Another reason for clinical interest in adding hsCRP to current risk algorithms derives from the fact that inflammation may play a key role in processes associated with metabolic syndrome, a condition that confers increased cardiovascular risk (72). hsCRP levels are correlated positively with components of metabolic syndrome commonly measured in
clinical practice, such as elevated triglycerides, low HDL-C, obesity, high fasting glucose, and high blood pressure (BP). In the Women's Health Study, e.g., after adjustment for multiple potential confounders, the RRs of incident hypertension for increasing hsCRP quintiles were 1.00 (referent), 1.07 (95% CI: 0.95-1.20), 1.17 (95% CI: 1.04-1.31), 1.30 (95% CI: 1.17-1.45), and 1.52 (95% CI: 1.36-1.69), respectively (p for trend of <0.001) (73). hsCRP levels are also correlated with other components of the syndrome not easily assessed during routine office visits, such as fasting insulin, microalbuminuria, and impaired fibrinolysis. Indeed, among Women's Health Study participants without diabetes, hsCRP and BMI were the only independent correlates of fasting insulin level modeled as a continuous dependent variable. After adjustment for BMI and other risk factors for diabetes, the RR for elevated fasting insulin (©51.6 pmol/L) increased with the tertile of hsCRP (for hsCRP <1.4, 1.4-4.4, and ©4.4 mg/L, RRs were 1.0, 3.7, and 4.4, respectively; p for trend <0.001) (74). This association was observed among both lean and overweight women.
Data from the Women's Health Study also show that hsCRP levels <1, 1-3, and >3 mg/ L successfully differentiated women with metabolic syndrome into low-, moderate-, and high-risk groups (Fig. 8) (75). In analyses comparing the predictive ability of hsCRP alone (©3 vs <3 mg/L) with that of metabolic syndrome alone, the area under the receiver operating characteristic curve was 0.77 for hsCRP and 0.78 for metabolic syndrome, indicating that the two variables are equally useful for cardiovascular risk assessment. However, as with LDL-C and the Framingham risk score, the addition ofhsCRP to the traditional metabolic syndrome definition provided the best predictive algorithm. Similar results were observed in a cohort of 6447 middle-aged men followed for 5 yr in the West of Scotland Coronary Prevention Study (76). hsCRP, coded as ©3 vs <3 mg/L, was predictive of inci dent CHD after stratification by metabolic syndrome status. Among participants in the "low-CRP/metabolic syndrome absent," "high-CRP/metabolic syndrome absent," "low-CRP/metabolic syndrome present," and "high-CRP/metabolic syndrome present" groups, the RRs for incident CHD were 1.0 (referent), 1.6 (95% CI: 1.3-2.1), 1.6 (95% CI: 1.2-2.1), and 2.75 (95% CI: 2.1-3.6), respectively. In a 7-yr follow-up of 3037 men and women without diabetes in the Framingham Offspring Study, persons in the highest quartile of hsCRP had nearly twice the risk of developing CVD than did those in the lowest quartile after adjustment for age, sex, and the presence of the metabolic syndrome (hsCRP ©4.5 vs <0.25 mg/L; RR: 1.9; 95% CI: 1.2-2.9) (77). hsCRP levels have additionally been found to predict cardiovascular risk among persons with diabetes. Among 746 men with diabetes followed for 5 yr in the Health Professionals Follow-up Study, those in the top quartile of hsCRP were nearly three times more likely to develop cardiovascular events than those in the bottom quartile after adjustment for traditional risk factors, including blood lipids, as well as fibrinogen, creatinine, and glycosylated hemoglobin (RR: 2.62; 95% CI: 1.29-5.32) (median hsCRP levels in the top and bottom quartiles were 4.86 and 0.53 mg/L, respectively) (78).
Prospective studies have also found strong monotonic relationships between hsCRP and incident diabetes, often after adjustment for BMI and other risk factors for diabetes. In the West ofScotland Coronary Prevention Study, the top quintile ofhsCRP was associated with a threefold increase in the incident diabetes rate (hsCRP >4.18 vs <0.66 mg/L; multivariable-adjusted 5-yr RR: 3.07; 95% CI: 1.33-7.10) (79), and hsCRP remained significantly predictive after stratification by metabolic syndrome status. Among men in the "low-CRP/metabolic syndrome absent," "high-CRP/metabolic syndrome absent," low-CRP/metabolic syndrome present," and "high-CRP/metabolic syndrome present" groups, the RRs for incident diabetes were 1.0 (referent), 1.8 (95% CI: 1.1-3.0), 3.6 (95% CI: 2.35.6), and 5.3 (95% CI: 3.3-8.3), respectively (76). In the Women's Health Study, women in the top quartile ofthe hsCRP distribution were more than four times as likely to develop diabetes than women in the bottom quartile during 4 yr of follow-up (hsCRP >6.1 vs <1 mg/ L; multivariable-adjusted RR: 4.2; 95% CI: 1.2-12) (80). Similarly, in the Nurses' Health Study, the extreme quintile comparison (hsCRP ©4.05 vs <0.55 mg/L) yielded a multivariable-adjusted RR of4.36 (95% CI: 2.80-6.80) over 10 yr of follow-up (81). Among 5888 persons age 65 yr or older in the Cardiovascular Health Study, a comparison of the extreme hsCRP quartiles revealed a near doubling of risk over 4 yr (hsCRP >2.86 mg/L vs <0.82 mg/L; multivariable-adjusted RR: 1.83; 95% CI: 1.24-2.86) (82). By contrast, despite strong age-adjusted associations between hsCRP and incident diabetes in the 7-yr MONICA Augsburg study of2052 middle-aged men (83) and the 5-yr Insulin Resistance Atherosclerosis Study (84) of1047 middle-aged men and women, hsCRP was not predictive of diabetes in these cohorts after factoring out the effect of BMI. Nevertheless, in the aggregate, these data support the hypothesis that inflammation, atherothrombosis, and diabetes are closely related disorders of the innate immune system.
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