John B. Buse, MD, PhD Associate Professor of Medicine

1. Difficulties in Achieving Target A1c Values John B. Buse, MD, PhD Associate Professor of Medicine Chief, Division of General Medicine and Clinical Epidemiology Director, Diabetes Care Center University of North Carolina Chapel Hill, NC jbuse@med.unc.edu

2. 12.4% 37.2% >8% 7.8% 63% 7% 17.0% 25.8% 37.0% 63% of Patients With Diabetes are Not At ADA A1CGoal <7% Adults aged 20-74 years with previously diagnosed diabetes who participated in the interview and examination components of the National Health Examination Survey (NHANES), 1999-2000. A1C % of Subjects n = 404 • Only 7% of adults with diabetes in NHANES 1999-2000 attained: • A1C level <7% • Blood pressure <130/80 mm Hg • Total cholesterol <200 mg/dL Saydah SH et al. JAMA. 2004;291:335-342.

3. Case

4. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

5. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

6. Intensive Diabetes Therapy: Reduced Incidence of Complications DCCT 9  7.2% 63% 54% 60% 41% (NS) Kumamoto 9  7% 69% 70% Improved - UKPDS 8  7% 17-21% 24-33% - 16% (NS) HbA1c Retinopathy Nephropathy Neuropathy Cardiovascular disease DCCT Research Group. N Engl J Med. 1993;329:977-986. Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117. UKPDS 33: Lancet 1998; 352, 837-853. Slide modified from D. Kendall - International Diabetes Center, Minneapolis.

7. Potential Adverse Effects Related to Pursuit of Stringent Glycemic Goals • Hypoglycemia • Cost • Long-term exposure to poorly studied combinations of medications • Lessened attention to other difficult to manage health care risks (e.g. BP, HDL, immunization, cancer screening) • Weight gain

8. Severe hypoglycemia Diabetic retinopathy Nephropathy Neuropathy Microalbuminuria 120 Rate of Severe Hypo. (per 100 patient-years) 100 80 60 40 20 0 Risk of Progression of Complications:DCCT Study 15 13 11 9 7 5 3 1 Relative Risk 7 8 9 10 11 12 6 HbA1c, % Skyler JF. Endocrinol Metab Clin North Am. 1996;25:243-254.

9. EDIC 12-year Follow-Up of DCCT Study Nathan D. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA.

10. Incidence Rate for Complications in UKPDS: Epidemiological Analysis* Adjusted incidence per 1000 patient years (%) 160 140 120 100 80 60 40 20 90 60 40 20 Any diabetes related endpoint Myocardial infarction Microvascular endpoints 5 6 7 8 9 10 11 5 6 7 8 9 10 11 Updated mean hemoglobin A1c * Expressed for white men aged 50-54 years at diagnosis and with mean duration of diabetes of 10 years Stratton, et al. BMJ. 321:405-412, 2000

11. Glycemic Goals of Therapy Verbal Target ~100 <<200 As low as possible w/o unacceptable AE Goal Premeal plasma glucose (mg/dl) 2-h postprandial plasma glucose HbA1c ADA 90-130 <180* <7%** ACE <110 <140 <6.5% • Evaluation and treatment of postprandial glucose may be useful in the setting of suspected postprandial hyperglycemia, with the use of agents targeting postprandial hyperglycemia and for suspected hypoglycemia. • More stringent glycemic goals (i.e. a normal A1C, <6%) may further reduce complications at the cost of increased risk of hypoglycemia Diabetes Care 28:s4-36, 2005 http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php

12. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

13. Screening for Diabetes • Fasting plasma glucose at least every 3 years starting at age 30-45 • Earlier and more frequent screening in people with risk factors: • Family history - Dyslipidemia (TG >150 or HDL <40/50) • Overweight - History gestational DM or child >9# • High-risk ethnicity - Hypertension (> 140/90) • Prior FPG >99 mg/dl - Known vascular disease • Characteristics of insulin resistance American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004; 27 Suppl 1:S15-35. Diabetes Guidelines Task Force. AACE guidelines for the management of diabetes mellitus. Endocr Pract. 1995; 1:149-157.

14. Must have two measures to make a diagnosis* “Pre-Diabetes” Impaired Fasting Glucose 100 mg/dL 5.6 mmol/L Glucose Tolerance Categories Fasting Plasma Glucose 2-Hour Plasma Glucose on OGTT Diabetes Mellitus Diabetes Mellitus 126 mg/dL 7.0 mmol/L 200 mg/dL 11.1 mmol/L Impaired Fasting Impaired Glucose Glucose Tolerance 110 mg/dL 6.1 mmol/L 140 mg/dL 7.8 mmol/L Normal Normal * One can also make the diagnosis of diabetes based on unequivocal symptoms and a random glucose > 200 mg/dl Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. Supplement 1, January 2004.

15. Effect of Early TZD Use on A1C 6.8 - 6.6 - 6.4 - 6.2 - 6.0 - 5.8 - 5.6 - 5.4 - 5.2 - 5.0 - Rosiglitazone (n=39) Pioglitazone (n=62) Control (n=71) * † † A1C (%) * * * * * * * P<0.001 vs. baseline; † P<0.001 vs. rosiglitazone and pioglitazone Switch 2-yr check 3-yr final Baseline Durbin RJ Diabetes, Obesity & Metabolism 6:280-285, 2004

16. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

17. Stepwise Management of Type 2Diabetes: Treat-to-Failure Approach Diet, exercise, lifestyle… wait for failure Monotherapy… wait for failure Combination therapy… wait for failure Based on failure,consider:Higher order combination therapy . . . Slide provided by Steve Edelman, MD.

18. Patients Remain on Monotherapy >1 Year After First A1c >8.0%* Length of time that the patient’s A1c remained above 8.0% before a switch/addition in therapy* 25 20 months 20 14 months Months 15 10 5 0 Metformin Only Sulfonylurea Only (n=2517) (n=354) * May include up-titration. Length of time between first A1c >8.0% and switch/addition in therapy could include periods where patients had subsequent A1c test values below 8%. Based on nonrandomized retrospective database analysis. Data from Kaiser Permanente Northwest 1994-2002. Patients had to be continuously enrolled for 12 months with A1c lab values. Brown et al. Diabetes. 2003;52(suppl 1):A61-A62. Abstract 264-OR.

19. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

20. Patient Centered Team Diabetes Management Providers are coaches Patients are clients

21. Role of the Providerin Diabetes Management • Provide guidance in goal setting and evaluation to manage the risk of complications • Suggest strategies to achieve goals and techniques to overcome barriers • Provide skills training (self-management techniques) • Screen for complications

22. Role of the Patientin Diabetes Management • Commit to self-care • Participate in the development of a treatment plan • Make ongoing decisions regarding self-care • Communicate frequently and honestly with the rest of the team

23. Prioritizing Lifestyle Messages • Emphasize blood glucose control, not weight loss. • Focus on carbohydrate foods, portions, and number of servings per meal. • Encourage physical activity. • Use food records with blood glucose monitoring data. Medical Nutrition Therapy

24. Compliance/Adherence • Comply: “to act in accordance with and fulfillment of requests, demands, conditions or regulations” • Is “non-compliance” a patient or provider problem? • Compliance model • Greyhound motto: “Leave the driving to us” • Informed choice/empowerment model • Hertz motto: “We put you in the driver’s seat”

25. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

26. Progressive Hyperglycemia Despite Insulin, Sulfonylurea, or Metformin 9 Conventional Glibenclamide Metformin Chlorpropamide 8 Insulin Median HbA1c (%) 7 6 0 2 4 6 8 10 Years from randomization UKPDS 34, Lancet 1998.

27. ZDF rat model Obese, insulin resistant Progressive decline in b cell function and mass Lean control Obese 6 weeks Obese 12 weeks TZD 12 weeks Obese 16 weeks TZD 16 weeks Impact on TZD Therapy on b-cell Function in ZDF Rats • Effect of Glitazone • Improve insulin resistance and normalize glucose • Rosiglitazone prevents decline in b cell mass and maintains normal glucose Finegood D. Diabetes 50:1021–1029, 2001

28. Pioglitazone Comparator Studies – EuropeDurability R. Urquhart. IDF 2003.

29. Pioglitazone Comparator Studies – EuropeDurability R. Urquhart. IDF 2003.

30. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

31. Anti-Hyperglycemic Agents in Type 2 Diabetes

32. Diabetes Therapy and Weight Gain:Management • Inform the patient of the risk • Greatest risk of weight gain • Young • Female • Shorter duration of DM • Higher A1C at baseline • Lifestyle intervention • Use metformin, α-glucosidase inhibitors, exenatide, pramlintide • Consider weight loss medications • Monitor weight • Dose reduction in response to excessive weight gain

33. Diabetes Therapy and Hypoglycemia:Management • Inform the patient of the risk • Longer duration of DM • Lower A1C • Sliding scale insulin • Lifestyle intervention, patient education • Use metformin, glitazones, α-glucosidase inhibitors, exenatide, nateglinide, analog insulin • Monitor glucose, keep logs • Goal resetting and dose reduction in response to severe or asymptomatic hypoglycemia

34. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

35. Core Treatments to Prevent Complications • Blood glucose control • Blood pressure control • Lipid management • Smoking cessation • Specific therapies

36. Difficulties in AchievingTarget A1C Values • What is the appropriate A1C target • Challenges • Late diagnosis and initiation of therapy • Therapeutic inertia • Lack of effective lifestyle intervention • Secondary failure • Adverse events associated with antihyperglycemic therapies • Complexity of care • Role of postprandial glucose in failure

37. 100 80 60 40 20 0 As Patients Get Closer to A1c Goal, the Need to Manage PPG Increases 30% 50% 55% 60% 70% % Contribution FPG PPG 70% 50% 45% 40% 30% >10.2 10.2-9.3 9.2-8.5 8.4-7.3 <7.3 A1C Range (%) Monnier L, et al. Diabetes Care. 2003;26:881-885.

38. Lifestyle Intervention nutrition, exercise, education Quarterly to semi-annual follow-up Monthly to quarterly follow-up Are A1c/FPG Targets Achieved? Yes No * FPG < 130 mg/dL FPG > 200 mg/dL Target Insulin Deficiency Target Insulin Resistance Target PPG *Keep adding agents until target is reached. Self-titration at home when possible. Metformin, glitazone Exenatide, nateglinide, α-glucosidase inhibitors, rapid-acting insulin, pramlintide SFUs/glinide, insulin, exenatide Treatment Algorithm - Glucose Diagnosis by screening or with symptoms