John B. Buse, MD, PhD Professor of Medicine Chief, Division of Endocrinology Director, Diabetes Care Center University o

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

2. CVD and Glycemia

3. Glycemic Goals of Therapy Goal Premeal plasma glucose (mg/dl) 2-h postprandial plasma glucose HbA1c ADA 70-130 (<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) http://www.aace.com/pub/press/releases/diabetesconsensuswhitepaper.php

4. Recent Glycemia CVD Studies Skyler J, et al. Diabetes Care. 2009; 32:187-92.

5. Summary: Glucose Lowering on CVD in Type 2 Diabetes *P=0.04

6. ACCORD Treatment Effect onPrimary Outcome 25 Standard therapy 20 HR=0.90 (0.78-1.04), P=0.16 2.29%/yr Patients with events % 15 2.11%/yr 10 Intensive therapy 5 0 0 3 4 5 1 2 6 Time (yrs) ACCORD Study Group N Engl J Med 358:2545-59; 2008

7. ACCORD: Hazard Ratios for Primary Outcome by Subgroup Protocol Defined N Events Interaction P-value Subgroups Overall 10251 723 Primary Prevention 6643 330 0.04 Secondary Prevention 3608 393 Women 3952 212 0.74 Men 6299 511 Baseline Age<65 6779 383 0.65 Baseline Age≥65 3472 340 Baseline A1C≤8.0 4868 284 0.03 Baseline A1C>8.0 5360 438 Non-White 3647 222 0.29 White 6604 501 0.6 1.0 1.4 ACCORD Study Group N Engl J Med 358:2545-59;2008. HR (Intensive vs. Standard)

8. A1C During DCCT and Follow-Up Intensive Conventional group encouraged to switch to intensive treatment Conventional 11 10 9 A1C (%) 8 7 6 0 1 2 3 4 5 6 7 8 9 2 3 4 5 6 7 1 DCCT end DCCT EDIC Year Adapted from: NEngl J Med 329:977–86,1993; EDIC: JAMA 287: 2563–9;2002

9. Cumulative Incidence of the First of Any Predefined CVD Outcomes nonfatal MI, stoke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization 0.12 Conventional treatment 0.10 Risk reduction 42%, CI - 9,63 Log-rank p = 0.016 0.08 Cumulative incidence of any CVD outcome 0.06 0.04 Intensive treatment 0.02 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years since entry Fatal MI, CVA, or CVD death ↓57% DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-53.

10. UKPDS: “Legacy Effect”of Insulin/Sulfonylurea Therapy After median 8.8 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR:12%9% P:0.0290.040 Microvascular disease RRR:25% 24% P: 0.009 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction P = Log Rank Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589

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

12. ADA – AHA – ACCRevised 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; 32:187-92.

13. ADA – AHA – ACCRevised 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; 32:187-92.

14. ADA – AHA – ACCRevised 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; 32:187-92.

15. ADA – AHA – ACCRevised 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; 32:187-92.

16. Adjusted log(Hazard Ratio) by Treatment Strategy Relative to Standard at A1c of 6% Risk of Death over a Range of Average A1c Steady increase of risk from 6 to 9% A1c with intensive strategy Intensive strategy Standard strategy 6 7 8 9 Average A1c % Excess risk with intensive strategy vs standard occurred above A1c 7%

17. Adjusted Mortality Rates by Treatment Strategy Rates of Death During 3.4 Years of Treatmentover a Range of 1-year Change of A1c Intensive strategy Excess risk with intensive strategy vs standard occurred when intensive participants failed to reduce A1c in year 1 Death rates per year Standard strategy 0.0 0.5 1.0 1.5 2.0 A1c decline from baseline over 12 months (%)

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/m2) 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 < 35 mg/dL and/or triglyceride level > 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. 5-10%/yr 10-15%/yr ADA and WHO Glucose Tolerance Categories 2-hr Plasma Glucose on OGTT Fasting Plasma Glucose Diabetes Mellitus Diabetes Mellitus 126 mg/dL 200 mg/dL Impaired Fasting Glucose (IFG) Impaired Glucose Tolerance (IGT) “Pre- Diabetes” 100 mg/dL 140 mg/dL Normal Normal * 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.

21. Glucose is NOT a Standardized Analyte • CAP survey for glucose “120-170 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 3.9-10.9% • 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: 403-409, 2007.

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

23. Consensus StatementIFCC, 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/mol • eAG (estimated average glucose) in mg/dL All clinical guidelines should be expressed in these units Diabetes Care 30:2399-2400, 2007

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

25. HbA1c Advantages Compared with FPG, OGTT • 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

26. HbA1c: Limitations • 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

27. Numbers of people with HbA1c ≥ 6.5%, FPG ≥ 126 mg/dl, or 2hPG ≥ 200 mg/dl.2435 adult Pima Indians without previous dx. 2-hr PG (n=237) 10% HbA1c (n=182) 7% 18 73 37 125 21 2 None = 2142 Any = 293 (12%) Total = 2435 17 FPG (n=165) 7%

28. Prevention of Type 2 Diabetes Behavior Medication Li et al., Lancet 2008;371:1783-1789. ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25:742-749. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. DREAM Trial Investigators. Lancet. 2006;368:1096-1105. DREAM Trial Investigators. N Engl J Med. 2006;355:1551-1562. DeFronzo RA, et al. ADA 68th Scientific Sessions 2008. Origin Trial Investigators. Am Heart J 2008;155:26-32.

29. Prevention Of Type 2 Diabetes: Completed Lifestyle Trials In IGTKey Points • 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

30. Prevention of Type 2 Diabetes Behavior Medication NOT FDA APPROVED FOR PREVENTION NOT FDA APPROVED FOR PREVENTION Li et al., Lancet 2008;371:1783-1789. ADA Position Statement on the Prevention or Delay of Type 2 Diabetes. Diabetes Care. 2002;25:742-749. Torgerson JS, et al. Diabetes Care. 2004;27:155-161. DREAM Trial Investigators. Lancet. 2006;368:1096-1105. DREAM Trial Investigators. N Engl J Med. 2006;355:1551-1562. DeFronzo RA, et al. ADA 68th Scientific Sessions 2008. Origin Trial Investigators. Am Heart J 2008;155:26-32.

31. Normal Re-evaluate in ≤3 years if risk factors remain IFG or IGT IFG and IGT + Other Features* Diabetes Lifestyle intervention; follow-up† @ 1 year Lifestyle intervention and/or metformin; follow-up†@ 6 mo. Lifestyle intervention plus metformin; follow-up†@ 3 mo. • IFG: fasting (8 hours) plasma glucose 100-125 mg/dL • IGT: 2-hour value in 75-g OGTT 140-199 mg/dL † Follow-up here refers to formal reassesment of glycemic status. Follow-up should be individualized with respect to venue, frequency and goals. * “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-degreerelative • Diabetes: fasting ≥126 mg/dl or 2-hour ≥200 mg/dl; should be confirmed on a separate day unless unequivocally elevated and/or symptomatic 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. METFORMIN IS NOT FDA APPROVED FOR PREVENTION

32. STEP 1 STEP 2 STEP 3 Tier 1: Well-validated therapies Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Intensive Insulin At Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylureaa Tier 2: Less well-validated therapies Lifestyle + Metformin + Pioglitazone + Sulfonylureaa Lifestyle + Metformin + Pioglitazone Lifestyle + Metformin + GLP-1 agonistb Lifestyle + Metformin + Basal Insulin Updated ADA/EASD Consensus Algorithm 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 %. 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.

33. 1.43 Nissen meta-analysis: MI 1.64 Nissen meta-analysis: CV death GSK analysis: CV death, MI, stroke 1.31 Psaty/Furberg (RECORD, ADOPT, DREAM, all small trials): MI 1.33 1.16 RECORD: MI 1.2 FDA: CV death, MI, stroke 0.75 1.4 FDA: all ischemic events, no CI given FDA-PIO meta-analysis 0.84 PROactive 2° FDA-PIO meta-analysis + PROactive 0.83 0.75 1.0 1.25 1.5 1.75 Hazard Ratio for Cardiovascular Events Rosiglitazone vs Pioglitazone 0.90 PROactive 1°  Hazard Ratio Adapted from: Lincoff AM, et al. JAMA. 2007;298:1180-1188; Singh S, et al. JAMA. 2007;298:1189-1195.

34. Fractures in Women Treated With Glitazones Kahn SE, et al. Diabetes Care. 2008;31:845-851.

35. 13 Classes of Antihyperglycemic Agents Available for Treatment of Type 2 Diabetes Adapted from: Nathan DM, et al. Diabetes Care. 2007;30:753-759. Nathan DM, et al. Diabetes Care. 2006;29:1963-1972. Nathan DM, et al. Diabetes Care. 2009;32:193-203. ADA. Diabetes Care. 2008;31:S12-S54. WelChol PI. 1/2008. Cycloset PI. 5/2009.

36. Suggested Treatment Goals in Patients with CMR and Lipoprotein Abnormalities Brunzell JD, et al. Diabetes Care 31:811-822, 2008

37. Effectiveness of Aspirin in Diabetes RR .81 p < 0.002 25 22% 20 PatientsExperiencingCardiovascularEvents(%) RR .83 p = 0.004 18% RR .39 p = ns 15 12% 10% 10 9% 5 4% 0 Placebo Placebo Placebo ASA ASA ASA US MDs* APT† ETDRS‡ * Physician’s Health Study, NEJM 1989 † Antiplatelet Trialists’ Collaboration, BMJ 1994 ‡ Early Treatment Diabetes Retinopathy Study, JAMA 1992

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

39. 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% Gaede P. N Engl J Med 2008; 358: 580-591

40. Room for Improvement in Therapy Implementation and Change Rates of Medical Regimen Change in 30 US Academic Medical Centers 100 N=1765 Patients With Diabetes 90 <50% of Patients With A1C Above Goal had Their Medication Changed 80 70 % of Patients 60 Even Lower Percentage of Patients Whose CV Goals Were not Met had Medication Started 50 40 30 20 10 0 >130/80 >7 >8 >9 >140/90 >150/100 >100 >130 >160 A1C (%) 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;28:337-442.