3Glycemic Goals of Therapy Premeal plasma glucose (mg/dl)2-h postprandial plasma glucoseHbA1cADA70-130(<180)*<7%†ACE<110<140<6.5%*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)
4Recent Glycemia CVD Studies CharacteristicACCORDADVANCEVADTN10,25111,1401,791Mean age626660Hx CVD35%32%40%BMI32.22831.3BL mean A1C8.3%7.5%9.4%BL meds34% Ins/1.4 OAD1% Ins/1.5 OAD51% Ins/??Statin use62% %28% %58% %Antiplatelet use54.5% %48% %76% %Study duration3.45.06.0Target 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 end9110275BP at end127 / 67136 / 74127 / 69Smokers at end9.9%8%17%Skyler J, et al. Diabetes Care. 2009; 32:
5Summary: Glucose Lowering on CVD in Type 2 Diabetes VADTACCORDADVANCEPrimary outcomeNon-fatal MINon-fatal strokeCVD deathHospitalization for CHFRevascularizationHazard Ratio forprimary 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)*P=0.04
6ACCORD Treatment Effect on Primary Outcome 25Standard therapy20HR=0.90 ( ), P=0.162.29%/yrPatients with events %152.11%/yr10Intensive therapy5123456Time (yrs)ACCORD Study Group N Engl J Med 358: ; 2008
7ACCORD: Hazard Ratios for Primary Outcome by Subgroup Protocol Defined N Events Interaction P-valueSubgroupsOverallPrimary PreventionSecondary PreventionWomenMenBaseline Age<Baseline Age≥Baseline A1C≤Baseline A1C>Non-WhiteWhite0.61.01.4ACCORD Study Group N Engl J Med 358: ;2008.HR (Intensive vs. Standard)
8A1C During DCCT and Follow-Up IntensiveConventionalConventional group encouraged to switchto intensive treatment11109A1C (%)8During DCCT, intensive insulin therapy in people with type 1 diabetes significantly reduced HbA1C relative to those receiving conventional treatment. The intensively-treated group achieved a mean HbA1C of 7.1%, while the conventionally-treated patients had HbA1C of approximately 9.0%. During the EDIC (Epidemiology of Diabetes Intervention and Complications research group) follow-up of the DCCT cohort, all patients were encouraged to adopt intensive insulin therapy. During this time, HbA1C stablised to a similar level (just over 8%) in both treatment groups.76123456789DCCT end1234567DCCTYearEDICAdapted from: N Engl J Med 329:977–86,1993; EDIC: JAMA 287: 2563–9;20028
9Cumulative Incidence of the First of Any Predefined CVD Outcomes nonfatal MI, stoke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization0.12Conventional treatment0.10Risk reduction 42%,CI - 9,63Log-rank p = 0.0160.08Cumulative incidence of any CVD outcome0.060.04Intensive treatment0.020.00123456789101112131415161718192021Years since entryFatal MI, CVA, or CVD death ↓57%DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:9
10UKPDS: “Legacy Effect” of Insulin/Sulfonylurea Therapy After median 8.8 years post-trial follow-upAggregate EndpointAny diabetes related endpoint RRR: 12% 9%P:Microvascular disease RRR: 25% 24%P:Myocardial infarction RRR: 16% 15%P:All-cause mortality RRR: 6% 13%P:RRR = Relative Risk Reduction P = Log RankHolman RR, et al. New England Journal of Medicine 2008; 359:10
11The “Natural History” of Type 2 Diabetes Build up “bad” metabolic memoryDrive the risk for complicationsA1C (%)TIME (yrs since diagnosis)
12ADA – AHA – ACC Revised Glycemic Control Recommendations 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. Diabetes Care. 2009; 32:
13ADA – 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:
14ADA – AHA – ACC Revised Glycemic Control Recommendations 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. Diabetes Care. 2009; 32:
15ADA – AHA – ACC Revised Glycemic Control Recommendations 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. Diabetes Care. 2009; 32:
16Risk of Death over a Range of Average A1c Adjusted log(Hazard Ratio) by Treatment StrategyRelative to Standard at A1c of 6%Steady increase of risk from 6 to 9% A1c with intensive strategyIntensive strategyStandard strategy6789Excess risk with intensive strategy vs standard occurred above A1c 7%Average A1c %
17Rates of Death During 3.4 Years of Treatment over a Range of 1-year Change of A1c Adjusted Mortality Rates by Treatment StrategyIntensive strategyExcess risk with intensive strategy vs standard occurredwhen intensive participants failed to reduce A1c in year 1Death rates per yearStandard strategy0.00.51.01.52.0A1c decline from baseline over 12 months (%)
19Screening Triggers for Prediabetes and Type 2 Diabetes Preferred screening test is a venous FPGScreen all individuals aged ≥ 45 years; if normal, repeat at 3-year intervalsConsider earlier and more frequent screening in individuals who are overweight (BMI ≥ 25 kg/m2) with additional risk factors:Habitual physical inactivityFirst-degree relative with diabetesMembers 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 GDMHypertension (≥ 140/90 mm Hg)HDL-C < 35 mg/dL and/or triglyceride level > 250 mg/dLPolycystic ovarian syndromeHistory of IGT or IFGOther conditions associated with insulin resistance (eg, acanthosis nigricans)History of vascular diseaseSlide 9 – Page 6 (PRACTICE PEARL)The ADA recommendations for diabetes and prediabetes screening are listed here; however, new ADA guidelines will be issued soon.Many people in general medical care have 1 or more of these risk factors listed under the third bullet point.FPG screening every 3 years in most patients in primary care practices is probably reasonable.Note: There is currently no FDA-approved pharmacological treatment for prediabetes, but as you will see on the next slide, there are situations in which the ADA recommends using metformin in prediabetes.American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.
20ADA and WHO Glucose Tolerance Categories Fasting PlasmaGlucose2-hr Plasma Glucose on OGTT5-10%/yr10-15%/yrDiabetesMellitusDiabetesMellitus126mg/dL200mg/dLImpairedFastingGlucose (IFG)ImpairedGlucoseTolerance (IGT)“Pre-Diabetes”100mg/dL140mg/dLNormalNormal* 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.
21Glucose 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 groupInter-laboratory CV is 15.1%Variability in part due to differences between instrumentsCVs 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% rangeIn comparison, this is ~5% for many other analytes*Dungan K, et al. Diabetes Care 30: , 2007.
23Consensus Statement IFCC, EASD, IDF, ADA HbA1c assay to be standardized worldwide using the new IFCC standard and expressed as:% as currently used (DCCT values)IFCC units in mmol/moleAG (estimated average glucose) in mg/dLAll clinical guidelines shouldbe expressed in these unitsDiabetes Care 30: , 2007
24ADA Expert Committee on Diagnosis, 1997 Relation of FPG, 2hPG, HbA1c to Retinopathy: EgyptADA Expert Committee, 1997
25HbA1c Advantages Compared with FPG, OGTT The HbA1c assay is standardized and aligned to DCCT/UKPDSBetter index of overall glycemic exposureEquivalent in predicting risk for long-term complicationsPredicts CVDSubstantially less laboratory variabilitySubstantially less pre-analytic instabilityNo need for fasting or timed samplesUnaffected by acute (e.g. stress or illness-related) perturbations in glucose levelsUsed to guide management and adjust therapy
26HbA1c: Limitations Laboratory Expense Not universally available Patient-related: determinants in addition to glycemiaHemoglobinopathiesVariation in red cell lifespan (hemolysis, blood loss, etc.)Unexplained racial differencesNot useful as acute measureSelecting a diagnostic cut pointOn what basis?Will not always agree with diagnoses by FPG or OGTTBreak with the past
27Numbers of people with HbA1c ≥ 6 Numbers of people with HbA1c ≥ 6.5%, FPG ≥ 126 mg/dl, or 2hPG ≥ 200 mg/dl adult Pima Indians without previous dx.2-hr PG (n=237)10%HbA1c (n=182)7%187337125212None = 2142Any = (12%)Total = 243517FPG (n=165)7%
28Prevention of Type 2 Diabetes StudySubjectsInterventionRelative Risk ReductionDaQingFinnish DPSUS DPPIGTIGT + “IFG”Diet or Exercise or BothLifestyle64%/53%/61%STOP-NIDDMEDITTRIPODXENDOSDREAMACT-NOWORIGINNAVIGATORIFGPrior GDMIFG or IGTIGT+IFGMetforminAcarboseMetformin or Acarbose or BothTroglitazoneOrlistatRosiglitazone or Ramipril or BothPioglitazoneGlargine or Fish oil or BothNateglinide or Valsartan or Both31%25%NS35%45%61%/NS81%~2010~2009BehaviorMedicationDuring year 3 or 4 of the EDIC study, microalbuminuria was detected for the first time in 11% of 573 patients in the former conventional therapy groups, as compared with 5% in the intensive-therapy group, representing a 53% odds reduction.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 68th Scientific Sessions Origin Trial Investigators. Am Heart J 2008;155:26-32.
29Prevention Of Type 2 Diabetes: Completed Lifestyle Trials In IGT Key Points Lifestyle therapy can be very effective in preventing or delaying diabetesThe lifestyle therapy that works involves three core featuresBalanced low-calorie nutrition:low fat, high in fiber (vegetables, fruits, whole grains)Regular physical activity:aerobic and resistance, 30+ minutes most days of the weekFrequent intervention with dietitians and lifestyle coaches:~weekly for first month~monthly for the first three months~every three months for life
30Prevention of Type 2 Diabetes StudySubjectsInterventionRelative Risk ReductionDaQingFinnish DPSUS DPPIGTIGT + “IFG”Diet or Exercise or BothLifestyle64%/53%/61%STOP-NIDDMEDITTRIPODXENDOSDREAMACT-NOWORIGINNAVIGATORIFGPrior GDMIFG or IGTIGT+IFGMetforminAcarboseMetformin or Acarbose or BothTroglitazoneOrlistatRosiglitazone or Ramipril or BothPioglitazoneGlargine or Fish oil or BothNateglinide or Valsartan or Both31%25%NS35%45%61%/NS81%~2010~2009BehaviorMedicationNOT FDA APPROVED FOR PREVENTIONNOT FDA APPROVED FOR PREVENTIONDuring year 3 or 4 of the EDIC study, microalbuminuria was detected for the first time in 11% of 573 patients in the former conventional therapy groups, as compared with 5% in the intensive-therapy group, representing a 53% odds reduction.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 68th Scientific Sessions Origin Trial Investigators. Am Heart J 2008;155:26-32.
31Screening and Diagnosis: Intervention and Follow-Up Screen for Diabetes:FPGor2-hour, 75-g OGTTNormalRe-evaluate in ≤3 years if risk factors remainIFG: fasting (8 hours) plasma glucose mg/dLIGT: 2-hour value in 75-g OGTT mg/dLLifestyle intervention;1 yearIFG or IGT† Follow-up here refers to formal reassesment of glycemic status. Follow-up should be individualized with respect to venue, frequency and goals.IFG and IGT+ Other Features*Lifestyle intervention and/or metformin; 6 mo.* “Other features”: < 60 years of age and BMI ≥ 30 kg/m2 and either A1C > 6.0%, hypertension, low HDL, high triglycerides or family history of diabetes in first-degree relativeDiabetesLifestyle intervention plus metformin; 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 symptomaticSlide 10 – Page 7Slide 10 is adapted from ADA position statements on: 1) management of type 2 diabetes and 2) management of impaired fasting glucose (IFG) or IGT. The key points include:Everybody older than 45 should be screened for diabetes.People younger than 45 who are overweight and have a risk factor should be screened as well.Overweight children with 2 risk factors for diabetes should be screened even in childhood at the time of puberty.Screen at least every 3 years, or more frequently in patients with risk factors or elevated glucose.The screening test is FPG (where the fasting interval is 8 hours) or the 2-hour, 75-g oral glucose tolerance test (OGTT).In children, the dose is 1.75 g/kg up to a maximum of 75 g.The criteria for abnormalities of glucose tolerance are listed toward the bottom of the slide.To use metformin, you should do OGTT. If you do the OGTT you’ll find that a fair number of people with IFG are actively diabetic, and metformin would be effective in this situation.Note to speaker: please turn the meeting over to the moderatorBREAK: 5 minutes (:10 / :40 to :15 / :45)Moderator will first present the answers to the first polling question, JanelleSpeaker:- Please give your thoughts on the pollingThe moderator will ask the group for questions. If there are no questions, the moderator can ask the speaker / audience:Since the prevalence of type 2 diabetes is increasing, and obesity is so widespread in this country, should we just be doing mass screenings for diabetes?What proportion of patients do you screen for type 2 diabetes in your own practice?Note to Speaker: Moderator will turn the call back over to you to present the next section, starting with slide 11 once the question-and answer session is complete.American Diabetes Association. Diabetes Care. 2009;32(suppl 1):S13-S61.METFORMIN IS NOT FDA APPROVED FOR PREVENTION
32Updated ADA/EASD Consensus Algorithm At Diagnosis:Lifestyle+MetforminLifestyle + MetforminSulfonylureaaBasal InsulinIntensive InsulinPioglitazoneGLP-1 agonistbSTEP 1STEP 2STEP 3Tier 2: Less well-validated therapiesTier 1: Well-validated therapiesReinforce 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 %.aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide.bInsufficient clinical use to be confident regarding safety.Nathan DM, et al., Diabetes Care 2008;31:1-11.
33Hazard Ratio for Cardiovascular Events Rosiglitazone vs Pioglitazone 1.43Nissen meta-analysis: MI1.64Nissen meta-analysis: CV death1.31GSK analysis:CV death, MI, strokePsaty/Furberg (RECORD, ADOPT, DREAM, all small trials): MI1.331.16RECORD: MIFDA: CV death, MI, stroke1.2FDA-PIO meta-analysis0.751.4 FDA: all ischemic events, no CI given0.90PROactive 1°PROactive 2°0.840.83FDA-PIO meta-analysis + PROactiveHazardRatio0.718.104.22.1681.0Adapted from: Lincoff AM, et al. JAMA. 2007;298: ; Singh S, et al. JAMA. 2007;298:
34Fractures in Women Treated With Glitazones Kahn SE, et al. Diabetes Care. 2008;31:
3513 Classes of Antihyperglycemic Agents Available for Treatment of Type 2 Diabetes A1CReductionFastingvs PPGHypo-glycemiaWeightChangeDosing(times/day)OutcomeStudiesMetformin1.5NoNeutral2UKPDSInsulin, long actingYesGain1, InjectedDIGAMI, UKPDS, (DCCT)Insulin, rapid actingPPG1-4, InjectedSulfonylureas1ThiazolidinedionesPROactive, RECORDGLP-1 agonistsLoss2, InjectedNoneRepaglinideBoth3NateglinideRareNAVIGATOR Pendingα-Glucosidase inhibitorACE pendingAmylin mimetics3, InjectedDPP-4 inhibitorsTECOS pendingBile acid sequestrant0.51-2Bromocriptine0.7Adapted 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/ Cycloset PI. 5/2009.
36Brunzell JD, et al. Diabetes Care 31:811-822, 2008 Suggested Treatment Goals in Patients with CMR and Lipoprotein AbnormalitiesGoalsLDL cholesterolNon-HDL cholesterolApoB(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<80High-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<130<90Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD.Brunzell JD, et al. Diabetes Care 31: , 2008
37Effectiveness of Aspirin in Diabetes RR .81p < 0.0022522%20Patients Experiencing Cardiovascular Events (%)RR .83p = 0.00418%RR .39p = ns1512%1010%9%54%PlaceboASAPlaceboASAPlaceboASAUS MDs*APT†ETDRS‡* Physician’s Health Study, NEJM 1989† Antiplatelet Trialists’ Collaboration, BMJ 1994‡ Early Treatment Diabetes Retinopathy Study, JAMA 1992
38Improvement In Key Clinical Measures % of Adult Patients with* Lower is better for this measure.38
39STENO -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%Gaede P. N Engl J Med 2008; 358:
40Room for Improvement in Therapy Implementation and Change Rates of Medical Regimen Change in 30 US Academic Medical Centers100N=1765 Patients With Diabetes90<50% of Patients With A1C Above Goal had Their Medication Changed8070% of Patients60Even Lower Percentageof Patients Whose CV Goals Were not Met had Medication Started504030OBJECTIVE: To assess both standard and novel diabetes quality measures in a national sample of U.S. academic medical centers. RESEARCH DESIGN AND METHODS: This retrospective cohort study was conducted from 10 January 2000 to 10 January It involved 30 U.S. academic medical centers, which contributed data from 44 clinics (27 primary care clinics and 17 diabetes/endocrinology clinics). For 1,765 eligible adult patients with type 1 or type 2 diabetes with at least two clinic visits in the 24 months before 10 January 2002, including one visit in the 6 months before 10 January 2002, we assessed measurement and control of HbA(1c), blood pressure, and cholesterol and corresponding medical regimen changes at the most recent clinic visit. RESULTS: In this ethnically and economically diverse cohort, annual testing rates were very high (97.4% for HbA(1c), 96.6% for blood pressure, and 87.6% for total cholesterol). Fewer patients were at HbA(1c) goal (34.0% <7.0%) or blood pressure goal (33.0% <130/80 mmHg) than lipid goals (65.1% total cholesterol <200 mg/dL, 46.1% with LDL cholesterol <100 mg/dL). Only 10.0% of the cohort met recommended goals for all three risk factors. At the most recent clinic visit, 40.4% of patients with HbA(1c) concentrations above goal underwent adjustment of their corresponding regimens. Among untreated patients, few with elevated blood pressure (10.1% with blood pressure >130/80 mmHg) or elevated LDL cholesterol (5.6% with LDL >100 mg/dL) were started on corresponding therapy. Patients with type 2 diabetes were no less likely to be intensified than patients with type 1 diabetes. CONCLUSIONS: High rates of risk factor testing do not necessarily translate to effective metabolic control. Low rates of medication adjustment among patients with levels above goal suggest a specific and novel target for quality improvement measurement.2010>7>8>9>130/80>140/90>150/100>100>130>160A1C (%)BP (mm Hg)LDL (mg/dL)*P<.05 for A1C and LDL (P values are derived from Mantel-Haenszel test for trend).Grant RW, et al. Diabetes Care. 2005;28:40