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Preventing CAD in Diabetesby Trevor Orchard
• Definition of Diabetes
• Magnitude of the Risk
• Reasons for the Risk
• Evidence for Preventive Interventions
• Clinical Recommendations
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M.D. SURVEY : DxDIABETES
Frequency of OGTT Use #1 2%
#2 19%
#3 16%
No mention 68%
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Current Diagnostic Criteria for Diabetes (plasma glucose mg/dl) –
WHO/ADA
1979 NDDG/1980 WHO1997 ADA
Fasting 140 1262 hr1 200 2002
Random glucose3 200 200
1Post 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.
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Prevalence of Diabetes USA40-74 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.
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CHS Study – ADA v WHO3984 aged 65 yrs+ followed 5-9 yrs (no known diabetes/CVD).*Adjusted* RR compared to common normal2 for CVD events.
WHO ADA Fasting Criteria 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.
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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 1.33 (1.06 – 1.67)2 hr G 140 mg/dl 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.
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DeCode Study22,476 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 1.10 (1.07-1.13) 1.17 (1.14-1.21)CVD 1.08 (1.03-1.13) 1.15 (1.10-1.20)Non-CVD 1.10 (1.06-1.14) 1.16 (1.12-1.20)
*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.
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0
10
20
30
40
50
Ischemicheart
disease
% o
f D
eath
s
Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.
Mortality in People with DiabetesCauses of Death
Otherheart
disease
Diabetes Cancer Stroke Infection Other
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Relative Risks of Cardiovascular EventsDiabetes v Nondiabetes. Framingham
45-74 year old
0
1
2
3
4
5
6
7
8
9
10
Male Female
Any CVD CVD Death
CardiacFailure
BrainInfarct
CHD IntClaud
Unadj.Adjust.
Unadj.Adjust.
Kannel, Diabetes Care 1979; 2:120-126.
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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.
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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.
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Effect of Diabetes on 30-Day SurvivalAfter MI: GUSTO-I
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WOMENWOMENMENMEN
0
10
20
30
40
50
60
Cardiovascular Mortality in People with Diabetes
% o
f D
eath
s (C
rude R
ate
)
Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75.
Diabetes No Diabetes
28.628.622.122.1
10.910.9 11.911.9
Diabetes
No Diabetes
15.415.4
9.69.622.722.7
9.09.0
9.19.1
4.24.2 11.111.1
2.82.8
28 d – 1 y
Hospitalization – 28 d
Out of Hospital
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NondiabetesNondiabetesDiabetesDiabetes
0
5
10
15
20
*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.
Trends in Mortality Rates for Ischemic Heart Disease in NHANES Subjects with and without Diabetes*
17.0
6.8
-16.6% +10.7%
Men, cohort 1*Men, cohort 1*
Men, cohort 2**Men, cohort 2**
Women, cohort 1* Women, cohort 1* Women, cohort 2**Women, cohort 2**
-43.8% -20.4%
14.2
7.6 7.4
4.22.4 1.9
(P=0.46) (P=0.76) (P<0.001) (P=0.12)
Rate
per
1000 p
ers
on-y
ears
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AGE-ADJUSTED RATES OF NONFATAL MI AND FATAL CHD COMBINED
PER 100,000 PERSON-YEARS
0
100
200
300
400
500
No Yes
NondiabeticDiabetic
Rateof CHD
High Cholesterol
Diabetes in Women, Manson et al. Arch Intern Med, 1991; 151: 1144.
37
262
133
452
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• 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
Glycemia in Diabetes and Heart Disease
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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 Any Mention
Cause of Death HR 95% CI HR 95% CI
Diabetes 1.25 (1.13-1.38) 1.18 (1.10-1.28)
Ischemic heart disease 1.18 (1.00-1.40) 1.17 (1.03-1.33)
Other heart disease . . . . . . 1.18 (1.06-1.31)
Renal disease . . . . . . 1.07 (0.92-1.25)
All causes 1.12 (1.04-1.21) . . . . . .
Moss SE. Arch Intern Med 1994; 154: 2473-2479.
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The 14-Year Cumulative Incidence of Amputation for a Specified Increment in Baseline Characteristics in Multivariate
Logistic Regression: WESDRCharacteristic Increment P OR (95% CI)
Younger-onset Age (years) 10 <0.0001 1.71 (1.30-2.24) Sex Male <0.0001 5.21 (2.50-10.88) Glycosylated hemoglobin (%) 1 <0.0001 1.39 (1.22-1.59) Diastolic blood pressure (mmHg) 10 <0.005 1.58 (1.20-2.07) History of ulcers Present <0.0005 3.19 (1.71-5.95) Retinopathy One step <0.0001 1.16 (1.08-1.24)
Moss SE. Diabetes Care 1999; 22: 951-959.
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Baseline Risk Factor Levels for CAD in Both Sexes, by First Event, EDC 10 year Follow-up
No Angina Hard TotalVariable CAD Pectoris CAD CAD
N 495 49 42 108
Sex (% Male) 50.1 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***
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Baseline Risk Factor Levels for CAD in Both Sexes, by First Event, EDC 10 year Follow-up (Cont.)
No Angina Hard TotalVariable CAD Pectoris CAD CAD
WBC x 103/mm2‡ 6.4 ±1.8 7.1 ±2.2* 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 ±30.8 125.3 ±32.3** 147.0 ±44.0*** 132.4 ±41.8***
HDLc (mg/dl) 54.8 ±12.2 50.9 ±13.0* 48.3 ±9.8** 50.0 ±11.8***
ApoA1/HDLc 2.6 ±0.5 2.8 ±0.6* 2.9 ±0.5*** 2.9 ±0.5***Values are given as mean ±SD or prevalence (%). ¶Mann-Whitney. Fisher’s exact ‡Log-transformed before t-testComparisons with no CAD: *p<0.05 **p<0.01 ***p<0.001
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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
Serum Creatinine (mg/dl)¶ 0.96 ±0.9 1.03 ±0.5* 1.6 ±1.6*** 1.3 ±1.2**
Log median AER (µg/min)¶ 3.2 ± 1.8 4.2 ±2.1** 5.9 ±2.2*** 4.8 ±2.3***
SBP (mm Hg) 111.1 ±13.2 118.5 ±14.1*** 127.5 ±21.1*** 121.3 ±18.5***
QTc 407.1 ±30.0 414.1 ±25.9 412.5 ±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*** 7.0 ±2.0***
Beck Depression Inventory¶ 6.8 ±6.2 9 .7 ±7.1** 7.7 ±5.7 8.1 ±6.5*
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Baseline Risk Factor Levels for CAD in Both Sexes, by First Event, EDC 10 year Follow-up (Cont.)
No Angina Hard TotalVariable CAD Pectoris CAD CAD
Smoke Ever (%) 32.8 50.0* 59.5** 54.7***
Hypertension (%) 9.9 34.7*** 42.9*** 34.3***
DSP (%) 20.3 61.2*** 50.0*** 52.8***E/I < 1.10 (%) 12.9 32.6** 47.1*** 37.9***
Overt Nephropathy (%) 17.2 38.8** 69.0*** 48.1***MA or ON (%) 38.8 69.4*** 85.7*** 71.3***
ABI < 0.8 or ABD 75+ % 6.4 14.3 26.8*** 19.6*** eGDR<6.22 (mg/kg/min)(%)¶ 14.1 22.4 56.1*** 34.9***
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EDC 6 Yr Follow-up: Multivariate Analysis (Cox Proportional Hazards)
CHD LEAD
Men* Women† Men† Women†
Duration 0.002 Duration 0.000 Duration 0.004 LDLc 0.02
HDLc 0.009 WHR 0.001 HbA1 0.000 WHR 0.04
WBC 0.008 BDI 0.040 Smoking 0.03
Fibrinogen 0.092 Hypertension 0.000
Hypertension 0.016
*Nephropathy (0.000) replaces WBC/Fibrinogen/Hypertension and improves model. †Nephropathy doesn’t enter model.
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Multivariate Models of CVD in EDC and Eurodiab Prevalence Analyses of Comparable Populations
Standardized Coefficient Coefficient P value
MalesEurodiab Age 0.071 0.36 0.007
HDL Cholesterol -1.867 -0.38 0.008
EDC Triglycerides 0.40 0.23 0.02Hypertension 2.163 0.49 0.0001
FemalesEurodiab Age 0.043 0.21 0.008
HbA1c -0.288 -0.29 0.008Hypertension 0.734 0.16 0.032
EDC Age 0.079 0.32 0.01HbA1 0.266 0.27 0.03Macroalbuminuria 1.289 0.31 0.006
Int J. of Epidemiology 1998.
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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.
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DOES IMPROVED GLYCEMIC CONTROL REDUCE CVD
RISK IN DIABETES?
• UGDP
• DIS
• KUMAMOTO
• DCCT
• VA FEASIBILITY
• UKPDS
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GLUCOSE LOWERING AND CARDIOVASCULAR RISK IN DIABETES
Study Intervention Result
UGDP Tolbutamide Possible increased cardiovascular risk
Phenformin Increased lactoacidosis
Insulin variable No benefit
Insulin standard No benefit
DCCT/ Intensive(insulin) Possible decrease inEDIC glycemic therapy macrovascular events in type 1 diabetes (largely lower extremity
arterial disease )
No effect on ankle-brachial index small effect on carotid
IMT
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EPIC - Norfolk4,662 men, 45-79 years (18% of total cohort). Followedapproximately 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=0.03Non CVD mortality=1.20 (1.01-1.44) p=0.04Total 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.
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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. BUTHyperglycemia, the hallmark of diabetes, is only weakly (at best) related to CHD.