? -???????????? ??ACE?????

1
? -??????????????ACE?????

• Jean-Louis Chiasson, M.D.
• Professor of MedicineUniversité de Montréal

2
Potential conflicts of interest

• Bayer Schering Pharma AG
• BellusHealth
• Eli Lilly
• GlaxoSmithKline
• Innodia
• Merck Frosst Canada
• Novo Nordisk
• Pfizer Canada
• sanofi aventis

3
OGTT?????
15.5
13.3
Type 2 diabetes (DM) Impaired glucose tolerance
(IGT) Normal glucose tolerance (NGT)
11.1
?? (mmol/L)
8.8
6.6
4.4
-30
0
30
60
90
120
?? (min)
Adapted from Sobel, R. et al. Diabetes 44
187A, 1995
4
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5
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6
?????????????????????????????
Adapted from Edelstein, S. et al. Diabetes 46
701710, 1997
7
??????????HbA1c??? (EPIC-Norfolk 3??? n
25,623)
8
7
6
5.04
5
CVD????
4
2.77
2.74
3
1
2
1
0
lt 5.0
5.0 - 5.4
5.5 - 6.9
gt 7.0
HbA1c
Adapted from Khaw, K.T. et al. BMJ 322 15-18,
2001
8
???????????????????
???/ 1000 ?
p lt 0.001
?????
??? ???
NGT
IGT
Adapted from Eschwege, E. et al. Horm. Metab.
Res. 15 41-46, 1985
9
???????????
Diabetes Intervention Study (1996)
Rancho Bernardo Study (1998)
Honolulu Heart Program (1987)
Whitehall, Paris and Helsinki Study (1998)
PPG
CVD
DECODA (2004)
Funagata Diabetes Study (1999)
Pacific and Indian Ocean (1999)
DECODE (2001)
10
2-hPG??????????????? - DECODE
1.0 0.8 0.6 0.4 0.2 0
???????????
3.0
³7.0
lt4.5
³11.1
3.16.5
6.67.7
6.16.9
4.66.0
7.810.0
10.111.0
???????
FPG (mmol/L)
2-h PG (mmol/L)
CV ??? FPG ????
Adapted from DECODE. Diabetes Care 26
688696, 2003
11
2-hPG ??????????????? DECODA??
?????????
n 17,512
p lt 0.001
p 0.83
lt 7.8
7.8-11.0
? 11.1
lt 6.1
6.1-6.9
? 7.0
2-hPG (mmol/L)
FPG (mmol/L)
Adapted from Nakagami, T., The DECODA Study
Group. Diabetologia 47 385-394, 2004
12
??1

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• IGT?????2????
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13
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14
a-????????
Adapted from Bischoff, H. Clin. Invest. Med.
18 303-11, 1995
15
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???????
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?????? ??
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????
??
??
16
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Adapted from Bischoff, H. Clin. Invest. Med.
18 303-11, 1995
17
??????2???????Cochrane ????
HbA1c
??
??
0 1.0 2.0 3.0 4.0
0 0.5 1.0 1.5
-1.1
n 2,838
-0.8
?????(mmol/L)
-2.3
HbA1c ??? ()
n 2,831
n 2,238
30? ??, ???????
Adapted from Van de Laar, F. et al. Diabetes
Care 28 154-75, 2005
18
????????????
?? ??? ???? p?

???? 39.0 73.6 lt 0.05 ?? 20.3 43.6 lt
0.05 ???? 8.8 25.0 lt 0.05 ?? 8.8 14.5 NS ?? 5.5 5
.2 NS
Adapted from Chiasson, J.-L. et al. Ann.
Intern. Med. 121 928-935, 1994
19
?????,?????????????????
???? ? ????(n54)
70
50
???? ??????? ?? (n55)
????????????? ()
30
10
???
0
80
20
50
30
10
2
40
60
70
???? (?)
Adapted from May, C. Diabetes Stoffw 4 3-8,
1995
20
??2

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21
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22
?????????????/??????IGT?????????(n 321)
?????? (/?)
(85)
(60)
(88)
(88)
RRR () - 29 83
65
Adapted from Yang W et al. Chin. J.
Endocrinol. Metab. 17 131-136, 2001
23
??????IGT??2??????STOP-NIDDM??
20
(n 1429 )
18
???
16
p 0.0018
14
12
????? ()
10
????
8
6
4
2
0
0
4
3
2
1
5
?????????
Adapted from Chiasson, J.-L. et al. Lancet 359
2072-2077, 2002
24
?????????????BMI?IGT??????????? STOP-NIDDM ??
Adapted from Chiasson, J.-L. et al. Lancet 359
2072-2077, 2002
25
??????IGT?NGTSTOP-NIDDM??
Hazard ratio 1.42 (95 CI 1.24 - 1.62) p lt
0.0001

????
n 212 (30.9)
n 241 (35.3)
???
????
Adapted from Chiasson, J.-L. et al. Lancet
359 2072-2077, 2002
26
?? 3

• ?????????????????????IGT??2??????????? 83
• STOP-NIDDM????????????IGT????????,??
• ??IGT?????????????36
• ????????IGT???NGT

27
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28
STOP-NIDDM ??????

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Adapted from Chiasson, J.-L. et al. JAMA 290
486-494, 2003
29
?????IGT???????????The STOP-NIDDM Trial





No. of subjects (n 47)
p 0.0326
n 15
n 32
Placebo
Acarbose
Adapted from Chiasson, J.-L. et al. JAMA 290
486-494, 2003
30
?????IGT????????????????STOP-NIDDM ??
Adapted from Chiasson, J.-L. et al. JAMA 290
486-494, 2003
31
?????IGT????????????????
Adapted from Chiasson, J.-L. et al. JAMA 290
486-494, 2003
32
???????????????
???? (n 682)
??? (n 686)
P?
???????? 1 12 0.0226 ???????? 1 7 0.0390 ????
??? 2 19 0.0002
??Cox??????? ???2 ??

Adapted from Chiasson, J.-L. et al. JAMA 290
486-494, 2003
33
?????IGT?????????(IMT)?????STOP-NIDDM????(n
115)
50
(p 0.027)
? IMT (mm)
n 56
n 59
???
????
Adapted from Hanefeld, M. et al. Stroke 35
1073-1078, 2004
34
?????2???????IMT??????FPG?HbA1c RAID??
0.95
0.9
0.85
IMT (mm)
0.8
0.75
5.8-11.6
0.7
5.4-5.7
HbA1C ()
8.05-23.11
3.2-5.3
6.07-8.04
2.7-6.06
2-hour pc glucose in OGTT (mmol/L)
IMT intima media thickness
Adapted from Temelkova-Kurktschiev, T.S. et al.
Diabetes Care 23 1830-1834, 2000
35
??????2???????????????
MeRIA ????
No. of patients ()
Favours
Cardiovascular event
RRR()
p
Acarbose (n1,248)
Placebo (n932)
Acarbose
Placebo
(0.4)
(0.6)
Cardiovascular death 5 6 38 Myocardial
infarction 9 19 64 Angina 26 25 21 Heart
failure 7 10 45 Revascularisation 6 5
22 Peripheral vascular disorder 14 14
25 Stroke/cerebrovascular event 10 10 25 Any
cardiovascular event 76 88 35
0.437 0.012 0.388 0.225 0.678 0.456 0.527 0.006
(0.7)
(2.0)
(2.0)
(2.7)
)
(0.6
(1.0)
(0.5)
(0.5)
(1.5)
(1.1)
(0.8)
(1.0)
(6.0)
(9.4)
Adapted from Hanefeld, M. et al. Eur. Heart J.
25 1016, 2004
36
?? 4

• STOP-NIDDM??????????????IGT??????,??
• ?????????????49
• ????????????50.
• Hanefeld ???2??????????
• PPG?CIMT?????????
• ????????????????????????35

37
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38
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15 12 9 6 3 0
NGT IGT Diabetes




Plasma glucose levels (mmol/L)
Fasting 1 hour 2 hours
p lt 0.01 versus fasting p lt 0.01 versus
fasting and 1 hour
Adapted from Kawano, H. et al. J. Am. Coll.
Cardiol. 34 146154, 1999
39
??????????
NGT IGT Diabetes
3 2 1
4 3 2 1 0



??TBARS??(nmol/mL)

??TBARS??(nmol/mL)
p lt 0.01
Fasting 1 hour 2 hours
0 6 12 18 24
????(mmol/L)
p lt 0.05 versus fasting p lt 0.05 versus
fasting and 1 hour TBARS thiobarbituric acid
reactive substances
Adapted from Kawano, H. et al. J. Am. Coll.
Cardiol. 34 146154, 1999
40
????????????
8 6 4 2 0
NGT IGT Diabetes
Flow-mediated dilation of brachial artery ()



plt0.01

Fasting 1 hour 2 hours
p lt 0.01 versus fasting p lt 0.01 versus
fasting and 1 hour
Adapted from Kawano, H. et al. J. Am. Coll.
Cardiol. 34 146154, 1999
41
??????LDL??-IGT?????????
LDL ??-? ???LDL ????? ??-? ?????LDL ?????
Adapted from Inoue, I. et al. Metabolism Clin.
Exp. 55 946-952, 2006
42
??????IGT???????CRP??
???
????
n 30
CRP (mg/L)
p lt 0.01
n 30
??16??
Adapted from Lu, J.M. et al. Chin. J.
Endocrinol. Metab. 19 254-56, 2003
43
??????IGT????????????





4.0 3.4 2.8 2.2
3.0 2.4 1.8 1.2 0.6
??? (n 17)
??? (n 17)
p lt 0.05
Prothrombin fragment 12 (nmol/L)
p lt 0.01
D-dimer (g/L)
???? (n 17)
???? (n 17)
0 60 120 180 240
0 60 120 180 240
Duration (minutes)
Duration (minutes)
Adapted from Ceriello, A. et al. Diabetologia
39 469-73, 1996
44
????????????
???
????
0.6 0.4 0.2 0 0.2 0.4 0.6 0.8
2.5 2.0 1.5 1.0 0.5 0
p 0.046
??????? (mmol/L)
FMD ???()
p 0.0007
???????????????FMD (n 28)
???
????
FMD ???????
Adapted from Wascher T. et al. Eur. J. Clin.
Invest. 35 551-57, 2005
45
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46
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