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John B. Buse, MD, PhD Professor of Medicine Chief, Division of Endocrinology Director, Diabetes Care Center University of North Carolina Chapel Hill, NC.

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Presentation on theme: "John B. Buse, MD, PhD Professor of Medicine Chief, Division of Endocrinology Director, Diabetes Care Center University of North Carolina Chapel Hill, NC."— Presentation transcript:

1 John B. Buse, MD, PhD Professor of Medicine Chief, Division of Endocrinology Director, Diabetes Care Center University of North Carolina Chapel Hill, NC Diabetes Management

2 CVD and Glycemia

3 *If A1C remains above the desired target, postprandial levels, usually measured 90–120 min after a meal, may be checked. They should be <180 mg/dl to achieve A1C levels in the target range. † An A1C of ≥7% should serve as a call to action to initiate or change therapy with the goal of achieving an A1C level as close to the nondiabetic range as possible or, at a minimum, decreasing the A1C to 7%. Diabetes Care 30: S4-41, 2007 (http://care.diabetesjournals.org/cgi/reprint/30/suppl_1/S4) Goal Premeal plasma glucose (mg/dl) 2-h postprandial plasma glucose HbA1c ADA (<180)* <7% † ACE <110 <140 <6.5% Glycemic Goals of Therapy

4 Recent Glycemia CVD Studies CharacteristicACCORDADVANCEVADT N10,25111,1401,791 Mean age Hx CVD35%32%40% BMI BL mean A1C8.3%7.5%9.4% BL meds34% Ins/1.4 OAD1% Ins/1.5 OAD51% Ins/?? Statin use62% 88%28% 47%58% 84% Antiplatelet use54.5% 75.5%48% 62%76% 93% Study duration Target A1C<6% vs 7-8%<6.5% vs “Usual”<6% vs 8-9% Achieved mean A1C6.5% and 7.5%6.3% and 7.0%6.9% and 8.4% LDL at end BP at end127 / / / 69 Smokers at end9.9%8%17% Skyler J, et al. Diabetes Care. 2009; 32:

5 *P=0.04 Summary: Glucose Lowering on CVD in Type 2 Diabetes VADTACCORDADVANCE Primary outcome Non-fatal MI Non-fatal stroke CVD death Hospitalization for CHF Revascularization Non-fatal MI Non-fatal stroke CVD death Non-fatal MI Non-fatal stroke CVD death Hazard Ratio for primary outcome (95% CI) 0.87 (0.73 – 1.04)0.90 (0.78 – 1.04)0.94 (0.84 – 1.06) Hazard Ratio for mortality (95% CI) 1.07 (0.80 – 1.42)1.22 (1.01 – 1.46)*0.93 (0.83 – 1.06)

6 ACCORD Treatment Effect on Primary Outcome Standard therapy Intensive therapy Patients with events % Time (yrs) HR=0.90 ( ), P= %/yr 2.11%/yr ACCORD Study Group N Engl J Med 358: ;

7 Protocol Defined N Events Interaction P-value Subgroups Overall Primary Prevention Secondary Prevention Women Men Baseline Age< Baseline Age≥ Baseline A1C≤ Baseline A1C> Non-White White ACCORD: Hazard Ratios for Primary Outcome by Subgroup HR (Intensive vs. Standard) ACCORD Study Group N Engl J Med 358: ;2008.

8 A1C (%) Year DCCT DCCT end EDIC Conventional group encouraged to switch to intensive treatment Adapted from: N Engl J Med 329:977–86,1993; EDIC: JAMA 287: 2563–9;2002 A1C During DCCT and Follow-Up Intensive Conventional

9 Cumulative Incidence of the First of Any Predefined CVD Outcomes Years since entry Cumulative incidence of any CVD outcome Conventional treatment Intensive treatment Risk reduction 42%, CI - 9,63 Log-rank p = nonfatal MI, stoke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization Fatal MI, CVA, or CVD death ↓57% DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:

10 After median 8.8 years post-trial follow-up Aggregate Endpoint Any diabetes related endpointRRR:12%9% P: Microvascular diseaseRRR: 25%24% P: Myocardial infarctionRRR:16%15% P: All-cause mortalityRRR:6%13% P: UKPDS: “Legacy Effect” of Insulin/Sulfonylurea Therapy RRR = Relative Risk Reduction P = Log Rank Holman RR, et al. New England Journal of Medicine 2008; 359:

11 TIME (yrs since diagnosis) A1C (%) Drive the risk for complications Build up “bad” metabolic memory The “Natural History” of Type 2 Diabetes

12 12 Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, for microvascular disease prevention, the A1C goal for non- pregnant adults in general is <7%. (A) ADA – AHA – ACC Revised Glycemic Control Recommendations ADA/AHA/ACC. Diabetes Care. 2009; 32:

13 13 ADA – AHA – ACC Revised Glycemic Control Recommendations In type 1 and type 2 diabetes, randomized controlled trials of intensive vs. standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. Long-term follow-up of the DCCT and UKPDS cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable for many adults for macrovascular risk reduction. (B) ADA/AHA/ACC. Diabetes Care. 2009; 32:

14 14 Subgroup analyses of clinical trials such as the DCCT and UKPDS, and the microvascular evidence from the ADVANCE trial, suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. (B) ADA – AHA – ACC Revised Glycemic Control Recommendations ADA/AHA/ACC. Diabetes Care. 2009; 32:

15 15 Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self- management education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin. (C) ADA – AHA – ACC Revised Glycemic Control Recommendations ADA/AHA/ACC. Diabetes Care. 2009; 32:

16 Risk of Death over a Range of Average A1c Average A1c % Adjusted log(Hazard Ratio) by Treatment Strategy Relative to Standard at A1c of 6% Standard strategy 6897 Steady increase of risk from 6 to 9% A1c with intensive strategy Excess risk with intensive strategy vs standard occurred above A1c 7% Intensive strategy

17 Rates of Death During 3.4 Years of Treatment over a Range of 1-year Change of A1c A1c decline from baseline over 12 months (%) Intensive strategy Standard strategy Death rates per year Excess risk with intensive strategy vs standard occurred when intensive participants failed to reduce A1c in year 1 Adjusted Mortality Rates by Treatment Strategy

18 The Algorithm Screen, Diagnose, Treat

19 Screening Triggers for Prediabetes and Type 2 Diabetes Preferred screening test is a venous FPG Screen all individuals aged ≥ 45 years; if normal, repeat at 3-year intervals Consider earlier and more frequent screening in individuals who are overweight (BMI ≥ 25 kg/m 2 ) with additional risk factors: – Habitual physical inactivity – First-degree relative with diabetes – Members of a high-risk ethnic population (eg, African American, Latino, Native American, Asian American, Pacific Islander) – History of delivering a baby weighing > 9 lbs and/or GDM – Hypertension (≥ 140/90 mm Hg) – HDL-C 250 mg/dL – Polycystic ovarian syndrome – History of IGT or IFG – Other conditions associated with insulin resistance (eg, acanthosis nigricans) – History of vascular disease American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.

20 ADA and WHO Glucose Tolerance Categories Fasting Plasma Glucose Normal 2-hr Plasma Glucose on OGTT Diabetes Mellitus * Diagnosis of DM can also be made based on unequivocal symptoms and a random glucose >200 mg/dL. Any abnormality should be repeated and confirmed on a separate day. “Pre- Diabetes” 100 mg/dL Impaired Fasting Glucose (IFG) Normal Diabetes Mellitus Impaired Glucose Tolerance (IGT) 126 mg/dL 200 mg/dL 140 mg/dL

21 Glucose is NOT a Standardized Analyte CAP survey for glucose “ mg/dL”, mean 144 mg/dl* – In order for an institution to be considered “proficient”, results should deviate by no more than 12 mg/dL or 20% from the peer group – Inter-laboratory CV is 15.1% -Variability in part due to differences between instruments -CVs for individual instruments range from % – Bottom line, depending on the type of device used, the mean glucose measurement for a particular sample reported by CAP certifiable institutions varies across an approximately 30% range – In comparison, this is ~5% for many other analytes *Dungan K, et al. Diabetes Care 30: , 2007.

22 NGSP Standardization of the HbA1c Assay ©2007 David M. Nathan CAP = College of American Pathologists

23 HbA1c assay to be standardized worldwide using the new IFCC standard and expressed as: Consensus Statement IFCC, EASD, IDF, ADA All clinical guidelines should be expressed in these units % as currently used (DCCT values) IFCC units in mmol/mol eAG (estimated average glucose) in mg/dL Diabetes Care 30: , 2007

24 ADA Expert Committee, 1997 ADA Expert Committee on Diagnosis, 1997 Relation of FPG, 2hPG, HbA1c to Retinopathy: Egypt

25 The HbA1c assay is standardized and aligned to DCCT/UKPDS Better index of overall glycemic exposure Equivalent in predicting risk for long-term complications Predicts CVD Substantially less laboratory variability Substantially less pre-analytic instability No need for fasting or timed samples Unaffected by acute (e.g. stress or illness-related) perturbations in glucose levels Used to guide management and adjust therapy HbA1c Advantages Compared with FPG, OGTT

26 Laboratory ► Expense ► Not universally available Patient-related: determinants in addition to glycemia ► Hemoglobinopathies ► Variation in red cell lifespan (hemolysis, blood loss, etc.) ► Unexplained racial differences Not useful as acute measure Selecting a diagnostic cut point ► On what basis? ► Will not always agree with diagnoses by FPG or OGTT ► Break with the past HbA1c: Limitations

27 2-hr PG (n=237) 10% HbA1c (n=182) 7% FPG (n=165) 7% None = 2142 Any = 293 (12%) Total = 2435 Numbers of people with HbA1c ≥ 6.5%, FPG ≥ 126 mg/dl, or 2hPG ≥ 200 mg/dl adult Pima Indians without previous dx.

28 StudySubjectsIntervention Relative Risk Reduction DaQing Finnish DPS US DPP IGT IGT + “IFG” Diet or Exercise or Both Lifestyle 64%/53%/61% IGT US DPP STOP-NIDDM EDIT TRIPOD XENDOS DREAM ACT-NOW ORIGIN NAVIGATOR IGT + “IFG” IGT IFG Prior GDM IGT IFG or IGT IGT+IFG Metformin Acarbose Metformin or Acarbose or Both Troglitazone Orlistat Rosiglitazone or Ramipril or Both Pioglitazone Glargine or Fish oil or Both Nateglinide or Valsartan or Both 31% 25% NS 35% 45% 61%/NS 81% ~2010 ~2009 Prevention of Type 2 Diabetes Behavior Medication Li et al., Lancet 2008;371: ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25: Torgerson JS, et al. Diabetes Care. 2004;27: DREAM Trial Investigators. Lancet. 2006;368: DREAM Trial Investigators. N Engl J Med. 2006;355: DeFronzo RA, et al. ADA 68 th Scientific Sessions Origin Trial Investigators. Am Heart J 2008;155:26-32.

29 Lifestyle therapy can be very effective in preventing or delaying diabetes The lifestyle therapy that works involves three core features – Balanced low-calorie nutrition: -low fat, high in fiber (vegetables, fruits, whole grains) – Regular physical activity: -aerobic and resistance, 30+ minutes most days of the week – Frequent intervention with dietitians and lifestyle coaches: -~weekly for first month -~monthly for the first three months -~every three months for life Prevention Of Type 2 Diabetes: Completed Lifestyle Trials In IGT Key Points

30 StudySubjectsIntervention Relative Risk Reduction DaQing Finnish DPS US DPP IGT IGT + “IFG” Diet or Exercise or Both Lifestyle 64%/53%/61% IGT US DPP STOP-NIDDM EDIT TRIPOD XENDOS DREAM ACT-NOW ORIGIN NAVIGATOR IGT + “IFG” IGT IFG Prior GDM IGT IFG or IGT IGT+IFG Metformin Acarbose Metformin or Acarbose or Both Troglitazone Orlistat Rosiglitazone or Ramipril or Both Pioglitazone Glargine or Fish oil or Both Nateglinide or Valsartan or Both 31% 25% NS 35% 45% 61%/NS 81% ~2010 ~2009 Prevention of Type 2 Diabetes Behavior Medication Li et al., Lancet 2008;371: ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25: Torgerson JS, et al. Diabetes Care. 2004;27: DREAM Trial Investigators. Lancet. 2006;368: DREAM Trial Investigators. N Engl J Med. 2006;355: DeFronzo RA, et al. ADA 68 th Scientific Sessions Origin Trial Investigators. Am Heart J 2008;155: NOT FDA APPROVED FOR PREVENTION

31 Screening and Diagnosis: Intervention and Follow-Up Screen for Diabetes: FPG or 2-hour, 75-g OGTT American Diabetes Association. Diabetes Care. 2009;32(suppl 1):S13-S61. Normal Re-evaluate in ≤3 years if risk factors remain Diabetes Lifestyle intervention plus metformin; follow-up 3 mo. Diabetes: fasting ≥126 mg/dl or 2-hour ≥200 mg/dl; should be confirmed on a separate day unless unequivocally elevated and/or symptomatic IFG and IGT + Other Features* Lifestyle intervention and/or metformin; follow-up 6 mo. * “Other features”: 6.0%, hypertension, low HDL, high triglycerides or family history of diabetes in first-degree relative IFG: fasting (8 hours) plasma glucose mg/dL IGT: 2-hour value in 75-g OGTT mg/dL Lifestyle intervention; follow-up 1 year IFG or IGT †Follow-up here refers to formal reassesment of glycemic status. Follow-up should be individualized with respect to venue, frequency and goals. METFORMIN IS NOT FDA APPROVED FOR PREVENTION

32 Updated ADA/EASD Consensus Algorithm Nathan DM, et al., Diabetes Care 2008;31:1-11. At Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylurea a Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Intensive Insulin Lifestyle + Metformin + Pioglitazone Lifestyle + Metformin + GLP-1 agonist b Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Pioglitazone + Sulfonylurea a STEP 1STEP 2STEP 3 Tier 2: Less well-validated therapies Tier 1: Well-validated therapies Reinforce lifestyle interventions at every visit and check A1C every three months until A1C < 7.0 %, then at least every 6 months thereafter. Change interventions whenever A1C ≥ 7.0 %. a Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. b Insufficient clinical use to be confident regarding safety.

33 FDA: all ischemic events, no CI given Hazard Ratio 1.43 Nissen meta-analysis: MI 1.64 Nissen meta-analysis: CV death 1.31 GSK analysis: CV death, MI, stroke 1.16 RECORD: MI Psaty/Furberg (RECORD, ADOPT, DREAM, all small trials): MI 1.33 FDA: CV death, MI, stroke 1.2 FDA-PIO meta-analysis 0.75 PROactive 2° FDA-PIO meta-analysis + PROactive Adapted from: Lincoff AM, et al. JAMA. 2007;298: ; Singh S, et al. JAMA. 2007;298: PROactive 1° 0.90 Hazard Ratio for Cardiovascular Events Rosiglitazone vs Pioglitazone

34 Kahn SE, et al. Diabetes Care. 2008;31: Fractures in Women Treated With Glitazones

35 Class A1C Reduction Fasting vs PPG Hypo- glycemia Weight Change Dosing (times/day) Outcome Studies Metformin 1.5 FastingNoNeutral2UKPDS Insulin, long acting FastingYesGain1, InjectedDIGAMI, UKPDS, (DCCT) Insulin, rapid acting PPGYesGain1-4, InjectedDIGAMI, UKPDS, (DCCT) Sulfonylureas 1.5 FastingYesGain1UKPDS Thiazolidinediones FastingNoGain1PROactive, RECORD GLP-1 agonists PPGNoLoss2, InjectedNone Repaglinide BothYesGain3None Nateglinide PPGRareGain3NAVIGATOR Pending α-Glucosidase inhibitor PPGNoNeutral3ACE pending Amylin mimetics PPGNoLoss3, InjectedNone DPP-4 inhibitors BothNoNeutral1TECOS pending Bile acid sequestrant 0.5 FastingNoNeutral1-2None Bromocriptine 0.7 PPGNoNeutral1None Adapted from: Nathan DM, et al. Diabetes Care. 2007;30: Nathan DM, et al. Diabetes Care. 2006;29: Nathan DM, et al. Diabetes Care. 2009;32: ADA. Diabetes Care. 2008;31:S12-S54. WelChol PI. 1/2008. Cycloset PI. 5/ Classes of Antihyperglycemic Agents Available for Treatment of Type 2 Diabetes

36 Suggested Treatment Goals in Patients with CMR and Lipoprotein Abnormalities Goals LDL cholesterol Non-HDL cholesterol ApoB (mg/dl) Highest-risk patients, including those with 1) known CVD or 2) diabetes plus one or more additional major CVD risk factor <70<100<80 High-risk patients, including those with 1) no diabetes or known clinical CVD but two or more additional major CVD risk factors or 2) diabetes but no other major CVD risk factors <100<130<90 Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD. Brunzell JD, et al. Diabetes Care 31: , 2008

37 Effectiveness of Aspirin in Diabetes Patients Experiencing Cardiovascular Events (%) * * Physician’s Health Study, NEJM 1989 † Antiplatelet Trialists’ Collaboration, BMJ 1994 ‡ Early Treatment Diabetes Retinopathy Study, JAMA % Placebo ASA 4% 22% Placebo ASA 18% Placebo 12% ASA 9% US MDs*APT † ETDRS ‡ RR.39 p = ns RR.81 p < RR.83 p = 0.004

38 Improvement In Key Clinical Measures % of Adult Patients with * Lower is better for this measure.

39 Gaede P. N Engl J Med 2008; Gaede P. N Engl J Med 2008; 358: STENO -2 Multi-Risk Factor Intervention in Type 2 DM Intensive group end results: A1C 7.7%, BP 140/74, LDL 71 mg/dL, HDL 51 mg/dl, TG 99 mg/dL, aspirin 85%

40 Room for Improvement in Therapy Implementation and Change A1C (%)BP (mm Hg)LDL (mg/dL) >8>9>130>160>140/90>150/100 <50% of Patients With A1C Above Goal had Their Medication Changed Even Lower Percentage of Patients Whose CV Goals Were not Met had Medication Started % of Patients N=1765 Patients With Diabetes *P<.05 for A1C and LDL (P values are derived from Mantel-Haenszel test for trend). Grant RW, et al. Diabetes Care. 2005;28: Rates of Medical Regimen Change in 30 US Academic Medical Centers >7> >130/80


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