabetic male comes in for his regular clinic visit – HbA1C = 8.7 – Fasting glucose = 160-190 – On glipizide 10 mg twice daily and metformin XL 1000mg twice daily 31

32. Case Study 2 56-year-old diabetic female comes in for her regular clinic visit 56-year-old diabetic female comes in for her regular clinic visit – HbA1C = 7.4 – Fasting glucose = 120-140 – Postprandial glucose = 180-220 – On glyburide/metformin 5/500 BID and sitagliptin 100mg QD 32

33. Summary Long acting Rapid Acting Long + Rapid NPH + Rapid PremixedNPH Noninsulin antidiabetic FBG IA70/30↔↓↔X↑↔↓ IL 75/25 ↑XXX↔X↓ IL 50/50 ↑↔↑X↑XX PPBG IA70/30↓↑↔X↓↔↓ IL 75/25 ↓XXX↓X↓ IL 50/50 ↓↔↑X↓XX HbA1c IA70/30↓ ↔§↔§↔§↔§↓*↔↔↔↓ IL 75/25 ↓XXX↔X↔ IL 50/50 ↓↔↑X↔XX Hypogly- cemia IA70/30↑↔↓*↔↔↔↑ IL 75/25 ↑*XXX↔X↔ IL 50/50 ↑↔↔X↔XX Weight Change IA70/30↑↓↔↑↔↔↑ IL 75/25 XXXX↔X↑ IL 50/50 ↑*↓*↔X↔XX ↑=variable increases with premixed analogue versus comparator ↓=variable decreases with premixed analogue versus comparator ↔= premixed analgoue and comparator has same effect on variable X= No studies have looked at the comparison *= Overall evidence is not of sufficient strength §=benefit with premixed insulin analogue almost reached statistical significance 33

34. Questions To submit a question: – Press the “Ask Question” button located at the bottom of the screen. – When you click on the button, a box will appear at the bottom of your screen requesting that you enter your question. – Once completed, press the “Submit” button. 34

35. For more information about…  AHRQ’s Effective Health Care Program: www.effectivehealthcare.ahrq.gov. www.effectivehealthcare.ahrq.gov  Accessing these FREE resources through AHRQ’s Publications Clearinghouse: (800) 358-9295.  E-mail notices: http://www.effectivehealthcare.ahrq.gov/index.cfm/ join-the-email-list1/. http://www.effectivehealthcare.ahrq.gov/index.cfm/ join-the-email-list1/ http://www.effectivehealthcare.ahrq.gov/index.cfm/ join-the-email-list1/  If you have a question about utilizing AHRQ resources please e-mail us at: EHC_Clinicians@ahrq.hhs.gov. EHC_Clinicians@ahrq.hhs.gov 35

36. Thank you! Thank you for joining us today! Thank you for joining us today! Please take a moment to provide us feedback at the end of this event. Please take a moment to provide us feedback at the end of this event. A recording and transcript for today’s event will be available on AHRQ’s Web site. A recording and transcript for today’s event will be available on AHRQ’s Web site. 36