Session II: Glycemic control, when the lower is not the better Strict glycemic control and cardiovascular diseases Stefano Genovese Diabetologia e Malattie Metaboliche Thirteenth International Symposium Heart Failure & Co. “My Sweet Heart” Città della Scienza, Napoli April 2013

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:

UKPDS

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? UGDP UKPDS 34 UKPDS 33 DIGAMI Kumamoto ACCORD VADT ADVANCE

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

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

VADT In the VADT study a HbA1c value around 6,5% has been reached in one year and maintained Baseline1 year2 years3 years4 years5 years6 years Years on Study HbA1c (%) Standard Intensive

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

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

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

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

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

VADT – Predictors of CVD death VariableHazard Ratio P Value Prior CVD event Age (per 10 yr)2.090<.0001 HDL (per 10 mg) Baseline HbA1c per 1% Severe Hypoglycemia

The ACCORD suggests that outcomes differ according to – HbA1c below or above a 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? Hypothesis…..

ACCORD vs ADVANCE CharacteristicsACCORDADVANCE Baseline data Participants, n Mean age (years) 6266 Duration of diabetes (years) 108 Mean HbA 1C (%) History of CVD (%) 3532 Dluhy R.G. et al. NEJM 2008;358:2630-3

Characteristics ACCORDADVANCE Intervention Target HbA 1C (%) <6.0<6.5 Duration of the study (years) Drugs at study end (intensive vs standard) (%) Insulinn77 vs 5541 vs 24 Metformin95 vs 8774 vs 67 Secretagogues (sulfonilureas or glinides)87 vs 7494 vs 62 TZD92 vs 5817 vs 11 Incretin18 vs 5 NA Statin88 vs 8846 vs 48 Any anti-hypertensive91 vs 9289 vs 88 ACE inhibitors70 vs 72 NA Aspirin76 vs 7657 vs 55 ACCORD vs ADVANCE Dluhy R.G. et al. NEJM 2008;358:2630-3

CharacteristicsACCORDADVANCE Results (intensive vs standard) Median HbA 1C 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 vs 3.8 Serious Hypoglycemia (%/anno) 3.1 vs 1.0*0.7 vs 0.4 Weight gain(kg) 3.5 vs vs -1.0* Smokers (%) 10 vs 108 vs 8 Dluhy R.G. et al. NEJM 2008;358: ADVANCE does not confirm the reduction of MI suggested by ACCORD

ADVANCE Collaborative Group et al. NEJM 2008;358: 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=0,28

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

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

Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus Lancet 2009; 373: 1765–72

Hypothetical representation of the natural history of diabetic patients enrolled in the study VADT Generation of “bad glycaemic legacy” Risk of complications Time from diagnosis (years) 9,5 9,0 8,5 8,0 7,5 7,0 6,5 6, HbA 1c (%) Del Prato S. Diabetologia 2009 Before entering the VADT, intensive treatment arm After entering the VADT, intensive treatment arm The "bad" metabolic memory increases the macrovascular complications of T2DM

Position Statement ADA EASD Diabetologia Jun;55(6): Diabetes Care Jun;35(6):

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