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  1. Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease CVD Mortality and/or Events? Presenters: Jeff Probstfield, MD—University of WashingtonIrl B. Hirsch, MD—University of Washington Eliot A. Brinton, MD—University of Utah Paul Rosenblit, MD—University of California, Irvine Moderator: Eliot A. Brinton, MD—University of Utah

  2. Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease Total Mortality and/or CVD Events? Jeff Probstfield, MDProfessor of Medicine in the Division of CardiologyAdjunct Professor of Epidemiology,Director of the Clinical Trials DivisionUniversity of WashingtonSeattle, WA

  3. To determine whether CVD event rates can be reduced in people with diabetes by intensively targeting three important CVD risk factors: hyperglycemia, dyslipidemia, and high blood pressure. Three trials in one research program Double 2 by 2 factorial design ACCORD Trial Overall Goal Buse, JB, et al, AmJCard 2007 99:21i-33i.

  4. DSMB Recommendation and NHLBI Decision • NHLBI/NIH decision: • Discontinue intensive glycemia treatment • Transition all participants to the standard glycemia treatment • No interaction between BP and Lipid Trial Components and Glycemia Intervention. • Continue the BP and Lipid trials • “These trials continue to address important questions” (NHLBI Press Release, February 6, 2008)

  5. In middle aged/older people with type 2 DM at high risk for a CVD event, does a therapeutic strategy that targets an A1C < 6.0% reduce CVD event rates more than a strategy that targets an A1C between 7.0% & 7.9% (with the expectation of achieving a median level of 7.5%)? Glycemia Trial Research Question Buse, JB, et al, AmJCard 2007 99:21i-33i.

  6. Observational studies supportive Each 1% higher A1C associated with 18% greater risk of CVD1 CVD-glucose relationship extends into the normal range Clinical trials inconclusive2 Glycemia Trial Rationale 1. Selvin E, et al. Ann Intern Med. 2004;141:421-431. 2. Goff DC Jr, et al. Am J Cardiol. 2007;99[suppl]:4i-20i.

  7. Double 2 X 2 Factorial Design BP Lipid Intensive (SBP<120) Standard (SBP<140) Statin + Masked Study Drug Statin + Masked Study Drug Intensive Glycemia (A1C<6%) 1178 1193 1383 1374 5128* Standard Glycemia (A1C 7-7.9%) 1184 1178 1370 1391 5123* 2371* 2753* 2765* 10,251 2362* *Primary analyses compare the marginals for main effects Buse, JB, et al, AmJCard 2007 99:21i-33i.

  8. Participant Eligibility • Stable Type 2 Diabetes for 3+ months • A1C >7.5% AND <9% (more meds) OR <11% (fewer meds) • Age 40-79 + previous CVD events OR • Age 55-79 with: • anatomical ASCVD, albuminuria, LVH OR • > 2 CVD risk factors (dyslipidemia, hypertension, smoking, obesity) • BMI < 45; Cr <1.5 (133 uM) • No frequent/recent serious hypoglycemia • Able/willing to take insulin, do glucose monitoring • Eligible for BP or Lipid Trial Buse, JB, et al, AmJCard 2007 99:21i-33i.

  9. ACCORD Outcomes • Primary: • First occurrence of nonfatal MI OR Nonfatal Stroke OR CV Death • Secondary/Other: • Each component of 10 • Expanded CVD: 10 + Revasc & HF Hosp • Total mortality • Microvascular (nephropathy, neuropathy, eye) • Eye photo substudy (N = 3537) • HRQL (N = 2053); Cost (N = 4311) • MIND: cognition, brain volume (MRI) • Falls/Fractures/BMD Buse, JB, et al, AmJCard 2007 99:21i-33i.

  10. A1C Distribution Standard Rx Goal Intensive Rx Goal

  11. A1C Distribution: 48 Mo. Standard Rx Goal Intensive Rx Goal December 2007

  12. Median A1C and Interquartile Ranges ACCORD Study Group, NEJM 2008 358:2545-2549.

  13. All Cause Mortality 1.41%/yr 1.14%/yr HR = 1.22 (1.01-1.46) P = 0.04 ACCORD Study Group, NEJM 2008 358:2545-2549.

  14. Primary & Secondary Outcomes ACCORD Study Group, NEJM 2008 358:2545-2549.

  15. Primary & Secondary Outcomes ACCORD Study Group, NEJM 2008 358:2545-2549.

  16. Primary Outcome 2.29%/yr 2.11%/yr HR = 0.90(0.78-1.04) P = 0.16 ACCORD Study Group, NEJM 2008 358:2545-2549.

  17. Can the observed treatment group difference in mortality be explained by the observed post-randomization treatment group difference in severe hypoglycemia? The Question:

  18. Severe Hypoglycemia Requiring Medical Assistance Intensive Group Annual Incidence Rate = 3.3% Standard Group Annual Incidence Rate = 1.0% ACCORD Study Group, NEJM 2008 358:2545-2549.

  19. Background: Mortality By Severe Hypoglycemia Never Experienced a Hypoglycemic Event Experienced Hypoglycemic Event Overall Mortality Rates 1.2% / year 3.3% / year Intensive Glycemia 1.3% / year 2.8% / year Standard Glycemia 1.1% / year 4.9% / year Again, mortality is higher among participants who had experienced a Severe Hypoglycemic Event, regardless of treatment strategy ACCORD Study Group, NEJM 2008 358:2545-2549.

  20. Mortality By Treatment Group andSevere Hypoglycemia Mortality Higher in Intensive Group Mortality Higher in Standard Group Interaction P < 0.01 ACCORD Study Group, NEJM 2008 358:2545-2549.

  21. Conclusions—I • Among participants who never had a severe hypoglycemic event during follow-up, mortality was greater in the intensive group. However, among participants who had a hypoglycemic event, mortality was greater in the standard group • Participants who had experienced a severe hypoglycemic event were more likely to die • True for both treatment groups ACCORD Study Group, NEJM 2008 358:2545-2549.

  22. We have not been able to identify a single agent, or combination, that accounts for the imbalance in mortality. Exenatide  less mortality, but used rarely and more often in Intensive Glycemia group Premixed Insulin  greater mortality, but used more often in Standard Glycemia group Bolus Insulin  greater mortality, but no difference in mortality hazard ratios by randomized group and we don’t know if the relationship with mortality is a reflection of use or the participants to whom it was given Approximately a 20% increase in mortality associated with Intensive Glycemia even after controlling for participant characteristics and post-randomization use of glycemia medications. Conclusions—II ACCORD Study Group, NEJM 2008 358:2545-2549.

  23. Identifying a “Cause” of the Higher Mortality ACCORD identified a previously unknown harm of a strategy of intensive glucose lowering in high-risk individuals with T2DM ACCORD was designed to test atherapeutic strategy, nota specific component of the strategy or specific drug(s); numerous factors differed between the randomized groups In a strategy trial, potential causes are difficult, if not impossible, to separate out from other post-baseline factors that differ by group Example: An ACCORD participant may or may not be on a drug for various reasons, so we can’t separate out effects of the drug from effects of patient characteristics that change over time (some of which were not measured) ACCORD Study Group, NEJM 2008 358:2545-2549.

  24. I T S I T P I T T It’s The Strategy(the therapeutic approach to intensive glucose lowering) In This Population(with longstanding T2DM and CVD or CVD RFs) Intention To Treat analyses(comparing groups based on randomized assignment – the analysis that provides strong evidence of causality) Conclusion- what caused the difference ?

  25. ADVANCE Study Review: Which A1c Targets and Which Drugs for Diabetes? Irl B. Hirsch, MDProfessor of MedicineDivision of Metabolism, Endocrinology and NutritionUniversity of Washington School of Medicine Seattle, WA

  26. Differences Between ACCORD/ADVANCE BASELINE ACCORD ADVANCE # patients 10,251 11,140 duration DM (yrs) 10 8 Hx macrovasc. Dz (%) 35 32 Baseline A1C (%) 8.1 7.2 Intervention target A1C (%) <6 <6.5 insulin Rx (%) 77 vs. 55 41 vs. 24 TZD Rx (%) 92 vs. 58 17 vs. 11 Outcome (intensive vs. standard) Median A1C @ study end 6.4 vs. 7.5% 6.4 vs. 7.0% DEATH: any cause 5.0 vs. 4.0%* 8.9 vs. 9.6% NEJM 2008;358, 2630 *P<0.05

  27. ADVANCE Primary Outcomes ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

  28. ADVANCE Primary Outcomes ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

  29. ADVANCE: Primary Outcomes ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

  30. ADVANCE: Secondary Endpoints • All-cause mortality: P = NS • Total renal events 11% RR with intensive, P < 0.001 • Eye events: P = NS • CHF, PVD, neuropathy: P = NS ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

  31. Candidate Mechanisms: TGC and CVD Events • Hypoxia (remember the PDR story!) • Hypoglycemia (arrhythmias, brain dysfunction, vasoconstriction, new data leading to DAN) • Obesity (3 drugs resulting in weight gain) • Glucose variability in long-standing diabetes (insulin deficiency)

  32. Big Picture Messages • T1 and T2DM: early meticulous glucose control can prevent microvascular and neuropathic complications • T1DM: early meticulous glucose control appears to prevent CVD many years later • T2DM: early meticulous glucose control appears to prevent both micro- and macrovascular disease in T2DM

  33. The Benefit of Early Aggressive Glycemic Control • Metabolic memory • “Legacy effect”

  34. Big Picture Message • T2DM: patients with known CVD or long durations of DM may be harmed by meticulous control; although the mechanism(s) for this are not known, the leading candidate mechanism is hypoglycemia

  35. More Big Picture Messages • T1DM: impact of glycemia on microvascular disease not present after 20-25 years (probably true for T2DM too) • After long duration of either T1 or T2DM (or known CVD), it appears BP, LDL-C and ASA use better predict CVD mortality than A1C • Impact of hypoglycemia is not consistent between populations (under 5 year-olds, geriatrics, inpatient)

  36. SO WHAT A1C TARGETS?

  37. My Take, At Least While We Are Awaiting ADA/AACE Consensus Statements on T2DM Targets • < 10 years T2DM AND no CVD: Target at least < 7% • 1st line: metformin • 2nd line: SFU, sitagliptin, exenatide, basal insulin (A1C < 9%) • 3rd line: physiologic insulin therapy • 10-15 years T2DM AND no CVD: • No change from above but this population will be more likely to require insulin to reach A1C target

  38. Possible Strategy • >15 years T2DM OR known CVD: 7-7.5% A1C • Drugs with less risk of hypoglycemia • Metformin, SFU unlikely to be effective with longer durations of DM • Little data for TZDs, exenatide, sitagliptin • Greatest risk of hypoglycemia with insulin, but also greatest likelihood of efficacy to consistent A1C levels • Less hypoglycemia with basal insulin alone, but some prandial insulin required as duration of DM and A1C increases • Don’t use basal insulin to replace prandial needs!

  39. Conclusion • The 4 recent studies do not negate the years of research from other clinical trials • Different populations appear to have different A1C targets • It appears the same in the inpatient population! • It is difficult to recommend a generalization of one drug vs. another (depending on the situation) as there are so many variables and little clinical trial data to guide us • General: hypoglycemia, weight gain, pregnancy, cost • Specific: GI tolerability, edema, bone fx, increase CVD risk (?)

  40. Conclusion • Insulin is always an option, is under-utilized, and needs to be used in a physiologic manner in patients with severe insulin deficiency • In patients with known vascular disease, even more modest A1C targets require the use of insulin analogues (as opposed to human insulins) due to the consistent data showing less hypoglycemia even though there are no differences in A1C.

  41. Effects of Intensive vs. Standard Glucose Control on Cardiovascular Disease: the VA Diabetes Trial (VADT) Eliot A. Brinton, MD Diplomate, American Board of Clinical Lipidology Associate Professor, University of UtahDirector, Metabolism Section of Cardiovascular GeneticsSalt Lake City, UT

  42. VADT: Design Subject Inclusion: • DM-2 on insulin or unresponsive to maximal doses oral agents • Central A1c > 7.5%, or local A1c > 8.3% • No major CV events in last 6 months (MI, CVA, CV surgery) • Creatinine < 1.6 mg/dL, ALT < 3x ULN • N=1791 (20 centers) Prospective, randomized study of: • Intensive vs. standard glycemic Rx, 5-7.5 years • Background good diet & lifestyle + Rx BP & lipids (both arms) • 1o endpoint: CVD composite Abraira, C, et al, J Diab. Complic, 2003; 17: 314

  43. VADT: Design (cont’d) Primary outcome • Composite of: MI, CVA, CVD Death, CHF, PCI, CABG, “Inoperable” CAD, LE revascularization or amputation for ischemia Secondary outcomes • Total mortality • Angina • TIA • Claudication • Critical limb ischemia • Retinopathy • Nephropathy • Neuropathy • Quality of life • Cognitive function • Cost-effectiveness Abraira, C, et al, J Diab. Complic, 2003; 17: 314

  44. VADT: Baseline Subject Characteristics (similar in both arms) • Sex: 97% male • Age: 60.4 + 9.5 y • DM Duration: 11.5 + 7.7 y • BMI: 31.3 + 4.6 kg/m2 • A1c: 9.4 + 1.5% • Race • Non-Hispanic, White: 62% • African-American: 17% • Hispanic: 16% • Other: 5% • Smoking history • Current: 17% • Former: 55% • Never: 28% Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

  45. VADT: Glycemic Rx and Results A1c Goal by Study Arm Intensive: <7% Standard: 8-9% Method (same in both Rx arms): Metformin (BMI>27) or glimepiride (BMI<27) Rosiglitazone Insulin Other oral agents Toolbox: add any other drugs to get to Rx goals On-study A1c by Study Arm Intensive: 6.9% Standard: 8.4% Abraira, C, et al, J Diab. Complic, 2003; 17: 314

  46. VADT: Primary Endpoint Non-significant trend towards 12% decrease in CVD (composite) with intensive glycemic control Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

  47. VADT: Antiplatelet/Anticoagulant, Statins and Cigarette Use (%) Antiplatelet/Anticoagulant Statins Cigarette Smoking Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

  48. VADT: On-Study LDL-C (Median/IQR mg/dL) ~30% ↓ in LDL-C Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

  49. VADT: On-Study HDL-C (Median/IQR mg/dL) ~18% ↑ in HDL-C Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

  50. VADT: On-Study TG (Median/IQR mg/dL) ~21% ↓ in TG Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.