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Preventing CAD in Diabetes by Trevor Orchard

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%

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Preventing CAD in Diabetes by Trevor Orchard

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  1. Preventing CAD in Diabetesby Trevor Orchard • Definition of Diabetes • Magnitude of the Risk • Reasons for the Risk • Evidence for Preventive Interventions • Clinical Recommendations

  2. M.D. SURVEY : DxDIABETES Frequency of OGTT Use #1 2% #2 19% #3 16% No mention 68%

  3. Current Diagnostic Criteria for Diabetes (plasma glucose mg/dl) – WHO/ADA 1979 NDDG/1980 WHO 1997 ADA Fasting  140  126 2 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.

  4. 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.

  5. 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. WHO ADA Fasting Criteria n n Normal 184 1.09 (0.73-1.65)11421.20 (0.99-1.47) IGT or IFG 1264 1.23 (1.01-1.98)582 1.39 (1.09-1.77) New Diabetes 5631.56 (1.23-1.98) 2871.58 (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.

  6. 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.

  7. 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 glucose2 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.

  8. Mortality in People with DiabetesCauses of Death % of Deaths Ischemicheartdisease Otherheartdisease Diabetes Infection Cancer Stroke Other Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.

  9. Relative Risks of Cardiovascular EventsDiabetes v Nondiabetes. Framingham45-74 year old Any CVD CVD Death Cardiac Failure Brain Infarct CHD Int Claud Unadj. Unadj. Adjust. Adjust. Kannel, Diabetes Care 1979; 2:120-126.

  10. 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.

  11. 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.

  12. Effect of Diabetes on 30-Day SurvivalAfter MI: GUSTO-I

  13. Cardiovascular Mortality in People with Diabetes MEN WOMEN 28 d – 1 y Hospitalization – 28 d Out of Hospital 9.1 11.1 4.2 15.4 % of Deaths (Crude Rate) 9.6 2.8 22.7 9.0 28.6 22.1 11.9 10.9 No Diabetes Diabetes Diabetes No Diabetes Adapted from Miettinen H et al. Diabetes Care. 1998;21:69-75.

  14. Trends in Mortality Rates for Ischemic Heart Disease in NHANES Subjects with and without Diabetes* Diabetes Nondiabetes 17.0 Men, cohort 1* Men, cohort 2** Women, cohort 1* Women, cohort 2** 14.2 Rate per 1000 person-years 7.6 7.4 6.8 4.2 2.4 1.9 -16.6% +10.7% -43.8% -20.4% (P=0.46) (P<0.001) (P=0.12) (P=0.76) *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.

  15. AGE-ADJUSTED RATES OF NONFATAL MI AND FATAL CHD COMBINED PER 100,000 PERSON-YEARS 452 262 Rate of CHD 133 37 High Cholesterol Diabetes in Women, Manson et al. Arch Intern Med, 1991; 151: 1144.

  16. 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

  17. 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 CauseAny 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.

  18. The 14-Year Cumulative Incidence of Amputation for a Specified Increment in Baseline Characteristics in Multivariate Logistic Regression: WESDR Characteristic Increment P OR (95% CI) Younger-onset Age (years) 10<0.0001 1.71 (1.30-2.24) SexMale<0.00015.21 (2.50-10.88) Glycosylated hemoglobin (%)1<0.00011.39 (1.22-1.59) Diastolic blood pressure (mmHg)10<0.0051.58 (1.20-2.07) History of ulcers Present <0.00053.19 (1.71-5.95) Retinopathy One step<0.0001 1.16 (1.08-1.24) Moss SE. Diabetes Care 1999; 22: 951-959.

  19. Baseline Risk Factor Levels for CAD in Both Sexes, by First Event, EDC 10 year Follow-up No Angina Hard Total Variable CAD Pectoris CAD CAD N 4954942108 Sex (% Male)50.1 49.061.951.9 Age (yrs)2.59±7.333.4 ±6.2***32.9 ±6.6*** 33.0 ±6.8*** Duration (yrs)17.6 ±6.925.1 ±6.5***25.4 ±6.4*** 24.9 ±6.9*** HbA1 (%)10.4 ±1.89.9 ±1.9 10.7 ±1.810.3 ±1.8 Fibrinogen (mg/dl)¶280.1 ±87.1305.8 ±77.9** 343.3 ±97.2***319.6 ±89.5***

  20. 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 WBC x 103/mm2‡6.4 ±1.87.1 ±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 ±38.3151.0 ±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 ±12.250.9 ±13.0*48.3 ±9.8** 50.0 ±11.8*** ApoA1/HDLc 2.6 ±0.52.8 ±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-test Comparisons with no CAD: *p<0.05 **p<0.01 ***p<0.001

  21. Baseline Risk Factor Levels for CAD in Both Sexes, by First Event, EDC 10 year Follow-up (Cont.) NoAngina HardTotal VariableCAD Pectoris CAD CAD Serum Creatinine (mg/dl)¶0.96 ±0.91.03 ±0.5* 1.6 ±1.6***1.3 ±1.2** Log median AER (µg/min)¶3.2 ± 1.84.2 ±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*** QTc407.1 ±30.0414.1 ±25.9412.5 ±29.6 414.1 ±26.5* Physical Activity 2790.9 ±2999.81779.2 ±2176.4** 1917.4 ±1766.7 916.9 ±2053.6** WHR0.82 ±0.07 0.84 ±0.08* 0.86 ±0.07*** 0.85 ±0.07*** eGDR (mg/kg/min)8.1 ±1.87.3 ±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* 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

  22. 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 (%) 20.3 61.2*** 50.0*** 52.8*** E/I < 1.10 (%) 12.9 32.6** 47.1*** 37.9*** Overt Nephropathy (%) 17.238.8**69.0*** 48.1*** MA or ON (%) 38.8 69.4*** 85.7*** 71.3*** ABI < 0.8 or ABD 75+ % 6.414.326.8***19.6*** eGDR<6.22 (mg/kg/min)(%)¶ 14.1 22.4 56.1*** 34.9*** Baseline Risk Factor Levels for CAD in Both Sexes, by First Event, EDC 10 year Follow-up (Cont.)

  23. EDC 6 Yr Follow-up: Multivariate Analysis (Cox Proportional Hazards) CHDLEAD Men*Women†Men†Women† Duration 0.002 Duration 0.000 Duration 0.004 LDLc0.02 HDLc 0.009WHR0.001 HbA10.000WHR0.04 WBC 0.008BDI0.040 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.

  24. Multivariate Models of CVD in EDC and Eurodiab Prevalence Analyses of Comparable Populations Standardized Coefficient Coefficient P value Males Eurodiab Age 0.071 0.36 0.007 HDL Cholesterol -1.867 -0.38 0.008 EDC Triglycerides 0.40 0.23 0.02 Hypertension 2.163 0.49 0.0001 Females Eurodiab Age 0.043 0.21 0.008 HbA1c -0.288 -0.29 0.008 Hypertension 0.734 0.16 0.032 EDC Age 0.079 0.32 0.01 HbA1 0.266 0.27 0.03 Macroalbuminuria 1.289 0.31 0.006 Int J. of Epidemiology 1998.

  25. 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 VariableP 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.

  26. DOES IMPROVED GLYCEMIC CONTROL REDUCE CVD RISK IN DIABETES? • UGDP • DIS • KUMAMOTO • DCCT • VA FEASIBILITY • UKPDS

  27. GLUCOSE LOWERING AND CARDIOVASCULAR RISK IN DIABETES StudyInterventionResult UGDP Tolbutamide Possible increased cardiovascular risk Phenformin Increased lactoacidosis Insulin variableNo benefit Insulin standardNo benefit DCCT/ Intensive(insulin) Possible decrease in EDIC glycemic therapy macrovascular events in type 1 diabetes (largely lower extremity arterial disease ) No effect on ankle-brachial index small effect on carotid IMT

  28. 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.

  29. 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.

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