Download SCREENING FOR DIABETES

Preventing CAD in Diabetes
by Trevor Orchard
•
•
•
•
•
Definition of Diabetes
Magnitude of the Risk
Reasons for the Risk
Evidence for Preventive
Interventions
Clinical Recommendations
M.D. SURVEY : DxDIABETES
Frequency of OGTT Use
#1
2%
#2
19%
#3
16%
No mention
68%
Current Diagnostic Criteria for
Diabetes (plasma glucose mg/dl) –
WHO/ADA
1979 NDDG/1980 WHO1997 ADA
Fasting
2 hr1
Random glucose3
1Post
 140
 200
 200
 126
 2002
 200
75 gm glucose load, Midtest value also has to be > 200 mg/dl
for NDDG.
2Not recommended for routine use. 3In the presence of diabetes
symptoms.
Prevalence of Diabetes USA
40-74 Years Old
1997 ADA Criteria
1985 WHO Criteria
% Millions
% Millions
Undiagnosed
4.4
4.1
6.4
6.0
IFG/IGT
10.1
9.6
15.6
14.9
Diagnosed
7.9
7.5
7.9
7.5
Total Diabetes
12.3
11.6
14.3
13.5
Harris MI, et al. Diabetes Care 1997; 20(1): 1859-1862.
CHS Study – ADA v WHO
3984 aged 65 yrs+ followed 5-9 yrs (no known diabetes/CVD).
*Adjusted* RR compared to common normal2 for CVD events.
ADA Fasting Criteria
WHO
n
n
Normal
184
1.09 (0.73-1.65)
1142
1.20 (0.99-1.47)
IGT or IFG
1264
1.23 (1.01-1.98)
582
1.39 (1.09-1.77)
New Diabetes
563
1.56 (1.23-1.98)
287
1.58 (1.17-2.13)
2FG
< 6.1, 2 hrs < 7.8 mmol/L.
*Adjusted for gender, age, ethnicity, smoking, BMI, LDLc and HT.
Barzilay JL. Lancet 1999; 354: 622-625.
Metaregression Analysis:
Glucose v CVD Incidence
20 studies, 95,783 people (94% men) followed
12 yrs. (Studies excluded if purely diabetic).
RR (95% CI)
FPG  110 mg/dl
2 hr G  140 mg/dl
1.33 (1.06 – 1.67)
1.58 (1.19 – 2.10)
Exclude top groupings.
FPG p=0.056, 2 hr p=0.0006
Coutinho, M. Diabetes Care 1999; 22: 233-240.
DeCode Study
22,476 aged 30-89 yrs “non-diabetic”, 11 cohorts.
Followed mean 12 yrs for mortality, 262,811 person years.
*Adjusted RR of fasting glucose
2 hr glucose
Total
CVD
Non-CVD
1.17 (1.14-1.21)
1.15 (1.10-1.20)
1.16 (1.12-1.20)
1.10 (1.07-1.13)
1.08 (1.03-1.13)
1.10 (1.06-1.14)
*Adjusted for age, gender, center, BP, chol, smoking and
BMI.
If RR of fasting glucose adjusted for 2 hr: 1.00, 0.99, 1.00,
vice versa 1.07, 1.07, 1.07.
Personal Communication. IDF/EDEG, Acapulco, Nov. 2000.
Mortality in People with Diabetes
Causes of Death
% of Deaths
50
40
30
20
10
0
Ischemic Other DiabetesCancer Stroke Infection Other
heart heart
disease disease
Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.
Relative Risks of Cardiovascular Events
Diabetes v Nondiabetes. Framingham
45-74 year old
10
9
8
7
6
5
4
3
2
1
0
Any CVD
Unadj.
Adjust.
CVD
Death
Male
Cardiac
Brain
Failure
Infarct
Unadj.
Adjust.
CHD
Female
Kannel, Diabetes Care 1979; 2:120-126.
Int
Claud
CHS Study
Diabetes status and presence of subclinical/clinical CVD at baseline
and incidence of specific events among men and women in the CHS
(outcome: death).
Kuller LH. ATVB 2000; 20: 823-829.
CHS Study
Diabetes status and presence of subclinical/clinical CVD at baseline
and incidence of specific events among men and women in the CHS.
Kuller LH. ATVB 2000; 20: 823-829.
Effect of Diabetes on 30-Day Survival
After MI: GUSTO-I
% of Deaths (Crude Rate)
Cardiovascular Mortality in People
with Diabetes
MEN
60
50
40
WOMEN
28 d – 1 y
9.1
15.4
30
Hospitalization
– 28 d
4.2
9.6
20
10
0
28.6
11.1
22.7
Out of Hospital
2.8
9.0
22.1
Diabetes No Diabetes
10.9
11.9
Diabetes
No Diabetes
Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75.
Rate per 1000 person-years
Trends in Mortality Rates for Ischemic Heart Disease
in NHANES Subjects with and without Diabetes*
20
15
Diabetes
17.0
Men, cohort 1*
Men, cohort 2**
Women, cohort 1*
Women, cohort 2**
14.2
10
6.8 7.6
7.4
4.2
5
0
Nondiabetes
-16.6%
(P=0.46)
+10.7%
(P=0.76)
-43.8%
(P<0.001)
2.4 1.9
-20.4%
(P=0.12)
*Defined in 1971-1975, followed up through 1982-1984.
**Defined in 1982-1984, followed up through 1992-1993.
Gu K et al. JAMA 1999;281:1291-1297.
AGE-ADJUSTED RATES OF
NONFATAL MI AND FATAL CHD COMBINED
PER 100,000 PERSON-YEARS
500
400
452
Nondiabetic
Diabetic
262
300
Rate
of CHD
200
100
133
37
0
No
High Cholesterol
Yes
Diabetes in Women, Manson et al. Arch Intern Med, 1991; 151: 1144.
Glycemia in Diabetes and
Heart Disease
• Epidemiological Evidence
• Type 2
• Type 1
• Clinical Trial Evidence
• Type 2
• Type 1
• A potential explanation to the paradox
• Clinical evidence
• Pathology evidence
• Potential explanations for the increased
heart disease risk in diabetes
Hazard Ratio (HR) and 95% Conference Interval (CI)
for Mortality due to Specific Causes for a 1% Increase
in Glycosylated Hemoglobin After Controlling for
Other Risk Factors in Younger-Onset Diabetic Persons
Underlying Cause
Cause of Death
HR
95% CI
Diabetes
1.25 (1.13-1.38)
Ischemic heart disease 1.18 (1.00-1.40)
Other heart disease
...
...
Renal disease
...
...
All causes
1.12 (1.04-1.21)
Any Mention
HR
95% CI
1.18
1.17
1.18
1.07
...
(1.10-1.28)
(1.03-1.33)
(1.06-1.31)
(0.92-1.25)
...
Moss SE. Arch Intern Med 1994; 154: 2473-2479.
The 14-Year Cumulative Incidence of
Amputation for a Specified Increment in
Baseline Characteristics in Multivariate
Logistic Regression: WESDR
Characteristic
Increment
Younger-onset
Age (years)
Sex
10
Male
Glycosylated hemoglobin (%)
1
Diastolic blood pressure (mmHg) 10
History of ulcers
Retinopathy
Present
One step
P
<0.0001
<0.0001
<0.0001
<0.005
<0.0005
<0.0001
OR (95% CI)
1.71 (1.30-2.24)
5.21 (2.50-10.88)
1.39 (1.22-1.59)
1.58 (1.20-2.07)
3.19 (1.71-5.95)
1.16 (1.08-1.24)
Moss SE. Diabetes Care 1999; 22: 951-959.
Baseline Risk Factor Levels for CAD in Both
Sexes, by First Event, EDC 10 year Follow-up
Variable
N
No
CAD
495
Sex (% Male) 50.1
Angina
Pectoris
Hard
CAD
Total
CAD
49
42
108
49.0
61.9
51.9
Age (yrs)
2.59±7.3
33.4 ±6.2*** 32.9 ±6.6*** 33.0 ±6.8***
Duration (yrs)
17.6 ±6.9
25.1 ±6.5*** 25.4 ±6.4*** 24.9 ±6.9***
HbA1 (%)
10.4 ±1.8
9.9 ±1.9
10.7 ±1.8
10.3 ±1.8
Fibrinogen (mg/dl)¶ 280.1 ±87.1 305.8 ±77.9** 343.3 ±97.2*** 319.6 ±89.5***
Baseline Risk Factor Levels for CAD in Both
Sexes, by First Event, EDC 10 year Follow-up (Cont.)
Variable
No
CAD
WBC x 103/mm2‡
6.4 ±1.8
Angina
Pectoris
7.1 ±2.2*
Hard
CAD
Total
CAD
8.1 ±2.4*** 7.5 ±2.3***
Triglycerides (mg/dl)¶ 99.8 ±82.7 113.4 ±67.6* 156.5 ±80.1*** 134.4 ±90.9***
Non-HDLc (mg/dl)‡ 130.7 ±38.3 151.0 ±42.0*** 174.7 ±48.5*** 159.2 ±48.8***
LDLc (mg/dl)‡
111.0 ±30.8
HDLc (mg/dl)
54.8 ±12.2
50.9 ±13.0*
48.3 ±9.8**
ApoA1/HDLc
2.6 ±0.5
2.8 ±0.6*
2.9 ±0.5*** 2.9 ±0.5***
125.3 ±32.3** 147.0 ±44.0*** 132.4 ±41.8***
50.0 ±11.8***
Values are given as mean ±SD or prevalence (%). ¶Mann-Whitney.
Fisher’s exact ‡Log-transformed before t-test
Comparisons with no CAD: *p<0.05 **p<0.01 ***p<0.001
Baseline Risk Factor Levels for CAD in Both
Sexes, by First Event, EDC 10 year Follow-up (Cont.
Variable
Serum Creatinine (mg/dl)¶
No
Angina
Hard
Total
CAD
Pectoris
CAD
CAD
0.96 ±0.9
Log median AER (µg/min)¶ 3.2 ± 1.8
SBP (mm Hg)
QTc
1.03 ±0.5*
4.2 ±2.1**
111.1 ±13.2 118.5 ±14.1***
407.1 ±30.0
414.1 ±25.9
1.6 ±1.6***
5.9 ±2.2***
1.3 ±1.2**
4.8 ±2.3***
127.5 ±21.1*** 121.3 ±18.5***
412.5 ±29.6
414.1 ±26.5*
Physical Activity 2790.9 ±2999.8 1779.2 ±2176.4** 1917.4 ±1766.7 916.9 ±2053.6*
WHR
0.82 ±0.07
0.84 ±0.08*
0.86 ±0.07*** 0.85 ±0.07***
eGDR (mg/kg/min)
8.1 ±1.8
7.3 ±2.0**
6.4 ±1.9***
Beck Depression Inventory¶ 6.8 ±6.2 9 .7 ±7.1**
7.7 ±5.7
7.0 ±2.0***
8.1 ±6.5*
Baseline Risk Factor Levels for CAD in Both
Sexes, by First Event, EDC 10 year Follow-up (Cont.)
No
Angina
Hard
Total
Variable
CAD
Pectoris
CAD
CAD
Smoke Ever (%)
32.8
50.0*
59.5**
54.7***
Hypertension (%)
9.9
34.7***
42.9***
34.3***
DSP (%)
E/I < 1.10 (%)
20.3
12.9
61.2***
32.6**
50.0***
47.1***
52.8***
37.9***
Overt Nephropathy (%) 17.2
38.8**
69.4***
69.0***
85.7***
48.1***
71.3***
ABI < 0.8 or ABD 75+ % 6.4
14.3
26.8***
19.6***
eGDR<6.22
(mg/kg/min)(%)¶
22.4
56.1***
34.9***
MA or ON (%)
38.8
14.1
EDC 6 Yr Follow-up: Multivariate
Analysis (Cox Proportional Hazards)
CHD
LEAD
Women†
Men*
Men†
Women†
Duration
0.002
Duration
0.000
Duration 0.004
LDLc
0.02
HDLc
0.009
WHR
0.001
HbA1
WHR
0.04
WBC
0.008
BDI
0.040
Fibrinogen
0.092
Hypertension 0.000
Hypertension
0.016
*Nephropathy
0.000
Smoking 0.03
(0.000) replaces WBC/Fibrinogen/Hypertension and
improves model. †Nephropathy doesn’t enter model.
Multivariate Models of CVD in EDC and Eurodiab
Prevalence Analyses of Comparable Populations
Standardized
Coefficient Coefficient P value
Males
Eurodiab
Age
HDL Cholesterol
0.071
-1.867
0.36
-0.38
0.007
0.008
EDC
Triglycerides
Hypertension
0.40
2.163
0.23
0.49
0.02
0.0001
Eurodiab
Age
HbA1c
Hypertension
0.043
-0.288
0.734
0.21
-0.29
0.16
0.008
0.008
0.032
EDC
Age
HbA1
Macroalbuminuria
0.079
0.266
1.289
0.32
0.27
0.31
0.01
0.03
0.006
Females
Int J. of Epidemiology 1998.
Stepwise selection of risk factors, adjusted for age
and sex, in 2693 white patient with Type 2 diabetes
mellitus “time to first event” case model
Non-fatal or fatal MI (n=192)
Position in model
Variable
P value
First
LDLc
0.0022
Second
DBP
0.0074
Third
Smoking
0.025
Fourth
HDLc
0.026
Fifth
Haemoglobin A1c
0.053
UKPDS. BMJ 1998; 316: 823-828.
DOES IMPROVED GLYCEMIC
CONTROL REDUCE CVD
RISK IN DIABETES?
•
•
•
•
•
•
UGDP
DIS
KUMAMOTO
DCCT
VA FEASIBILITY
UKPDS
GLUCOSE LOWERING AND
CARDIOVASCULAR RISK IN DIABETES
Study
Intervention
Result
UGDP
Tolbutamide
Possible increased
cardiovascular risk
Phenformin
DCCT/
EDIC
Increased lactoacidosis
Insulin variable
No benefit
Insulin standard
No benefit
Intensive(insulin)
glycemic therapy
in type 1 diabetes
Possible decrease in
macrovascular events
(largely lower extremity
arterial disease )
No effect on ankle-brachial index
small effect on carotid IMT
EPIC - Norfolk
4,662 men, 45-79 years (18% of total cohort). Followed
approximately 4 yrs for mortality (41/131 due to IHD).
*Adjusted RR of 1% difference in HbA1c for:
IHD mortality=1.31 (1.02-1.67) p=0.03
Non CVD mortality=1.20 (1.01-1.44) p=0.04
Total mortality=1.46 (1.00-2.12) p=0.05
(excluding diabetes and h/o CVD)
HbA1c replaces diabetes in multivariate models.
*Adjusted for age, SBP, TC, BMI, Cigs, h/o CVD.
Khaw KT. BMJ 2001; 15-68.
The Paradox
Diabetes carries a greatly increased risk
of heart disease that is not explained by
traditional risk factors: Type 1 - 5+ fold;
Type 2 - 2-4 fold.
BUT
Hyperglycemia, the hallmark of
diabetes, is only weakly (at best) related
to CHD.