It has been recognized for almost 20 years that certain metabolic risk factors for cardiovascular disease tend to occur in clusters rather than in isolation. This clustering, now known as the metabolic syndrome, has been defined in different ways by various professional organizations, but insulin resistance, elevated fasting glucose, abdominal obesity, hypertension, and dyslipidemia are common to all definitions. The inflammatory marker C-reactive protein has also been associated with increased risk for cardiovascular disease, including in persons with the metabolic syndrome, but whether C-reactive protein should be considered part of the metabolic syndrome and routinely measured remains controversial. This article reviews the evidence and presents arguments for and against including C-reactive protein in the components of the metabolic syndrome.

Almost 2 decades ago, Dr Gerald Reaven identified a cluster of physiologic and metabolic characteristics that seek the company of one another.¹ Originally known as “syndrome X” or “insulin resistance syndrome,” when found in the same person, these characteristics are so ominous that they have also been called “the deadly quartet” or “the awesome foursome.” Currently referred to as the metabolic syndrome, 5 factors identified in the 2002 report by the National Cholesterol Education Program (NCEP) are thought to comprise this syndrome—large waist circumference, elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C) concentration, high blood pressure, and elevated fasting glucose.² The concomitant presence of 3 or more of these confers an approximate 2-fold increased risk of atherosclerotic cardiovascular disease (CVD) and an approximate 5-fold increased risk of diabetes mellitus.³ Other associated changes have also been described, including a prothrombotic and/or proinflammatory state.

Arterial inflammation has emerged as central to the pathogenesis and clinical manifestation of atherosclerosis. Furthermore, C-reactive protein (CRP), a nonspecific marker of inflammation, has been shown to predict outcomes in various atherosclerosis-related clinical situations.⁴ In fact, when the high-sensitivity (hs) CRP assay is used, it appears to add prognostic information, even in patients who have low-density lipoprotein cholesterol (LDL-C) levels that are considered normal.⁵ Several clinical trials using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins) suggest that these agents may benefit persons who have normal LDL-C but elevated CRP levels.^6,7

The robust ability of CRP to predict outcomes in a variety of clinical situations prompted the Centers for Disease Control and Prevention and the American Heart Association (AHA) to issue guidelines that endorse and provide a framework for the use of hs-CRP as a predictor of CVD risk to guide primary prevention efforts in patients who are at intermediate risk based on global risk assessment (ie, 10%-20% risk for coronary artery disease [CAD] within 10 years).⁸ Hs-CRP levels that are less than 1, 1 to 3, and more than 3 mg/L represent low, intermediate, and high cardiovascular (CV) risk, respectively.

Recent reports have demonstrated additional predictive power of CRP in patients with the metabolic syndrome (Figure).^9-11 This finding has led to 2 questions: (1) Should elevated CRP be included among the factors that define the metabolic syndrome? (2) Should CRP be routinely evaluated to better predict a patient’s CV risk?

Clinical Diagnosis of the Metabolic Syndrome
Although there is an appreciation of the clustering and the devastating consequences of the components of the metabolic syndrome, no consensus exists about the criteria for its diagnosis. The World Health Organization made the first attempt at defining such criteria,¹² and established insulin resistance—demonstrated by impaired fasting glucose, impaired glucose tolerance, impaired disposal of glucose as evaluated under hyperinsulinemic euglycemic conditions, or type 2 diabetes mellitus—as the primary criterion.¹² Subsequent recommendations by the European Group for the Study of Insulin Resistance¹³ and the American Association of Clinical Endocrinologists¹⁴ were followed by a definition published in the third report of the NCEP Adult Treatment Panel (ATP) guidelines, with a view toward facilitating clinical recognition of the syndrome.²

Because the existence of several definitions and criteria with slight variations made it difficult to evaluate the true impact of this cluster of characteristics across populations around the world, the International Diabetes Federation (IDF) and the AHA and National Heart, Lung, and Blood Institute (NHLBI) have recently published their own recommendations.^3,15 The new definitions endorsed by these organizations are similar to those of ATP III, but with a focus on clinical use and simplicity. In the IDF definition, obesity, which is highly correlated with insulin resistance, is a primary requisite of the metabolic syndrome.¹⁵ The IDF also requires any 2 of the other criteria identified by ATP III (Table). Recognizing that waist circumference varies across different ethnicities and nationalities, the IDF recommends that values used to define abdominal obesity be tailored to the best population estimates available.

The AHA/NHLBI maintain the ATP III criteria with minor modifications.³ First, these groups define impaired fasting glucose as 100 mg/dL or more rather than the 110 mg/dL threshold used in ATP III. This change was made to conform to the American Diabetes Association (ADA) criteria for impaired fasting glucose.¹⁶

In addition, the AHA/NHLBI recognized that in some Asian populations, minor increases in waist circumference may be sufficient to predispose individuals to insulin resistance and the metabolic syndrome. They therefore recommend that in Asians, the presence of 2 of the diagnostic criteria in the ATP III, along with moderate increases in waist circumference, could be considered equivalent to having 3 of the ATP III criteria and thus qualifies for a diagnosis of the metabolic syndrome.

The Metabolic Syndrome Controversy
In response to the attempts to standardize the definition of the metabolic syndrome, the ADA and the European Association for the Study of Diabetes (EASD) issued a statement in 2005 questioning the very concept of the syndrome.¹⁷ The ADA/EASD argue that although there is no doubt that the clustering of certain traits results in poor outcomes, the risk of CVD associated with the syndrome is not greater than the sum of the individual parts. They conclude that the medical value of the diagnosis is unclear, and the treatment of the syndrome is primarily the treatment of the individual risk factors. The AHA/NHLBI, in contrast, have maintained their support for the continued designation of the cluster as a syndrome, given its clinical utility in identifying risk.

Although further research is clearly required to better understand and treat patients with the metabolic syndrome, it is undeniable that a number of potent risk factors do tend to cluster together. Data show that these risk factors occur in isolation only 28% to 30% of the time; clusters of 3 or more risk factors occur approximately 17% of the time.¹⁸ If the presence of 1 or 2 of the factors helps motivate patients to adopt a healthier lifestyle and motivate physicians to closely monitor their patients and meet guideline-specified targets, the assignment of “syndrome” status will have done its job.

To address the controversy and emphasize their commitment to reducing the burden of diabetes and CVD, the ADA and the AHA have issued a joint statement, which was published simultaneously in Circulation and in Diabetes Care.¹⁹ Although the statement did not address the term “metabolic syndrome,” it did emphasize the importance of identifying patients at risk for diabetes or for CVD and the need for management of traditional as well as a number of “cardiometabolic” risk factors associated with these conditions.

The Metabolic Syndrome and CRP Levels
The idea that there is a close association between hs-CRP levels and the metabolic syndrome is easily understood, inasmuch as inflammation is closely linked to the metabolic syndrome itself, and cross-sectional studies have demonstrated a correlation between hs-CRP levels and all components of the NCEP ATP III definition of the metabolic syndrome.^10,20-22 The extent to which elevated hs-CRP levels confer a worse prognosis among patients with the metabolic syndrome has been evaluated in several prospective studies. For example, the interrelationship between CRP, the metabolic syndrome, and incident CV events was evaluated in 14,719 subjects enrolled in the Women’s Health Study.¹⁰ During the 8 years of follow-up, the age-adjusted relative risks for CV events—CV death, myocardial infarction (MI), stroke, or coronary revascularization—for patients with low CRP levels without metabolic syndrome (reference group), high CRP levels without metabolic syndrome, low CRP with metabolic syndrome, and high CRP levels with metabolic syndrome were 1.0, 1.5 (95% confidence interval [CI], 1.0-2.2), 2.3 (95% CI, 1.6-3.3), and 4.0 (95% CI, 3.0-5.4), respectively. (CRP values less than 3 mg/L were considered low, and values more than 3 mg/L were considered high.) Similarly, another study found that the relative risks for nonfatal MI or death from CAD in the West of Scotland Coronary Prevention Study population were 1.0, 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, for the same groups.⁹

In the population-based Framingham Offspring Study,¹ baseline CRP concentration and presence of metabolic syndrome were individually and significantly related to CV events.¹¹ Several other studies have reported that CRP levels are closely associated with both the metabolic syndrome and CV outcomes.

A cross-sectional study of 3873 adults (aged 18 years or older) in the 1999-2000 National Health and Nutrition Examination Survey (NHANES) classified the participants into groups based on the presence of diabetes mellitus, the metabolic syndrome, or neither and stratified them into 3 CRP categories: low (<1 mg/L), intermediate (1-3 mg/L), and high (>3 mg/L).²³ Compared with persons with low CRP levels who had neither the metabolic syndrome nor diabetes, the odds ratios of developing CVD were 7.73 for patients with diabetes and high CRP levels, 3.33 for those with the metabolic syndrome and high CRP levels, 3.21 for those with diabetes and low CRP levels, and 1.99 for those with high CRP levels alone. These results further support the potential value of using hs-CRP levels for stratifying the risk level of persons with the metabolic syndrome or diabetes.

The potential value of hs-CRP as a criterion in the management of the metabolic syndrome was further strengthened by results of a recent study that evaluated the association of hs-CRP, fasting insulin, and insulin resistance (measured by homeostasis model assessment [HOMA]). Of a cohort of 1658 middle-aged subjects, 241 persons were found to have normal body mass index, glucose tolerance, blood pressure, and lipid levels.²⁴ In this subgroup of 241 persons, a significant and independent relationship was found between hs-CRP levels of 3 mg/L or more and both insulin levels (median, 20.4 versus 6.0 pmol/L) and HOMA values. The likelihood that hs-CRP may identify the presence of insulin resistance in an apparently healthy cohort certainly adds to its value and benefit as an important marker of CV health.

Should CRP Be Included in the Metabolic Syndrome?
In the midst of the controversy regarding the metabolic syndrome, debate continues on whether CRP should be added to the factors currently considered to define the syndrome. In addition to having a positive correlation with the routinely assessed clinical components of the metabolic syndrome (ie, hypertension, high fasting glucose, obesity, and dyslipidemia), CRP has been correlated with other components linked to the syndrome that are not routinely measured, such as insulin levels, insulin sensitivity,^20,21,23,24 impaired fibrinolysis, and microalbuminuria.²⁵ Proponents argue that the additional information obtained from an inexpensive assay to determine CRP concentration can give physicians useful prognostic information, further motivate patients, and help set appropriate targets for statin therapy.

The argument against including CRP in the risk factors of what constitutes the metabolic syndrome comes from those who question the robustness of the available data. They report that in addition to being nonspecific, hs-CRP has poor predictive value.²⁶ This would seem to be substantiated by a report indicating that more than 30% of women aged 30 to 39 years have CRP concentrations of more than 3 mg/L, which would place them at high risk for CVD.²⁷ Furthermore, an examination of data from NHANES III showed that elevated CRP levels (>3 mg/L) could be attributed to any abnormal or borderline risk factor in as many as 78% of men and 67% of women.²⁸ In addition, isolated elevations of CRP are not common—in the absence of any abnormal or borderline risk factors—occurring in only 4.4% of men and 10.3% of women.

Other reports have questioned the accuracy of CRP, citing a lack of data for absolute risk,^29,30 poor reliability (with 1 report suggesting a 42% within-subject variability),³¹ and the inability to discriminate over a wide range of values.³²

What Is the Clinical Benefit of Reducing CRP Levels?
Several therapies—ncluding, but not limited to, aspirin, statins, fibrates, and niacin—have been shown to lower CRP levels. However, the clinical implications of reducing CRP have not been demonstrated so far. Results of many trials showing that high levels of CRP confer a significantly elevated risk for CAD, even in the presence of a low LDL-C concentration, prompted investigators to begin exploring this issue.⁶ The ongoing Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) includes 15,000 men and women (men aged 55 years and older, women aged 65 years and older) with LDL-C levels less than 130 mg/dL and hs-CRP levels of 2 mg/L or more.³³ Participants will be randomized to rosuvastatin calcium (Crestor) or to placebo and followed for 4 years. The trial is designed to assess whether patients with elevated CRP levels but with average to low LDL-C levels (<130 mg/dL) will benefit from statin therapy. JUPITER is expected to provide insight into the value of lowering CRP levels, but unanswered questions will likely remain even when the trial ends, and other investigators will need to further determine the benefit of lowering CRP levels.

It is clear that inflammation is integral to the process of atherosclerosis. However, whether CRP will continue to be the best method for evaluating inflammation or whether more specific markers will be identified remains to be seen. Ultimately, risk factors and markers are ways to improve risk assessment and hence enhance patient care. Such approaches will continue to evolve.

Conclusion
Despite recent controversy regarding the metabolic syndrome and the value of considering CRP level as an additional component of the syndrome, it is clear that the clustering of certain metabolic risk factors is a harbinger of atherosclerosis and poor patient outcomes. Future research can be expected to shed more light on these issues. In the meantime, physicians should continue to focus on the early identification, treatment, and prevention of all the individual risk factors that constitute the syndrome. As part of this effort, CRP may be considered as a useful adjunct to the major CVD risk factors, especially when considering primary prevention interventions for patients deemed to be at intermediate risk for CAD.

Disclosure Statement
Dr Nambi has received honoraria from Astra-Zeneca.

Self-assessment test
1. All these criteria are included in the definition of the metabolic syndrome, except:
A. Increased triglycerides
B. Increased LDL-C
C. Decreased HDL-C
D. Increased blood pressure

2. Which of these statements about the diagnostic criteria for the metabolic syndrome is NOT true?
A. The ATP III definition requires the presence of at least 3 components for diagnosis
B. The IDF definition requires the presence of at least 3 components, 1 of which must be central obesity
C. In Asians, minor increases in waist circumference plus 2 additional components are diagnostic
D. The AHA/NHLBI diagnostic criteria now define impaired fasting glucose as 110 mg/dL or more

3. Which of the following CRP levels represents an intermediate risk for CVD?
A. 0.5 mg/L
B. 0.75 mg/L
C. 2.5 mg/L
D. 3.75 mg/L

4. Which of the following statements about CRP is NOT true?
A. CRP is positively correlated with hypertension
B. High CRP levels predict increased CVD risk even in patients with low LDL-C levels
C. Fibrate therapy lowers CRP levels
D. CRP is a specific marker of CVD risk

5. Potential shortcomings of CRP measurement include all the following, except:
A. High cost of the assay
B. High CRP levels are often the results of an abnormal or borderline risk factor
C. No definitive evidence shows that lowering CRP provides clinical benefit
D. Potential within-subject variability

(Answers at end of references list)

References
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29. Horowitz GL, Beckwith BA. C-reactive protein in the prediction of cardiovascular disease. N Engl J Med. 2000; 343:512-513.

30. Kushner I, Sehgal AR. Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk? Arch Intern Med. 2002;162:867-869.

31. Macy EM, Hayes TE, Tracy RP. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clin Chem. 1997; 43:52-58.

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33. Ridker PM, for the JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003; 108:2292-2297.

Answers: 1. B; 2. D; 3. C; 4. D; 5. A.