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Glycemic Control: When the Lower is Not the “Better”?

Ninth International Symposium HEART FAILURE & Co. Rozzano (MI) - April 17-18, 2009. Glycemic Control: When the Lower is Not the “Better”?. Stefano Genovese UO di Endocrinologia e Diabetologia. Questions. Is hyperglycemia an independent risk factor for cardiovascular disease?

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Glycemic Control: When the Lower is Not the “Better”?

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  1. Ninth International Symposium HEART FAILURE & Co. Rozzano (MI) - April 17-18, 2009 Glycemic Control:When the Lower is Not the “Better”? Stefano Genovese UO di Endocrinologia e Diabetologia

  2. Questions • Is hyperglycemia an independent risk factor for cardiovascular disease? • Is hyperglycemia an independent risk factor for cardiovascular disease in diabetic patients? • Lowering glycemia reduces the risk for cardiovascular disease?

  3. Fasting blood glucose and cardiovascular mortality in healthy nondiabetic men Bjornholt JV et al . Diabetes Care 1999;22:45.

  4. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes N Engl J Med 2005;353:2643-53.

  5. UKPDS

  6. Kumamoto ACCORD VADT UKPDS 33 DIGAMI ADVANCE UGDP UKPDS 34 STOP-NIDDM PROactive Other Questions Is it feasible an intensive treatment of hyperglycemia? Are CV events reduced by an intensive treatment of hyperglycemia? Is there a first choice drug in intensive treatment to reduce CV events? The use of an oral hypoglycemic drug vs placebo can reduce CV events?

  7. In the ACCORD study a HbA1c value <6,5% has been reached in less than one year and maintained ACCORD ACCORD Study Group et al. NEJM 2008;358:2545-59

  8. In the ADVANCE study a HbA1c value <6,5% has been reached in three years and maintained ADVANCE ADVANCE Collaborative Group et al. NEJM 2008;358:2560-72

  9. In the VADT study a HbA1c value around 6,5% has been reached in one year and maintained VADT 10.5 10.0 Standard 9.5 9.0 8.5 8.0 HbA1c (%) Intensive 7.5 7.0 6.5 6.0 5.5 5.0 Baseline 1 year 2 years 3 years 4 years 5 years 6 years Years on Study

  10. Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD Nonfatal myocardial infarction, nonfatal stroke, death from cardiovascular causes p=0,16 p=0,04 ACCORD Study Group et al. NEJM 2008;358:2545-59

  11. Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD ACCORD Study Group et al. NEJM 2008;358:2545-59

  12. Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD ACCORD Study Group et al. NEJM 2008;358:2545-59

  13. Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD ACCORD Study Group et al. NEJM 2008;358:2545-59

  14. Causes of death: • Unexpected or presumed cardiovascular disease • Condition other than cancer or cardiovascular disease • What is the role of hypoglycemia? Causes of death in the ACCORD ACCORD Study Group et al. NEJM 2008;358:2545-59

  15. VADT – Predictors of CVD death Variable Hazard Ratio P Value Prior CVD event 3.116 0.0001 Age (per 10 yr) 2.090 <.0001 HDL (per 10 mg) 0.699 0.0079 Baseline HbA1c per 1% 1.213 0.0150 Severe Hypoglycemia 4.042 0.0076

  16. Hypothesis….. • The ACCORD suggests that outcomes differ according to • HbA1c below or abovea 8,0% • Presence of previous CV events • Is there a study on the intensive treatment in T2DM in a population with • Basal HbA1c <8,0% • No previous CV events?

  17. ACCORD vs ADVANCE Dluhy R.G. et al. NEJM 2008;358:2630-3

  18. ACCORD vs ADVANCE Dluhy R.G. et al. NEJM 2008;358:2630-3

  19. ADVANCE does not confirm the reduction of MI suggested by ACCORD Dluhy R.G. et al. NEJM 2008;358:2630-3

  20. In the ADVANCE the intensive treatment reduces the microvascular endpoint Mortality does not increase Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type Diabetes p=0,01 p=0,32 p=0,01 p=0,28 ADVANCE Collaborative Group et al. NEJM 2008;358:2560-72

  21. Hypothesis……. • Is there a study on the intensive treatment in T2DM in a population with • Basal HbA1c <8,0% • No previous CV events? Yes, the …….. UKPDS where participants had basal HbA1c of 7,0% without previous CV events

  22. UKPDS • In the UKPDS the effect of intensive treatment showed p=0,052 and no effect on mortality • In the UKPDS-PTM the reduction of MI was statistically significant • According to the UKPDS duration the follow-up of ACCORD, ADVANCE e VADT seems to short

  23. UKPDS 34 • In the UKPDS an intensive treatment with metformin as a first choice drug in overweight patients reduced mortality

  24. 5238 T2DM patients with high CV risk Pioglitazone 15-45 mg vs placebo with median follow-up of 34,5 months Primary endpoint (Total Mortality non fatal MI, stroke, ACS, coronary and peripheral revascularizations, lower limb amputation) Secondary endpoint (Total mortality non fatal MI, stroke) Secondary prevention of macrovascolar events in patients with type 2 diabetes in the PROactive Study: a randomised controlled trial Dormandy J.A. et al. Lancet 2005;366:1279-89

  25. Wilcox R. et al. Stroke 2007;38:865-73 Erdmann E. et al. JACC 2007;49:1772-80

  26. Erdmann E. et al. Diabetes Care 2007;30:2773-8

  27. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review Eurich D.T. et al. BMJ 2007;335:497-506

  28. If…… • The number of events in the PROactive is similar to thata of CARE and HPS, but PROactive duration was 3 years vs 5-6 years • We can only imagine the PROactive results at 5-6 years

  29. Answers Is it feasible an intensive treatment of hyperglycemia? YES Are CV events reduced by an intensive treatment of hyperglycemia? YES, in patients with HbA1c <8% and no previous CV events Pay attention to hypoglycemia and fragile patients and ….. don't hurry

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