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C-REACTIVE PROTEIN AND CARDIOVASCULAR DISEASE IN PEOPLE WITH DIABETES: High-sensitivity CRP testing can help assess risk for future cardiovascular dis

AJN, American Journal of Nursing
C-REACTIVE PROTEIN AND CARDIOVASCULAR DISEASE IN PEOPLE WITH DIABETES: High-sensitivity CRP testing can help assess risk for future cardiovascular disease events in this population.
ISSN: 0002-936X
Accession: 00000446-200608000-00027
Author(s):

Xu, Yin PhD, RN; Whitmer, Kyra PhD, RN

Issue:
Volume 106(8), August 2006, p 66–72
Publication Type:
[FEATURE]
Publisher:
© 2006 Lippincott Williams & Wilkins, Inc.
Institution(s):
Yin Xu is an assistant professor and Kyra Whitmer is an associate professor at the University of Cincinnati (UC) College of Nursing, Cincinnati, OH, where Whitmer is also associate director of the Institute of Nursing Research.
Contact author: Yin Xu, yin.xu@uc.edu.
The authors thank Marilyn S. Sommers, PhD, RN, FAAN, chairperson of the steering committee of the Council for the Advancement of Nursing Science and professor and associate dean for research at the UC College of Nursing, and Judith Laver Bierschbach, MSN, RN, CAPN, associate professor at the UC College of Nursing, for their reviews of the manuscript.
OVERVIEW

Having both diabetes and an elevated C-reactive protein (CRP) level compounds one's risk of developing cardiovascular disease, for which people with diabetes are at particularly high risk. CRP is both a biomarker for infectious and noninfectious disorders associated with inflammation and a risk factor for such conditions. Many researchers now believe that the protein also plays a role in the disease processes. The American Heart Association and the Centers for Disease Control and Prevention recently defined three cardiovascular risk categories relative to CRP levels. This article reviews the relevant literature and explores how CRP levels can be used in cardiovascular disease risk assessment, prevention, and treatment.



People with diabetes are known to be at high risk for developing cardiovascular disease—yet traditional cardiovascular risk factors such as obesity, dyslipidemia, and hypertension only partly account for this risk. Recently, considerable attention has been focused on the association between cardiovascular disease and C-reactive protein (CRP) in patients with diabetes. CRP levels serve as an inflammatory marker that reflects underlying disease processes such as cardiovascular disease and diabetes. An elevated CRP level is also a risk factor for these and other illnesses; researchers now believe that the protein plays a role in the disease processes, although the mechanism is not understood.1

The interactions among CRP, diabetes, and cardiovascular disease help to explain the increased risk of cardiovascular disease in people with diabetes. This article considers the relevant literature and explores how CRP levels can be used in risk assessment to prevent cardiovascular disease in this population.

WHAT IS C-REACTIVE PROTEIN?

CRP, an acute-phase reactant, is produced by the liver in response to inflammation. CRP functions much like an antibody in that it can bind with foreign antigens. It was first identified in 1930, when researchers discovered that CRP binds to C-polysaccharide in the pneumococcal cell wall. CRP is now known to bind to a number of antigens; according to one review, elevated CRP levels are associated with more than 70 different infectious and noninfectious disorders associated with inflammation.2

During the acute phase of inflammation, cells in the immune system release the cytokine interleukin-6, which stimulates the liver to produce CRP. CRP acts in several ways: it “recognizes” and binds to a variety of antigens, marking them for phagocytosis; it also binds to certain types of leukocytes, further stimulating cytokine production. And it binds to C1, the enzyme that activates the classical complement pathway, thereby triggering phagocytosis.

Recent studies indicate that an even slightly increased level of CRP is associated with both cardiovascular disease and diabetes. And in a review discussing the relationships among inflammation, cardiovascular disease, and chronic diseases often associated with aging (such as type 2 diabetes, cancer, and dementia), Tracy suggested that CRP and other inflammatory markers not only reflect underlying atherothrombotic disease but may actually “participate in the disease process, making it worse.”1

It has been reported that CRP can cause endothelial cells to release intracellular adhesion molecule-1 and vascular adhesion molecule-1, two molecules that are associated with the development of atherosclerosis and coronary heart disease.3 Both low-density lipoprotein (LDL) cholesterol and CRP are known to “deposit in the arterial wall during atherogenesis”4; a study by Zwaka and colleagues demonstrated that CRP mediated LDL cholesterol uptake, possibly enhancing LDL cholesterol oxidation and thus foam cell formation during atherogenesis. There is also evidence that CRP is released from atherosclerotic sites. Yasojima and colleagues reported that CRP, which is localized in atherosclerotic plaques, may be synthesized there as well as in the liver.5

CRP serum concentrations

Trace amounts of CRP are present in the serum of healthy people. The normal range used to be considered to be between 0 and 10 mg/L. But there is strong evidence that when the CRP level rises above 3 mg/L, cardiovascular risk increases. Indeed, in a joint scientific statement, the American Heart Association (AHA) and the Centers for Disease Control and Prevention (CDC) recently defined three cardiovascular risk categories relative to CRP levels—all of which are within the range previously considered normal.6 These categories are as follows: people with CRP levels of less than 1 mg/L, 1 to 3 mg/L, and greater than 3 mg/L are considered to be at low, moderate, and high risk, respectively, for future cardiovascular disease events.

The serum concentration of CRP rises quickly in response to both infectious and noninfectious inflammatory stimuli. Plasma levels start to increase within six hours of exposure to an acute inflammatory stimulus and peak after about 50 hours.7 In the presence of bacterial infection, CRP levels can rise above 100 mg/L. CRP levels also fall rapidly once the stimulus is removed.7 In the absence of acute inflammation, CRP levels “are stable over long periods of time, are not affected by food intake, and demonstrate almost no circadian variation.”8 Thus there is no need for fasting when testing CRP levels; they can be assessed at any time.

Until a few years ago, CRP was measured by traditional CRP assay. Although it is still sometimes used in cases of acute inflammation, it has limited ability to detect CRP levels below 10 mg/L. Within the past decade, the high-sensitivity CRP (hs-CRP) immunoassay, which is capable of measuring CRP levels lower than 1 mg/L, has been developed. (Although results are sometimes referred to in terms of hs-CRP levels, there is no biochemical difference between CRP and hs-CRP.) The hs-CRP assay is widely available and has acceptable reliability.6 It also appears to be cost effective. Blake and colleagues found that CRP screening coupled with statin therapy to prevent future cardiovascular disease events was cost-effective in adults with LDL cholesterol levels lower than 149 mg/dL.9

Distribution of CRP levels in the general population

Data from large-scale cohort studies have provided information on CRP levels in generally healthy people. Distribution levels are about the same regardless of age and sex. For example, Ridker and colleagues found that among 15,745 women ages 45 and older who were not on hormone replacement therapy (HRT), those in the 10th, 25th, 50th, 75th, and 90th percentiles had hs-CRP levels of below 0.3 mg/L, 0.6 mg/L, 1.5 mg/L, 3.5 mg/L, and 6.6 mg/L, respectively; the researchers added that “these distributions are very similar to those reported for men and women in previous U.S. and European studies.”10 The AHA–CDC joint statement noted that HRT in women who are postmenopausal increases CRP levels 6; but estrogen-related increases in CRP don't appear to affect atherogenesis.11 Data from the Third National Health and Nutrition Examination Survey (NHANES III) also suggested that CRP concentrations do not differ across racial or ethnic groups but do steadily increase with age, a finding borne out by at least one literature review.8, 12


Graphic
FIGURE 1. C-Reactive Protein: Its Role in Cardiovascular Disease
CRP AND CARDIOVASCULAR DISEASE

During the last 10 years, studies have demonstrated that a higher CRP level is a risk factor for future cardiovascular morbidity and death from cardiovascular causes. A nested case–control study among participants of the Multiple Risk Factor Intervention Trial demonstrated a strong association between higher CRP levels and death from coronary heart disease among men who smoked.13 Participants with CRP levels higher than 3.5 mg/L were more than four times as likely to die from coronary heart disease as participants with CRP levels lower than 1.3 mg/L. A similar association between CRP levels and future cardiovascular events was demonstrated in 1,086 apparently healthy men, both smokers and nonsmokers, participating in the Physicians' Health Study.14 Those with CRP values higher than 2.1 mg/L had three times the risk of first myocardial infarction (MI) and two times the risk of ischemic stroke of those with CRP values of 0.55 mg/L or less. The associations between CRP and a first MI or stroke remained significant after adjusting for other risk factors, including a high body mass index (BMI), diabetes, hypertension, a family history of coronary artery disease, and elevated plasma lipid concentrations. Therefore, even a slightly elevated CRP level is considered an independent risk factor for cardiovascular disease in men.

The association between CRP and future cardiovascular events also holds for women. Two studies of apparently healthy postmenopausal women demonstrated that CRP is a strong predictor of future cardiovascular events.15, 16 Women who developed cardiovascular disease had higher baseline CRP levels than those who did not develop the disease. For example, women with baseline CRP values of 3.8 to 7.3 mg/L had more than three times the risk of developing MI or stroke of those with CRP values lower than 1.5 mg/L.15

CRP AND DIABETES

Several prospective studies indicate a relationship between CRP levels and the development of diabetes or glucose disorders (such as impaired fasting glucose). In a study involving 2,052 men ages 45 to 74, Thorand and colleagues found that CRP levels in the highest quartile were associated with an increased risk of type 2 diabetes.17 Compared with men whose CRP baseline values were less than 0.67 mg/L, those whose values were higher than 2.91 mg/L had nearly three times the risk of future diabetes-related events. Although the association lessened and “became nonsignificant” after adjustment for BMI, smoking status, and blood pressure, the researchers concluded that it suggests “a role for inflammation in the etiology of diabetes.” A similar relationship between CRP and the development of diabetes was observed among middle-aged men in the West of Scotland Coronary Prevention Study.18 Based on both univariate and multivariate analyses, CRP was predictive of the development of diabetes, independent of BMI, fasting triglyceride levels, and glucose concentrations.

Two prospective studies, one involving women ages 45 and older and the other involving adults ages 65 and older, have indicated that CRP is a powerful independent predictor of diabetes.19, 20 In both studies, participants who developed type 2 diabetes during three to four years of follow-up had higher baseline levels of CRP than those who did not develop the disease. In the study involving women ages 45 and older, this association persisted even after adjusting for BMI, family history of diabetes, smoking status, frequency of exercise, frequency of alcohol consumption, and the use of HRT.19 In the study involving adults ages 65 and older, it persisted even after adjusting for BMI, age, sex, fasting insulin and fasting glucose levels, chronic respiratory conditions, smoking status, and subclinical or clinical cardiovascular disease.20

Although substantial evidence has shown that CRP is a powerful predictor of diabetes, it is also plausible that diabetes may trigger vascular inflammation. The NHANES III data also showed elevated CRP levels among people who already had diabetes.21 Healthy people with normal fasting glucose levels had the lowest CRP concentrations (mean, 2.8 mg/L), people with impaired fasting glucose levels had higher CRP concentrations (mean, 3.2 mg/L), and those diagnosed with diabetes had the highest CRP concentrations (mean, 4.6 mg/L).21 Sigurdardottir and colleagues found that CRP levels were higher in men with newly diagnosed diabetes, as well as in men with established diabetes, than in clinically healthy men.22 This too suggests a reciprocal relationship between inflammation and diabetes.

CRP, CARDIOVASCULAR DISEASE, AND DIABETES

People with diabetes are at high risk for cardiovascular disease; indeed, according to the American Diabetes Association, cardiovascular disease and stroke cause more than 65% of deaths in this population.23 Traditional cardiovascular disease risk factors for patients with diabetes, which include older age, smoking, obesity, hypertension, and dyslipidemia, only partly account for this high risk. It's been suggested that there are some “novel” risk factors, including CRP, that contribute to the development of cardiovascular disease in this population.24 There is a reciprocal relationship between increased CRP levels and diabetes, and each of these independently predicts cardiovascular disease. Moreover, diabetes and increased CRP levels have a synergistic effect on the development of cardiovascular disease.

One study found higher CRP concentrations in younger adults (mean age, 22 years) with type 1 diabetes than were found in age-matched, healthy controls; the researchers also found that higher CRP levels were positively correlated with greater severity of early-stage atherosclerosis in both diabetic and nondiabetic participants.25 Mojiminiyi and colleagues considered CRP levels in patients with type 2 diabetes with and without coronary heart disease and found that CRP levels were significantly higher in those patients who had both diabetes and coronary heart disease than in those with diabetes alone.26

Similar results were confirmed in a large, population-based prospective study.27 The study subjects (14,719 apparently healthy women) were divided into four groups, based on whether their levels of CRP were higher or lower than 3 mg/L and on the presence or absence of at least three components of metabolic syndrome. (Metabolic syndrome refers to a cluster of risk factors, including “abdominal obesity, atherogenic dyslipidemia … raised blood pressure, insulin resistance [with or without glucose intolerance], and prothrombotic and proinflammatory states”28; people with this syndrome are at heightened risk for diabetes and cardiovascular disease, among other conditions. It's estimated that about 22% of American adults have the syndrome.29) The subjects were followed for eight years. The researchers found that even after adjusting for age, the group with CRP levels higher than 3 mg/L and with three or more components of metabolic syndrome had the highest risk of cardiovascular events.27 The study also showed that “CRP added important and independent prognostic information in terms of future cardiovascular risk.”27

And a prospective study of 746 men with type 2 diabetes found that baseline CRP level was a strong predictor of future cardiovascular disease events.30 The risk of future cardiovascular disease events among men in the top quartile (median CRP level, 4.86 mg/L) was more than double that in men in the bottom quartile (median CRP level, 0.53 mg/L) after adjustment for age. After further adjustment for numerous other risk factors (including physical activity level, smoking status, and family history of coronary heart disease), CRP remained strongly predictive of future cardiovascular disease events.

One possible explanation for the relationships among elevated CRP, diabetes, and cardiovascular disease is that multiple artery-wall derangements in people with diabetes may cause systemic inflammation.24 Pradhan and Ridker, citing findings linking subclinical inflammation to the development of type 2 diabetes, suggested that type 2 diabetes and atherosclerosis seem to have “a common inflammatory basis.”31 Bahceci and colleagues found that CRP and glycosylated hemoglobin (HbAIc) levels were positively correlated in men with type 2 diabetes, and concluded that inflammation, insulin resistance, and hyperglycemia jointly contribute to the high risk of developing cardiovascular disease in this population.32

An association between CRP levels and the degree of glycemic control could explain the role of CRP in the development of cardiovascular disease in people with diabetes. One study conducted in people with diabetes found that elevated CRP levels were more likely as HbAIc levels increased, after adjustment for age, race, sex, smoking status, BMI, fasting insulin levels, and duration of diabetes.33 Another study, conducted in people with advanced atherosclerosis, found that when both CRP and HbAIc levels were elevated, the risk of major cardiovascular events (including MI, coronary artery bypass grafting, stroke, and death) was greater than when only one of these was elevated.34 Patients with both CRP and HbAIc levels in the highest quartiles had 2.93 times the risk of a major cardiovascular event of patients with both CRP and HbAIc levels in the lowest quartiles and 2.13 times the risk of patients with either CRP or HbAIc levels in the uppermost quartiles.

CLINICAL IMPLICATIONS
Measuring CRP

An hs-CRP assay should be performed in the absence of obvious inflammatory or infectious conditions. Because there is some within-individual variability, “two assays, averaged, fasting or nonfasting, and optimally two weeks apart” are recommended.6 An average of higher than 10 mg/L indicates that infection or inflammation may be present; the result should be discarded and the testing started again in two weeks, after any existing infection or inflammation will have subsided. (For more on hs-CRP measurement guidelines, see Table 1, above.)


Graphic
Table 1. Guidelines for Testing CRP
Usefulness of CRP measurements

The CDC–AHA statement recommended that hs-CRP assays be used to “detect enhanced absolute risk” in people without known cardiovascular disease but who are at intermediate risk for it, according to the Framingham Risk Score (that is, those whose risk of developing coronary heart disease within 10 years is estimated at between 6% and 20%).6 And in 2004 Ridker and colleagues proposed that hs-CRP testing receive “careful consideration” as a criterion for metabolic syndrome and as part of global cardiovascular risk assessment.35

Findings from a recent study by Ridker and colleagues supported the hypothesis that inflammation and hyperlipidemia jointly contribute to the atherothrombotic process.36 Abnormal lipid levels are prevalent in patients with type 2 diabetes. It has been suggested that using a combination of hs-CRP and lipid measures may provide better overall prediction of cardiovascular disease events.16

Pharmacologic treatment

Knowing a patient's CRP level may help clinicians decide on a course of drug treatment aimed at lowering cardiovascular disease risk. Known for its antiplatelet effects, aspirin has often been used to help prevent cardiovascular disease in patients at risk. Studies have indicated that aspirin decreases CRP levels both in apparently healthy people 37 and patients with angina 14 (although in the latter study its effectiveness at preventing a first MI was reduced in people with lower baseline CRP levels). Statins have also been shown to be effective in decreasing CRP levels. Tan and colleagues reported that atorvastatin given 10 mg daily for three months followed by 20 mg daily for three months decreased CRP levels significantly below baseline levels in patients with type 2 diabetes.38 Nissen and colleagues found that “intensive” dosages of atorvastatin, 80 mg daily, significantly decreased CRP levels in patients with documented coronary artery disease; these reductions in CRP levels were associated with a slower rate of progression of atherosclerosis.39 A study by Blake and colleagues suggested that men and women without overt hyperlipidemia but with elevated CRP levels who were treated with statins could gain 6.6 and 6.4 months of life expectancy, respectively.40 Thiazolidinediones (such as rosiglitazone), when used as hypoglycemic agents, have been reported not only to improve insulin sensitivity but also to reduce CRP levels in patients with type 2 diabetes, according to one review.41

Lifestyle modifications

Elevated CRP levels have also been associated with obesity and with smoking.21, 42, 43 A recent review of several intervention trials found that weight loss, achieved through various diet programs in tandem with exercise or nutritional counseling, resulted in 7% to 48% reductions in CRP levels.44 Smoking cessation has also been linked with reduced CRP levels. A recent study investigated the relationship between CRP levels and the duration of smoking cessation in 1,926 adult men.45 Those who had quit smoking five or more years earlier had significantly lower CRP levels than those who had quit more recently; indeed, the mean CRP level in the long-term cessation group was similar to that of nonsmokers.45 This information may be helpful in motivating patients with diabetes who are obese to lose weight and those who smoke to quit.

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