1. 1. The Metabolic Memory is more than just tight Glucose Control Legacy effect of Diabetes Treatment By Megahed AbuElmagd Head of Diabetes and Endocrinology Unite Mansoura 2012
2. 2. Definition The concept of a Metabolic Memory that is of diabetic vascular Stresses persisting after glucose normalization, has been supported both in the laboratory and in the clinic and in both Type1 and Type2 diabetes.
3. 3. Evidence 1980s Diabetic animal and isolated cells 2000s - DCCT - UKDPS - EDIC
4. 4. *P=0.04 Summary: Glucose Lowering on CVD in Type 2 Diabetes VADT ACCORD ADVANCE 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)
5. 5. ACCORD Treatment Effect on Primary Outcome 25 0 20 15 10 5 0 1 2 3 4 5 Standard therapy Intensive therapy Patientswithevents% Time (yrs) HR=0.90 (0.78- 1.04), P=0.16 2.29%/yr 2.11%/yr ACCORD Study Group N Engl J Med 358:2545-59; 2008 6
6. 6. 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 Age8.0 5360 438 Non-White 3647 222 0.29 White 6604 501 ACCORD: Hazard Ratios for Primary Outcome by Subgroup 0. 6 1. 0 1. 4HR (Intensive vs. ACCORD Study Group N Engl J Med 358:2545-59;2008.
7. 7. A1C(%) YearDCCT 11 10 9 8 7 6 0 91 2 3 4 5 6 7 8 1 2 3 4 5 6 7DCCT end EDIC Conventional group encouraged to switch to intensive treatment Adapted from: N Engl J Med 329:97786,1993; EDIC: JAMA 287: 25639;2002 A1C During DCCT and Follow-Up Intensive Conventional
8. 8. Cumulative Incidence of the First of Any Predefined CVD Outcomes Years since entry Cumulati ve incidence of any CVD outcome Conventional treatment Intensive treatment 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Risk reduction 42%, CI - 9,63 Log-rank p = 0.016 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; 353:2643-53.
9. 9. After median 8.8 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 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 UKPDS: Legacy Effect of Insulin/Sulfonylurea Therapy RRR = Relative Risk Reduction P = Log Rank Holman RR, et al. New England Journal of Medicine 2008; 359:1577-1589
10. 10. 11 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