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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.