1. 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

2. 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?

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

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

5. UKPDS

6. 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?

7. 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:

8. 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:

9. 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

10. 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:

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

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

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

14. 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:

15. 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

16. 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?

17. 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

18. 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

19. 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

20. 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:

21. 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

22. 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

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

24. 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
Angina
Angioplastica
Morte
Insufficienza cardiaca —
Eventi cerebrovascolari
Vasculopatia periferica —
Tutti gli eventi
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“

25. 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 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:

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

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

28. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review
Eurich D.T. et al. BMJ 2007;335:

29. 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

30. 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