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John B. Buse, MD, PhD Associate Professor of Medicine Chief, Division of General Medicine and Clinical Epidemiology Director, Diabetes Care Center University.

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Presentation on theme: "John B. Buse, MD, PhD Associate Professor of Medicine Chief, Division of General Medicine and Clinical Epidemiology Director, Diabetes Care Center University."— Presentation transcript:

1 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 Difficulties in Achieving Target A1c Values

2 63% of Patients With Diabetes are Not At ADA A1C Goal <7% 37.2% >8% 63%  7% 7.8% 25.8% 37.0% 17.0% 12.4% % of Subjects n = 404 A1C 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. 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 Achieving Target 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 Achieving Target 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 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. HbA1c Retinopathy Nephropathy Neuropathy Cardiovascular disease DCCT 9  7.2% 63% 54% 60% 41% (NS) Kumamoto 9  7% 69% 70% Improved - UKPDS 8  7% 17-21% 24-33% - 16% (NS) Intensive Diabetes Therapy: Reduced Incidence of Complications

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 Risk of Progression of Complications: DCCT Study Skyler JF. Endocrinol Metab Clin North Am. 1996;25:243-254. Relative Risk HbA 1c, % 789101112 Diabetic retinopathy Nephropathy Neuropathy Microalbuminuria 15 13 11 9 7 5 3 1 Rate of Severe Hypo. (per 100 patient- years) 0 20 40 60 80 100 120 Severe hypoglycemia 6

9 Nathan D. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA. EDIC 12-year Follow-Up of DCCT Study End point Relative risk reduction (%) (95% CI) p Cardiovascular events 42 (19-63)0.016 Nonfatal MI, stroke, and cardiovascular death 57 (12-79)0.018

10 Incidence Rate for Complications in UKPDS: Epidemiological Analysis* * 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 Any diabetes related endpoint Myocardial infarction Microvascular endpoints 5 6 7 8 9 10 11 Updated mean hemoglobin A 1c 160 140 120 100 80 60 40 20 90 60 40 20 Adjusted incidence per 1000 patient years (%)

11 Diabetes Care 28:s4-36, 2005 http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php Goal Premeal plasma glucose (mg/dl) 2-h postprandial plasma glucose HbA1c ADA 90-130 <180* <7%** ACE <110 <140 <6.5% Glycemic Goals of Therapy 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 Verbal Target ~100 <<200 As low as possible w/o unacceptable AE

12 Difficulties in Achieving Target 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 Glucose Tolerance Categories Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. Supplement 1, January 2004. Fasting Plasma Glucose 126 mg/dL 110 mg/dL 7.0 mmol/L 6.1 mmol/L Impaired Fasting Glucose Normal 2-Hour Plasma Glucose on OGTT 200 mg/dL 140 mg/dL 11.1mmol/L 7.8mmol/L Diabetes Mellitus Impaired Glucose Tolerance Normal Diabetes Mellitus 100 mg/dL5.6 mmol/L Impaired Fasting Glucose Must have two measures to make a diagnosis* * One can also make the diagnosis of diabetes based on unequivocal symptoms and a random glucose > 200 mg/dl “Pre-Diabetes”

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

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

18 Patients Remain on Monotherapy >1 Year After First A1c >8.0% * *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. Length of time that the patient’s A1c remained above 8.0% before a switch/addition in therapy* 0 5 10 15 20 25 Metformin OnlySulfonylurea Only Months (n=354) (n=2517) 14 months 20 months

19 Difficulties in Achieving Target 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 Provider in 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 Patient in 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 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. Prioritizing Lifestyle Messages Medical Nutrition Therapy 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 Achieving Target 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 0 6 7 8 9 246810 Years from randomization Chlorpropamide Conventional Glibenclamide Insulin Metformin Median HbA 1c (%) UKPDS 34, Lancet 1998.

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

28 Pioglitazone Comparator Studies – Europe Durability R. Urquhart. IDF 2003.

29 Pioglitazone Comparator Studies – Europe Durability R. Urquhart. IDF 2003.

30 Difficulties in Achieving Target 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 Achieving Target 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 Achieving Target 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 As Patients Get Closer to A1c Goal, the Need to Manage PPG Increases Monnier L, et al. Diabetes Care. 2003;26:881-885. 30% 40% 45% 50% 70% 60% 55% 50% 30% >10.210.2-9.39.2-8.58.4-7.3<7.3 FPG PPG % Contribution 0 20 40 60 80 100 A1C Range (%)

38 Diagnosis by screening or with symptoms Target Insulin Resistance No Treatment Algorithm - Glucose Yes Quarterly to semi-annual follow-up Lifestyle Intervention nutrition, exercise, education Are A1c/FPG Targets Achieved? Target PPG Target Insulin Deficiency FPG > 200 mg/dL FPG < 130 mg/dL Monthly to quarterly follow-up * *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


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