Transcript Diapositiva 1 - Gastaldi Congressi

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
ACCORD
VADT
ADVANCE
Is it feasible
an intensive treatment
of hyperglycemia?
Kumamoto
Are CV events reduced
by an intensive treatment
of hyperglycemia?
UKPDS 33
DIGAMI
Is there a first choice drug
in intensive treatment
to reduce CV events?
UGDP
UKPDS 34
The use of an oral
hypoglycemic drug vs placebo
can reduce CV events?
STOP-NIDDM
PROactive
ACCORD
• 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
• 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
• In the VADT study
a HbA1c value
around 6,5% has
been reached in
one year and
maintained
HbA1c (%)
VADT
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
Standard
Intensive
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
• Causes of death:
• 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
Baseline data
 Participants, n
 Mean age (years)
 Duration of diabetes (years)
 Mean HbA1C (%)
 History of CVD (%)
ACCORD
ADVANCE
10 251
62
10
8.1
35
11 140
66
8
7.2
32
Dluhy R.G. et al. NEJM 2008;358:2630-3
ACCORD vs ADVANCE
Characteristics
ACCORD
ADVANCE
<6.0
3.4
<6.5
5.0
77 vs 55
95 vs 87
87 vs 74
92 vs 58
18 vs 5
88 vs 88
91 vs 92
70 vs 72
76 vs 76
41 vs 24
74 vs 67
94 vs 62
17 vs 11
Intervention
 Target HbA1C (%)
 Duration of the study (years)
 Drugs at study end (intensive vs standard) (%)
Insulinn
Metformin
Secretagogues (sulfonilureas or glinides)
TZD
Incretin
Statin
Any anti-hypertensive
ACE inhibitors
Aspirin
NA
46 vs 48
89 vs 88
NA
57 vs 55
Dluhy R.G. et al. NEJM 2008;358:2630-3
ADVANCE does not confirm the reduction of MI
suggested by ACCORD
Characteristics
Results (intensive vs standard)
 Median HbA1C mediana at study end(%)
 Total mortality (%)
 CV Mortality (%)
 Non fatal MI (%)
 Non fatal stroke (%)
 Serious Hypoglycemia (%/anno)
 Weight gain(kg)
 Smokers (%)
ACCORD
ADVANCE
6.4 vs 7.5*
5.0 vs 4.0*
2.6 vs 1.8*
3.6 vs 4.6*
1.3 vs 1.2
3.1 vs 1.0*
3.5 vs 0.4
10 vs 10
6.4 vs 7.0*
8.9 vs 9.6
4.5 vs 5.2
2.7 vs 2.8
3.8 vs 3.8
0.7 vs 0.4
0.0 vs -1.0*
8 vs 8
Dluhy R.G. et al. NEJM 2008;358:2630-3
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
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
Is it feasible
an intensive treatment
of hyperglycemia?
Are CV events reduced
by an intensive treatment
of hyperglycemia?
YES
YES,
in patients with HbA1c <8% and
no previous CV events
Pay attention to
hypoglycemia and fragile patients
and ….. don't hurry