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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
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 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.
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.
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.
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.
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.
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
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.
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 SurvivalAfter MI: GUSTO-I
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
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
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
• 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
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.
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.
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***
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
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*
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***
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.
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.
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 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
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.
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.