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

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

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

UKPDS

Other Questions Is it feasible an intensive treatment UGDP UKPDS 34 UKPDS 33 DIGAMI STOP-NIDDM PROactive Kumamoto ACCORD VADT ADVANCE 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?

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

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

VADT In the VADT study a HbA1c value around 6,5% has been reached in one year and maintained 10.5 10.0 9.5 Standard 9.0 8.5 HbA1c (%) 8.0 7.5 Intensive 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

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

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

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

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

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

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

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?

ACCORD vs ADVANCE Characteristics ACCORD ADVANCE Baseline data Participants, n 10 251 11 140 Mean age (years) 62 66 Duration of diabetes (years) 10 8 Mean HbA1C (%) 8.1 7.2 History of CVD (%) 35 32 Dluhy R.G. et al. NEJM 2008;358:2630-3 17

ACCORD vs ADVANCE Characteristics ACCORD ADVANCE Intervention Target HbA1C (%) <6.0 <6.5 Duration of the study (years) 3.4 5.0 Drugs at study end (intensive vs standard) (%) Insulinn 77 vs 55 41 vs 24 Metformin 95 vs 87 74 vs 67 Secretagogues (sulfonilureas or glinides) 87 vs 74 94 vs 62 TZD 92 vs 58 17 vs 11 Incretin 18 vs 5 NA Statin 88 vs 88 46 vs 48 Any anti-hypertensive 91 vs 92 89 vs 88 ACE inhibitors 70 vs 72 Aspirin 76 vs 76 57 vs 55 Dluhy R.G. et al. NEJM 2008;358:2630-3 18

ADVANCE does not confirm the reduction of MI suggested by ACCORD Characteristics ACCORD ADVANCE Results (intensive vs standard) Median HbA1C mediana at study end(%) 6.4 vs 7.5* 6.4 vs 7.0* Total mortality (%) 5.0 vs 4.0* 8.9 vs 9.6 CV Mortality (%) 2.6 vs 1.8* 4.5 vs 5.2 Non fatal MI (%) 3.6 vs 4.6* 2.7 vs 2.8 Non fatal stroke (%) 1.3 vs 1.2 3.8 vs 3.8 Serious Hypoglycemia (%/anno) 3.1 vs 1.0* 0.7 vs 0.4 Weight gain(kg) 3.5 vs 0.4 0.0 vs -1.0* Smokers (%) 10 vs 10 8 vs 8 Dluhy R.G. et al. NEJM 2008;358:2630-3 19

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

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

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

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

Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. The STOP-NIDDM randomised trial Chiasson JL et al JAMA 2003 Pazienti (n) Meglio acarbosio Meglio placebo RRR (%) Ac (n=682) Pl (n=686) p 0.5 1.0 1.5 2.0 Cardiopatia ischemica Infarto del miocardio 1 12 91 Angina 5 12 55 Angioplastica 11 20 39 Morte 1 2 45 Insufficienza cardiaca 0 2 — Eventi cerebrovascolari 2 4 44 Vasculopatia periferica 1 1 — Tutti gli eventi 15 32 49 0.02 0.13 0.18 0.63 — 0.51 0.93 0.03 Table 14.2 / 2.3A Final- after allocation of 8 events from „others“

Dormandy J.A. et al. Lancet 2005;366:1279-89 Secondary prevention of macrovascolar events in patients with type 2 diabetes in the PROactive Study: a randomised controlled trial 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) Dormandy J.A. et al. Lancet 2005;366:1279-89

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

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

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

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

Answers Pay attention to hypoglycemia and fragile patients 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