Session II: Glycemic control, when the lower is not the better

Strict glycemic control and cardiovascular diseases

Stefano GenoveseDiabetologia e Malattie Metaboliche

Thirteenth International Symposium Heart Failure & Co.“My Sweet Heart”

Città della Scienza, Napoli 12-13 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;353:2643-53.

UKPDS

Other Questions

Is it feasiblean intensive treatment of hyperglycemia?

Are CV events reduced by an intensive treatmentof hyperglycemia?

Is there a first choice drugin intensive treatment to reduce CV events?

UGDPUKPDS 34

UKPDS 33DIGAMI

Kumamoto

ACCORDVADT

ADVANCE

ACCORD Study Group et al. NEJM 2008;358:2545-59

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;358:2560-72

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

5.05.56.06.57.07.58.08.59.09.5

10.010.5

Baseline 1 year 2 years 3 years 4 years 5 years 6 years

Years on Study

HbA1

c (%

)

Standard

Intensive

ACCORD Study Group et al. NEJM 2008;358:2545-59

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;358:2545-59

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

Causes of death in the ACCORD

ACCORD Study Group et al. NEJM 2008;358:2545-59

• 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

Variable HazardRatio

PValue

Prior CVD event 3.116 0.0001

Age (per 10 yr) 2.090 <.0001

HDL (per 10 mg) 0.699 0.0079

Baseline HbA1cper 1%

1.213 0.0150

Severe Hypoglycemia 4.042 0.0076

• 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

Characteristics ACCORD ADVANCEBaseline 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

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 NA Aspirin 76 vs 76 57 vs 55

ACCORD vs ADVANCE

Dluhy R.G. et al. NEJM 2008;358:2630-3

Characteristics ACCORD ADVANCEResults (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

ADVANCE does not confirm the reduction of MI suggested by ACCORD

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=0,01

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 cardiovascularoutcomes 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

Generationof “bad glycaemic legacy”

Risk of complications

Time from diagnosis (years)

9,5

9,0

8,5

8,0

7,5

7,0

6,5

6,01 3 5 7 9 11 13 15 17

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. 2012 Jun;55(6):1577-96Diabetes Care. 2012 Jun;35(6):1364-79

Answers

Are CV events reduced by an intensive treatmentof hyperglycemia?

YES, in patients with HbA1c <8% and

no previous CV events

Is it feasiblean intensive treatment of hyperglycemia?

YES

•Pay attention to:•hypoglycemia• fragile patients

•don't hurry•choose the right drug!