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CVD Prediction- Diabetes/Lipids/Hypertension
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"In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes......In this community-based study population of black or white nondiabetic adults, glycated hemoglobin was superior to fasting glucose for assessment of the long-term risk of subsequent cardiovascular disease, especially at values above 6.0%. Such prognostic data may add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes"
Prediction of Coronary Heart Disease Using Risk Factor Categories
Circulation. 1998
Background-The objective of this study was to examine the association of Joint National Committee (JNC-V) blood pressure and National Cholesterol Education Program (NCEP) cholesterol categories with coronary heart disease (CHD) risk, to incorporate them into coronary prediction algorithms, and to compare the discrimination properties of this approach with other noncategorical prediction functions.
Methods and Results-This work was designed as a prospective, single-center study in the setting of a community-based cohort. The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up. During the 12 years of follow-up, a total of 383 men and 227 women developed CHD, which was significantly associated with categories of blood pressure, total cholesterol, LDL cholesterol, and HDL cholesterol (all P<.001). Sex-specific prediction equations were formulated to predict CHD risk according to age, diabetes, smoking, JNC-V blood pressure categories, and NCEP total cholesterol and LDL cholesterol categories.
The accuracy of this categorical approach was found to be comparable to CHD prediction when the continuous variables themselves were used.
After adjustment for other factors, ≈:28% of CHD events in men and 29% in women were attributable to blood pressure levels that exceeded high normal (≥130/85). The corresponding multivariable-adjusted attributable risk percent associated with elevated total cholesterol (≥200 mg/dL) was 27% in men and 34% in women.
Conclusions-Recommended guidelines of blood pressure, total cholesterol, and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample. A simple coronary disease prediction algorithm was developed using categorical variables, which allows physicians to predict multivariate CHD risk in patients without overt CHD. Diabetes was considered present if the participant was under treatment with insulin or oral hypoglycemic agents, if casual blood glucose determinations exceeded 150 mg/dL at two clinic visits in the original cohort, or if fasting blood glucose exceeded 140 mg/dL at the initial examination of the Offspring Study participants.
Data from Tables 3 and 4 demonstrate that blood pressure, TC, LDL-C, and HDL-C categories are predictive of CHD and suggest that risk factor prevention and intervention programs should be integrated, as recently suggested.28 29 30



Persons who exercise typically have a lower risk of CHD.49 50 51 Information on physical activity was not available at the baseline examinations used to develop this CHD risk prediction algorithm, but cigarette smoking, low HDL-C levels, and diabetes are less common among those who are physically active.52 53 54 55 Regular and vigorous exercise is often associated with higher levels of HDL-C, an important determinant for reduced CHD risk.56 57 58 Similarly, body mass index, an obesity index that expresses weight in kilograms divided by height in meters squared, has been considered a candidate variable for the CHD prediction algorithm. Greater obesity has been associated with higher TC, lower HDL-C, higher blood pressure, and diabetes, and the residual impact of obesity on CHD has typically been slight after incorporation of these other variables into the regression model.8
our prediction equations estimate coronary disease risk over a period of 10 years for a larger age range and include total CHD (angina pectoris, myocardial infarction, and coronary death).
study that considered CHD prediction using TC, LDL-C, TC/HDL-C ratio, and LDL-C/HDL-C ratio66 concluded that "total cholesterol/HDL is a superior measure of risk for CHD compared with either total cholesterol or LDL cholesterol, and that current practice guidelines could be more efficient if risk stratification was based on this ratio rather than primarily on the LDL cholesterol level." Such an approach appears attractive, but at the extremes of the TC or LDL-C distribution, equal ratios may not signify the same CHD risk. Moreover, use of a ratio may make it harder for the physician to focus on the separate values for TC, LDL-C, and HDL-C that have to be borne in mind to make appropriate clinical decisions concerning therapy. The current approach builds on established blood pressure (JNC-V) and cholesterol (NCEP ATP II) foundations, requires fasting samples only if LDL-C score sheets are used, and is easy to implement as part of a screening program.
Two blood pressure determinations were made after the participant had been sitting at least 5 minutes, and the average was used for analyses. Hypertension was categorized according to blood pressure readings by JNC-V definitions10 : optimal (systolic <120 mm Hg and diastolic <80 mm Hg), normal blood pressure (systolic 120 to 129 mm Hg or diastolic 80 to 84 mm Hg), high normal blood pressure (systolic 130 to 139 mm Hg or diastolic 85 to 89 mm Hg), hypertension stage I (systolic 140 to 159 mm Hg or diastolic 90 to 99 mm Hg), and hypertension stage II–IV (systolic ≥160 or diastolic ≥100 mm Hg). When systolic and diastolic pressures fell into different categories, the higher category was selected for the purposes of classification. Blood pressure categorization was made without regard to the use of antihypertensive medication.
Cutoffs for TC (<200, 200 to 239, 240 to 279, and ≥280 mg/dL), LDL-C (<130, 130 to 159, and ≥160 mg/dL), HDL-C (<35, 35 to 59, and ≥60 mg/dL), cigarette smoking, diabetes, and age were considered in this report. The cholesterol and LDL-C cutoffs are similar to those used for the NCEP ATP II guidelines and were partly dictated by the number of persons with higher levels of TC or LDL-C. For those reasons, we have provided information for cholesterol categories of 240 to 279 and ≥280 mg/dL and for LDL-C ≥160 mg/dL. Too few persons had LDL-C ≥190 mg/dL to provide stable estimates for CHD risk. Study subjects were followed up over a 12-year period for the development of CHD (angina pectoris, recognized and unrecognized myocardial infarction, coronary insufficiency, and coronary heart disease death) according to previously published criteria. "Hard CHD" events included total CHD without angina pectoris.17 Surveillance for CHD consisted of regular examinations at the Framingham Heart Study clinic and review of medical records from outside physician office visits and hospitalizations.
Age-adjusted 10-year CHD rates for blood pressure and cholesterol categories are shown for men and women in Table 3⇓. In prediction models, the CHD rates were significantly associated with the specified categories of blood pressure, TC, HDL-C, and LDL-C (all P<.001 for both sexes). The number of CHD events arising at each blood pressure and cholesterol category is also given. For blood pressure, the greatest number of CHD cases arose from the stage I hypertension category for both sexes. Conversely, the greatest number of CHD cases arose from the highest lipoprotein cholesterol levels (LDL-C ≥160 mg/dL or cholesterol ≥240 mg/dL).
Multivariable risk calculations for TC categories are shown in Table 4⇓. Normal or optimal blood pressure was used as the reference level, and estimated relative risk rose from 1.00 for normal or optimal blood pressure to 1.84 in men and 2.12 in women with stage II–IV hypertension. Similarly, for TC, the estimated relative risk rose from 1.00 for levels <200 mg/dL to 1.90 in men and 1.72 in women with TC ≥240 mg/dL. When typical HDL-C levels (35 to 59 mg/dL) were used as a reference, CHD risk was increased among men and women with low HDL-C (<35 mg/dL) and CHD risk was correspondingly decreased among subjects with high HDL-C (≥60 mg/dL). The population-attributable risk percent associated with hypertension was 6% for high normal, 13% for stage I, and 9% for stage II–IV hypertension among men. The corresponding values were 5% for high normal, 13% for stage I, and 12% for stage II–IV hypertension among women. An overall estimate of the attributable risk percent for blood pressure level greater than normal was 28% in men and 29% in women. When cholesterol <200 mg/dL was used as the reference range, attributable risks were 10% for TC 200 to 239 mg/dL and 17% for TC ≥240 mg/dL in men and 12% for TC 200 to 239 mg/dL and 22% for TC ≥240 mg/dL in women. The overall estimate of the attributable risk percent for TC level ≥200 mg/dL was 27% in men and 34% in women.
Glycated hemoglobin values reflect the 2-to-3-month average endogenous exposure to glucose, including postprandial spikes in the blood glucose level, and have low intraindividual variability, particularly in persons without diabetes.4,25 These characteristics may contribute to the superiority of glycated hemoglobin over fasting glucose for long-term macrovascular risk stratification.
Recommendations for the diagnosis of diabetes are based on the relations of fasting glucose and glycated hemoglobin with microvascular disease, typically retinopathy.1,3 Nonetheless, cardiovascular disease is the leading cause of illness, death, and hospitalization in persons with diabetes.26,27 Our data suggest that glycated hemoglobin values in the normal range can identify persons at increased risk for coronary heart disease, stroke, and death before the diagnosis of diabetes, indicating that glycated hemoglobin is a useful marker of cardiovascular risk and death from any cause. The J-shaped relation between the glycated hemoglobin value and the risk of death from any cause suggests that further exploration of the health risks associated with the low-normal glycemic state and possible nonglycemic determinants of glycated hemoglobin is warranted. As in the present study, the literature has documented an increase in cardiovascular risk with increases in glycated hemoglobin values within the nondiabetic range.28-36 We have previously shown (using a case–cohort design) associations of glycated hemoglobin with coronary heart disease and stroke in a subgroup of the ARIC population with low fasting glucose levels (at two time points) and low glycated hemoglobin values37 and, separately, among persons with diabetes.38 Nonetheless, recent clinical trials have shown little benefit, and possibly some harm, of lowering the glycated hemoglobin value in patients with diabetes to prevent cardiovascular outcomes.39-43 In contrast, the microvascular benefits of glucose control are well established.44,45 Although the causal role of glucose itself in the development of cardiovascular disease is unclear, our data demonstrate that glycated hemoglobin within the normal range can be a useful marker of cardiovascular risk. Therefore, glycated hemoglobin values exceeding 6.0% may be a clinically useful marker to identify persons at risk for the development of not only diabetes but also cardiovascular disease and death.
The fasting glucose categories were associated with the risks of outcomes in the minimally adjusted models, but these associations were attenuated after adjustment for other risk factors (Table 3. As compared with a baseline fasting glucose level of less than 100 mg per deciliter, a level of 100 to less than 126 mg per deciliter was associated with diagnosed diabetes (hazard ratio, 2.31; 95% CI, 2.06 to 2.59) but not with coronary heart disease (hazard ratio, 1.03; 95% CI, 0.91 to 1.18), ischemic stroke (hazard ratio, 0.97; 95% CI, 0.76 to 1.23), and death from any cause (hazard ratio, 1.07; 95% CI, 0.96 to 1.21) after adjustment for covariates (model 2b) (Table 3), whereas undiagnosed diabetes (defined as a fasting glucose level of 126 mg per deciliter or higher at baseline) was significantly, independently associated with the development of coronary heart disease (hazard ratio, 1.29; 95% CI, 1.04 to 1.61), ischemic stroke (hazard ratio, 1.89; 95% CI, 1.33 to 2.69), and death from any cause (hazard ratio, 1.31; 95% CI, 1.07 to 1.61). After additional adjustment for glycated hemoglobin in model 3b, there was no significant association between fasting glucose category and the risk of coronary heart disease, ischemic stroke, or death from any cause. Among the 10,069 participants with a fasting glucose level of less than 126 mg per deciliter at visit 1 and visit 2, the glycated hemoglobin category was similarly associated, in model 3b as compared with models 1b and 2b, with diagnosed diabetes, coronary heart disease, stroke, and death from any cause (Table 2 in the Supplementary Appendix).
We also assessed the associations of three categories of glycated hemoglobin (<6.0%, 6.0 to <6.5%, and ≥6.5%) with the risks of outcomes among participants stratified according to the fasting glucose category (<100, 100 to <126, and ≥126 mg per deciliter) (Table 3 in the Supplementary Appendix). The glycated hemoglobin categories of 6.0 to less than 6.5% and 6.5% or higher were significantly associated with all outcomes within each fasting glucose category, with the association increasing with higher glycated hemoglobin categories. In contrast, if the glycated hemoglobin value was less than 6.0%, fasting glucose was not significantly associated with coronary heart disease, ischemic stroke, or death from any cause.





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