1. Glucose Targets for Patients with Diabetes: 2011 Irl B. Hirsch, M.D. Professor of Medicine University of Washington School of Medicine

2. The Problem With Today’s Glycemic Guidelines There are always caveats!

3. Part of the Problem: We keep changing the targets! What to consider in November, 2011

4. Case 1 A 55-year-old man with type 1 diabetes for 51 years 20 years ago, he required laser surgery on both of his eyes Otherwise, he has no albuminuria, minimal neuropathy, and no history of heart disease

5. Case 1 (cont.) Based on this patient’s history, his A1C target should be: A.<6.5% B.<7.0% C.<7.5% D.<8.0% E.As low as reasonable without excessive hypoglycemia

6. Conclusions from Studies of Type 1 Diabetes Intensive control of type 1 diabetes prevents the development and reduces the progression of microvascular disease. (DCCT Research Group. N Engl J Med. 1993;329:977-986.) Intensive control of type 1 diabetes early in the course of disease prevents the development of macrovascular disease years later. (DCCT/EDIC Research Group. N Engl J Med. 2005;353:2643-2653.) The major risk of this therapy is hypoglycemia, but these episodes have no long-term cognitive consequences (DCCT/EDIC Research Group. N Engl J Med. 2007;356:1842-1852.)

7. Type 1 Diabetes: What Else to Consider The DCCT need not be extrapolated to young children or older adults with >20-25 years of type 1 diabetes. Glycemic goals for these populations (both growing in the United States) for primary prevention or secondary intervention of micro- or macrovascular complications are not clear and not evidence-based.

8. What About Type 2 Diabetes?

9. Type 2 Diabetes: UKPDS Intensive Therapy (Sulfonylurea/Insulin ) Population: newly diagnosed patients with type 2 diabetes, at high risk for myocardial infarction (MI) but having little to no cardiovascular disease (CVD) when entering the study Microvascular disease: reduced 21-34% (all P <0.01) MI: reduced 16% (P = 0.052) U.K. Prospective Diabetes Study Group. Lancet. 1998;352:837–853.

10. But what about the big problem of glycemic control and macrovascular disease (CAD, CVD, PVD) in long- standing type 2 diabetes?

11. Macrovascular Disease and Type 2 Diabetes About two-thirds of all people with type 2 diabetes die from CVD. There is major suffering and loss of productivity from microvascular disease. Epidemiological and prospectively followed populations show a relationship between CVD and glycemia. Intervention studies up until 2009 have not been as clear.

12. What Was the Highlight of 2008? Knowing that Sarah Palin could see Russia from her house?

13. No! The report of FOUR LANDMARK studies to better characterize the impact of glycemic control and CVD

14. ADA 2008: ACCORD Versus ADVANCE ACCORD = Action to Control Cardiovascular Risk in Diabetes ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Both published June 12, 2008, in the New England Journal of Medicine Both large studies of patients with established type 2 diabetes with primary endpoint of new CVD events

15. VA Diabetes Trial (VADT) Similar study design: intensive therapy versus standard therapy Primary endpoint: first CVD event after randomization Subjects with longer durations of diabetes, more CVD, higher baseline A1C Duckworth W, Abraira C, Moritz T, et al. N Engl J Med. 2009;360:129-139.

16. Differences in ACCORD/ADVANCE/VADT Skyler JS, Bergenstal R, Bonow RO, et al. Diabetes Care. 2009;32:187-192.

17. Gerstein HC et al. The ACCORD Study Group. N Engl J Med. 2008;358:2545–2559. Results of the Randomized Comparison of an Intensive Versus a Standard Glycemic Strategy Unadjusted HR forP-value Intensive vs. Standard (95% CI) All-cause mortality1.22 (1.01-1.46) 0.04 Primary endpoint: CV death, MI, stroke0.90 (0.78-1.04)0.16 CV death1.35 (1.04-1.76)0.02 Non-fatal MI0.76 (0.62-0.92)0.004 Non-fatal stroke1.06 (0.75-1.50)0.74

18. Baseline Characteristics: HR for Death with Intensive Versus Standard Strategies for Baseline Subgroups Hazard Ratio 12340 <7.5 7.5-8.4 ≥8.5 Yes No Yes No Aspirin use Self-report of neuropathy A1C Interaction P 0.044 0.0008 0.031 Calles-Escandon, Lovato LC, Simons-Morton DG, et al. Diabetes Care. 2010;33:721- 727.

19. 5-Year Outcomes After 3.7 Yrs Intensive Therapy NEJM 2011;364:818-28

20. So What Can We Conclude About Hypoglycemia in ACCORD?

21. How in the World Do We Interpret This?

22. As in other trials, higher average A1C in ACCORD associates with higher risk of death Conclusion from Epidemiological Analyses of the Whole Population For 1% higher A1C HOPE+12% UKPDS+14% ACCORD+22% Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

23. Association of Average A1C with Mortality by Strategy: Cox Proportional Hazards Model Adding Glycemic Strategy Assignment to Other Covariates Hazard ratio for 1% higher average A1C (95% CI) Intensive strategy1.66 (1.46, 1.89)P = 0.0001 Standard strategy1.14 (0.95, 1.38)P = 0.17 Interaction between Intensive and StandardP = 0.0007 The relationships between average A1C and mortality differed between treatment strategies Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

24. Risk of Cardiovascular Death over a Range of Average A1C Levels for the Intensive and Standard Strategies U-shaped curve with standard strategy Steady increase of risk from 6 to 9% A1C with intensive strategy 6789 Adjusted log hazard ratio Intensive Strategy Standard Strategy CV Death Average A1C Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

25. 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 (%) 0.0 0.5 1.0 1.5 2.0 Death rates per year Adjusted Mortality Rates by Treatment Strategy Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990. Excess risk with intensive vs. standard strategy occurred when intensive participants failed to reduce A1C in year 1

26. Are risks of cardiovascular death, MI, and stroke all greater with higher A1C in the whole ACCORD population? Are the relationships between A1C and these endpoints different for the intensive and standard strategies? How do cardiovascular death and non-fatal MI differ with the intensive strategy? Questions About the Primary Composite Endpoint and Its Components

27. Unadjusted Adjusted for baseline, site, and post-randomization factors CV death1.21 (1.04-1.40)1.19 (1.02-1.39) n = 229P = 0.01P = 0.0001 Non-fatal MI1.20 (1.08-1.33)1.20 (1.08-1.34) n = 421P = 0.0007P = 0.0007 Non-fatal stroke1.23 (1.03-1.46)1.18 (0.99-1.40) n = 128P = 0.02P = 0.07 Associations of Average A1C with Cardiovascular Death, MI, and Stroke Cox Proportional Hazards Models Hazard Ratios for 1% greater value (95% CI) Risk of each CV outcome is greater with higher average A1C Riddle MC, Ambrosius WT, Brillon DJ, et al. Diabetes Care. 2010;33:983-990.

28. What Should You Take Away from This? An intensive glycemic treatment strategy was associated with a higher risk of death over 3.4 years of follow-up In the whole population, a 20-22% greater risk of death was associated with each 1% higher average A1C Higher risk of death with an intensive than with a standard strategy was associated with three baseline characteristics: –A1C ≥8.5% –History of neuropathy –History of aspirin use

29. More Take-Away Points The excess risk of death with intensive treatment occurred in participants: –Whose average A1C was >7%, not <7% – Who did not reduce A1C from baseline in the first year Relationships differed between intensive and standard strategies; with an intensive strategy: –Risk of all-cause and cardiovascular death was higher when average A1C was >7% –Risk of MI was lower when A1C was <7%

30. ADVANCE ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

31. ADVANCE: Primary Outcomes ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

32. ADVANCE: Primary Outcomes (cont.) ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

33. ADVANCE ADVANCE Collaborative Group, et al. N Engl J Med. 2008;358:2560-2572.

34. 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, et al. N Engl J Med. 2008;358:2560-2572.

35. VADT 1,791 subjects; intensive versus conventional therapy; primary endpoint cardiovascular events Baseline A1C: 9.5% −Standard: 8.4% −Intensive: 6.9% (6 months) Duckworth W, Abraira C, Moritz T, et al. N Engl J Med. 2009;360:129-139.

36. VADT: Final Results Exploratory analyses (presented but not published) suggested that severe hypoglycemia within the past 90 days was a strong predictor of the primary outcome and of CVD mortality. And... Standard (n = 899) Intensive (n =92) Incidence (%) 264 (33.5) Incidence (%) 235 (29.5) P-value 0.14 Non-significant 12% decrease in composite CVD in IT

37. Hazard Ratio for Primary Outcome in Intensive Arm by Duration of Diabetes P<0.05 P = NS P <0.05

38. But What About Microvascular Disease in VADT? Initial publication: no evidence of improvement in endpoints But... on September 3, 2009, a correction is reported in the New England Journal of Medicine –Error was discovered in the initial computer code; actual results were different from those initially reported –Progression from normal to microalbuminuria was significant (P = 0.04) and progression from micro- to macroalbuminuria was also significant (P = 0.03), favoring intensive therapy

39. As in the ADVANCE trial, the VADT showed an improvement in the primary renal outcome, despite the fact that these patients were much more advanced in their disease process than those in the UKPDS. What This Means:

40. Maybe the Most Important Report from 2008 But the one that gets the least respect

41. UKPDS Newly diagnosed type 2 diabetes; intensive versus conventional policy; primary report published September 1998 Follow-up observation published October 2008 Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

42. Post-Trial Changes in A1C UKPDS results presented Mean (95%CI) Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

43. MI Hazard Ratio Fatal or Non-Fatal MI or Sudden Death) Intensive (Sulfonylurea/Insulin) Versus Conventional Glucose Control HR (95%CI) Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

44. After median 8.5 years post-trial follow-up Aggregate Endpoint 19972007 Any diabetes-related endpointRRR:12%9% P: 0.029 0.040 Microvascular diseaseRRR: 25%24% P: 0.00990.001 Myocardial infarctionRRR:16%15% P: 0.0520.014 All-cause mortalityRRR:6%13% P: 0.440.007 RRR = Relative Risk Reduction, P = Log Rank Legacy Effect of Earlier Glucose Control Holman RR, Paul SK, Bethel MA, Neil HA, Matthers DR. N Engl J Med. 2008;359:1565-1576.

45. Impact of Intensive Therapy in Diabetes Summary of Major Clinical Trials StudyMicrovascularCVDMortality DCCT/EDIC↓↓↔↓↔↔ UKPDS↓↓↔↓↔ ↓ ACCORD↓↔↑ ADVANCE↓↔↔ VADT↓↔↔ Long Term Follow-up Initial Trial

46. Big Picture Messages Type 1 and type 2 diabetes: early meticulous glucose control can prevent microvascular and neuropathic complications Type 1 and type 2 diabetes: early meticulous glucose control appears to prevent CVD many years later (“metabolic memory” and “legacy effect”)

47. More Big Picture Messages Type 2 diabetes: patients with known CVD or a long duration of diabetes may be harmed by meticulous control; although the mechanism(s) for this are not known, the leading candidate mechanism is hypoglycemia

48. Still More Big Picture Messages Type 1 diabetes: impact of glycemia on microvascular disease not present after 20-25 years (probably true for type 2 diabetes, too) After long duration of either type 1 or type 2 diabetes (or known CVD), it appears that blood pressure and LDL cholesterol levels better predict CVD mortality than A1C Impact of hypoglycemia is not consistent between populations (children <5 years of age, geriatrics, inpatients)

49. So, What Are the A1C Targets?

50. A1C TARGETS Several societies have published targets, but it is clearly complicated as so many factors involved, in addition to the fact A1C itself is at best a fair marker of average glycemia for an individual patient Our thoughts…

51. Individualizing Glycemic Targets in T2DM Ismail-Beigi, F., et al. Ann Inter Med. 154:554-559, 2011

53. Individualized Targets The available evidence, albeit limited, suggests that in younger patients with relatively recent onset of T2DM and little, if any, micro- and macrovascular complications, near-normal glycemic targets should be the standard. Here, the aim is to help prevent complications over the many years of life. In older individuals with longstanding T2DM and evidence of CVD (or multiple CVD risk factors), somewhat higher targets should be considered. Ann Inter Med. 154:554-559, 2011

54. Metabolic Control: Bottom Line Mother Nature keeps score.* *especially early in the course of diabetes

55. Thank You