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.