glycemic control: when the lower is not the “better”?

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

Stefano GenoveseUO di Endocrinologia e Diabetologia

Ninth International SymposiumHEART FAILURE & Co.

Rozzano (MI) - April 17-18, 2009

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.

Other Questions

Is it feasiblean intensive treatment

of hyperglycemia?

Are CV events reduced by an intensive treatment

of hyperglycemia?

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

The use of an oralhypoglycemic drug vs placebo

can reduce CV events?

UGDPUKPDS 34

UKPDS 33DIGAMI

STOP-NIDDMPROactive

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

HbA

1c (%

)

Standard

Intensive


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


Effects of Intensive Glucose Lowering in Type 2 Diabetes - ACCORD

Causes of death in the ACCORD


• 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 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?

Hypothesis…..

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

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


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


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

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

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

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 and fragile patients

and ….. don't hurry

glycemic control: when the lower is not the “better”?

Documents

smokers vs

intensive diabetes treatment

advance study

effects of intensive

study end

cardiovascular disease

cardiovascular mortality

diabetes care