|
 |
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© American Diabetes Association ®, Inc., 2007
Feature Article |
C-Reactive Protein and Cardiovascular Risk in the Metabolic Syndrome and Type 2 Diabetes: Controversy and Challenge
 |
Abstract |
|---|
IN BRIEF
Although recent findings link high levels of C-reactive protein (CRP) with occurrence of future cardiovascular events, views about its biological activity and predictive value vary. The conditions under which CRP indicates or mediates inflammatory processes remain undefined. Much evidence indicates that inflammation may drive the development of insulin resistance, type 2 diabetes, and the progression of atherosclerosis. The interaction among various cytokines and cell types in these pathogenic processes remains unclear. Thus, the indications for CRP measurement for risk prediction and disease surveillance steadily evolve.
|
Introduction |
|---|
C-reactive protein (CRP) has become the subject of avid interest in recent years, but the history of CRP began > 7 decades ago and has been one of discovery and continuing dispute. In 1930, Tillet and Francis1 observed a substance in the serum of people with pneumococcal infections that formed a precipitate when mixed with the C-polysaccharide coat of Streptococcus pneumoniae. This "C-reactive" activity was absent from the sera of healthy individuals. MacLeod and Avery2 subsequently found this substance to be a protein and coined the term "acute phase" to characterize the serum of patients with various acute infections. Lofstrom3 found a similar acute-phase response in acute and chronic inflammatory conditions, and CRP became recognized as a nonspecific acute-phase protein. Highly conserved in evolution, CRP has similar structural and functional homology in many species, even including the hemolymph of the horseshoe crab.4
The story of CRP has evolved rapidly in the past decade. The development of high-sensitivity CRP (hs-CRP), a stable and inexpensive assay, has increased the potential to obtain more reliable determinations of circulating levels of this inflammatory cytokine, and thereby to refine cardiovascular risk assessment, particularly for those whose risk is intermediate, such as individuals with average levels of LDL cholesterol.
|
What Is C-Reactive Protein? |
|---|
CRP is considered to be a major inflammatory cytokine that functions as a nonspecific defense mechanism in response to tissue injury or infection. Synthesized mainly in the liver, CRP activity is stimulated by other cytokines, especially interleukin (IL)-6, IL-1ß, and tumor necrosis factor-
(TNF-). CRP binds to a variety of
molecules, particularly liposomes and lipoproteins, such as LDL and VLDL
cholesterol, and is a powerful activator of the classic complement system.
Accumulating evidence suggests that CRP, which is also found within
macrophages of atheromatous plaques, is causally or mechanistically related to
atherothrombosis. |
CRP and the Atherogenic Process |
|---|
Whether CRP can mediate as well as predict the progression of atherosclerosis is under active investigation and is likely in some clinical conditions.5,6 A wealth of data suggests that chronic inflammation is a major factor that drives the progression of atherosclerosis and atherothrombosis.7,8 Diverse cardiovascular risk factors, such as smoking, high blood pressure, dyslipidemia, and hyperglycemia, play a proinflammatory role in the initiation of endothelial dysfunction and atherosclerotic plaque formation.6,9 The accumulation of lipids in the arterial wall is the result of a complex response that involves inflammation, and this inflammatory response promotes additional lipid accumulations (Figure 1).10 Elevated CRP levels are associated with diminished expression of endothelial nitric oxide (NO) synthase, which may attenuate production of NO, promote oxidative modification of LDL, and induce expression of plasminogen activator inhibitor-1.11
|
|
CRP Can Predict Cardiovascular Events |
|---|
 TopAbstractIntroductionWhat Is C-Reactive Protein?CRP and the Atherogenic... CRP Can Predict Cardiovascular... Cardiovascular Disease,...CRP in Clinical PracticeManagement ConsiderationsConclusionsREFERENCES |
|---|
Modest elevations of CRP can be found even in apparently healthy people.6 A progressive rise in CRP can reflect augmented stages of vascular inflammation, but the specific clinical conditions under which this occurs are incompletely understood. Although LDL cholesterol remains a major risk component for cardiovascular disease, at least one-third of coronary events occur in individuals with LDL levels < 130 mg/dl,12 which is generally considered an average level in individuals without overt coronary artery disease. Evaluation of CRP levels under those clinical conditions may be very helpful in risk stratification. Reports that CRP levels are elevated during acute cardiovascular and cerebrovascular events suggest that CRP has value in predicting the subsequent occurrence of such events.13,14
Results of the Scandinavian Simvastatin Survival Study suggested a potential increase in cardiovascular mortality in patients in the highest quartile of circulating CRP levels, particularly when these are evaluated with concomitant plasma lipoprotein levels.13 However, interpretation of these data is clouded by the presence of confounding variables.
Occurrence of first cardiovascular events in the observational Women's Health Study appeared to rise incrementally with increasing baseline levels of CRP. Elevated levels of LDL cholesterol and CRP were individually associated with increased cardiovascular risk. However, combined elevations of both analytes improved risk prediction to a greater degree than either one considered individually.15
A prospective observational study of > 15,000 middle-aged women apparently healthy at baseline was designed to determine the relative utility of standard lipoprotein, lipid, apolipoprotein, and CRP measures as predictors of 10-year cardiovascular event rates. The results provided some support for the additive prognostic value of CRP measurements.16 Nevertheless, more convincing data are required from randomized, prospective clinical trials to delineate the particular clinical conditions in which CRP measurements are useful.
|
Cardiovascular Disease, Metabolic Disease, and Inflammation |
|---|
The metabolic syndrome has been defined as a cluster of risk factors for atherosclerotic cardiovascular disease that includes insulin resistance, dyslipidemia, abdominal adiposity, and often hypertension. Investigators have long hypothesized links between the metabolic derangements of insulin resistance syndrome/type 2 diabetes and the development and progression of atherosclerosis.17 A number of investigators have similarly concluded that IL-6 and CRP are associated with hyperglycemia, insulin resistance, and overt type 2 diabetes, and both are strong predictors of cardiovascular disease in apparently healthy people.18-20
In a 10-year observational study21 of Dutch adults without diabetes or coronary heart disease (CHD) at baseline, the presence of the metabolic syndrome imparted a twofold increased risk for cardiovascular events. Similar results were found in an Italian survey study in which one-third of the study subjects were identified as having the metabolic syndrome at baseline.22 At the end of 5 years of follow-up, study subjects having the metabolic syndrome at baseline incurred a 3.7-fold increase in fatal and nonfatal CHD events compared with subjects without the syndrome at the start of the study.
CRP and the metabolic syndrome
The data showing the importance of CRP as an indicator of vascular
inflammation and a predictor of future events in patients with the metabolic
syndrome may be the most compelling. Among 8,570 participants in the National
Health and Nutrition Examination Survey, the age-adjusted prevalence of
elevated CRP was 29% in people with the metabolic syndrome, compared with
12.1% in those without the metabolic
syndrome.23 In
nondiabetic subjects enrolled in the Insulin Resistance Atherosclerosis Study,
CRP levels were significantly correlated with BMI, waist circumference,
systolic blood pressure, fasting levels of glucose and insulin, indicators of
insulin sensitivity, and the number of elements of the plurimetabolic syndrome
(Figure
2).24
One speculative hypothesis linking impaired insulin sensitivity to enhanced
CRP expression stems from a purported diminished physiological
immunomodulation of insulin on the transcription of acutephase plasma protein
genes.25,26
In the Insulin Resistance Atherosclerosis Study, CRP elevations were inversely
related to insulin sensitivity.
|
In the Mexico City Diabetes Study, baseline levels of CRP, indexes of adiposity, and insulin resistance were evaluated for their predictive value for development of the metabolic syndrome. Over the course of 6 years, 14.2% of men and 16.0% of women developed the metabolic syndrome. In women with CRP in the highest tertile, the relative risk for development of the metabolic syndrome and for development of diabetes was 4.0 and 5.5, respectively, compared with women in the lowest tertile. However, CRP was not a significant predictor of risk in men.27
A study was conducted in 14,719 apparently healthy women who were followed for 8 years for cardiovascular events; 24% had the metabolic syndrome at entry. Cardiovascular event-free survival rates based on CRP levels > 3.0 mg/l were similar to survival rates based on having at least three of the characteristics that define the metabolic syndrome. This indicated that measurement of CRP adds important prognostic information in patients with these metabolic abnormalities.28
Defining the metabolic syndrome
The metabolic syndrome has been defined by modestly differing criteria by
the third Adult Treatment Panel (ATP III) of the National Cholesterol
Education
Program,29 the
World Health
Organization,30 and
the American College of
Endocrinology.31
The American Diabetes Association and the European Association for the Study
of Diabetes developed a position paper concluding that further research is
required before this cluster can be managed as a syndrome. In the interim,
they recommend that the individual risk factors be evaluated and treated
separately.32 On
the other hand, a recent report from the National Heart, Lung, and Blood
Institute and American Heart Association (AHA) stated that, considered
together, the constellation of symptoms known as the metabolic syndrome is
highly predictive of new-onset
diabetes.33
The previously described Italian study22 used both the World Health Organization and ATP III criteria for metabolic syndrome and found that both definitions identified subjects at greater cardiovascular risk and that neither was superior in predicting cardiovascular risk. Whether any element or elements are considered as fundamental to the definition of this syndrome, some evidence suggests that each element may have a link to inflammation and its indicators.34 A major opinion adheres to the concept of the metabolic syndrome as a powerful unifying hypothesis of the metabolic factors underlying the development of both atherosclerotic cardiovascular disease and diabetes,35 whereas another point of view holds that insulin resistance alone is the fundamental feature, and the other clinical elements stem from this metabolic defect. In actual practice, much of this apparent difference may simply be one of emphasis.
CRP and diabetes
A growing body of
data24,36
reinforces the concept that inflammation also plays an important role in the
pathogenesis of type 2 diabetes and links diabetes with concomitant conditions
with inflammatory
components.37
Evidence exists for the prior linkage of euglycemic insulin resistance as a
proinflammatory state that may have existed for years before the occurrence of
frank type 2
diabetes.38
Much evidence exists that inflammatory mechanisms play a major role in the cascade of events that results in rupture of atherosclerotic plaque. Upregulation of receptors for advanced glycation end products has been associated with enhanced inflammatory reactions. Increased expression of these receptors has been found to be associated with impaired glycemic control and may be a contributory factor in the complex array of mechanisms that leads to accelerated atherosclerosis in patients with diabetes.39
In the nearly 6,000 participants in the Cardiovascular Health Study whose
circulating levels of inflammatory markers were determined both at baseline
and after 3-4 years of follow-up, those who developed diabetes had higher
measured levels of CRP than those who remained euglycemic. In addition, those
with elevated levels of CRP were found more likely to develop diabetes over
the course of the
study.40 In a
national survey study, respondents with hemoglobin A1c (A1C) levels
9% had a significantly higher rate of elevated CRP than those with A1C
levels < 7%. This suggests an association between diminished glycemic
control and systemic inflammation in people with established
diabetes.41
In a nested case-control study carried out as part of the Women's Health Study among initially nondiabetic participants who developed diabetes over the course of the study, median baseline levels of IL-6 and CRP were significantly higher among case than among control subjects (P < 0.001), and increasing levels of both markers were associated with a higher risk of developing diabetes.37 In this study, increased CRP levels predicted the new onset of diabetes even after adjustment for obesity, coronary risk factors, and fasting insulin levels.
The Monitoring of Trends and Determinants in Cardiovascular Disease Augsburg project involved 2,052 men who were nondiabetic at baseline. During an average follow-up of 7.2 years, 101 cases of diabetes occurred. Participants with CRP levels in the highest quartile had a 2.7-fold greater risk of development of diabetes than those in the lowest quartile.42 The results of this study suggest the potential involvement of inflammatory mechanisms in the development of diabetes.
Interestingly, the findings of the Strong Heart Study, carried out in an American Indian population with a high prevalence of diabetes, showed that CRP elevations were strongly related to the presence of cardiovascular disease among nondiabetic women but not among diabetic women or among men, irrespective of glycemic status. Thus, the predictive value of CRP elevations may vary among subsets of populations.43
|
CRP in Clinical Practice |
|---|
Although CRP is only one element of the inflammatory response system, levels of this cytokine reflect the activity of a larger response system.44 CRP is among the most rapidly acting acutephase proteins and has a prolonged elimination half-life of
19
hours.45
Concentrations of CRP usually appear to rise rapidly in proportion to the
degree and severity of inflammatory
stimuli.46 However,
thus far, diurnal levels appear to be stable, and CRP concentrations are
similarly distributed among men and women, except for women on hormone
replacement
therapy.47 These
properties of CRP would appear to render this analyte ideal to detect the
occurrence of various inflammatory, infectious, and other acute pathological
processes. In addition, it is likely that CRP measurements have potential
utility for following the activity of certain disease processes and the
response to therapeutic interventions. However, elevations of CRP may be uncommon in the absence of traditional risk factors for CHD.48 CRP elevations may therefore be attributable to and already accounted for by traditional risk factors. A recent meta-analysis of studies of CRP and other circulating markers of inflammation in CHD risk prediction concluded that CRP may be a somewhat moderate predictor of CHD risk.49 These data tend to argue against the routine use of CRP measurements for clinical risk assessment in the general population.
The Centers for Disease Control and Prevention and the AHA have published combined evidence-based guidelines for the optimal use of CRP in clinical practice.50 These guidelines confirm that, although hs-CRP measurement may be useful as an independent marker of prognosis for recurrent events, this analyte should not be used at present for routine screening, and application of secondary prevention measures should not be influenced by hs-CRP determination. However, in intermediate-risk patients without known CHD but with 10-year risk for CHD of 10-20%, the guidelines suggest that measurement of hs-CRP may be considered an independent marker of CHD risk and may be useful, at the discretion of the physician, to help determine optimal treatment. Patients are categorized according to hs-CRP level as follows: < 1 mg/l = low risk; 1.0-3.0 mg/l = average risk; and > 3.0 mg/l = high risk.
The report of the ATP III panel of the National Cholesterol Education Program also addressed the clinical use of CRP.29 This report does not recommend routine measurement of CRP for the purpose of modifying LDL cholesterol goals in primary prevention. However, because CRP may have predictive power beyond the classical lipid risk factors, this report indicates that some investigators consider lowering LDL cholesterol more aggressively in adults with elevated levels of CRP than may otherwise be indicated by an evaluation solely of the major risk factors. The 2004 update to the ATP III guidelines also suggests that CRP measurements may be useful as a guide to treatment targets. Thus, a patient with an hs-CRP > 3 mg/l would be allocated to the moderately high-risk category for cardiovascular disease, even with unremarkable lipid levels.51 Whichever guidelines are used, CRP as a nonspecific marker of inflammation must always be interpreted under the clinical conditions of the patient undergoing assessment.
|
Management Considerations |
|---|
Strategies that target obesity and insulin resistance, when found to be effective, may ameliorate both endothelial dysfunction and low-grade inflammation and have the theoretical potential to decelerate or prevent the occurrence of type 2 diabetes and cardiovascular disease.52 Pharmacological and lifestyle interventions may reduce both the risk for CHD and levels of CRP, if elevated. However, convincing evidence does not as yet exist to indicate that modalities directed toward lowering of circulating levels of CRP can reduce the occurrence of cardiovascular events.
Peroxisome proliferator-activated receptor agonists may improve insulin
sensitivity and glycemic control in patients with type 2 diabetes and
cardiovascular disease. These agents have reduced clinical inflammatory
responses53,54
and have possibly been responsible for a trend toward reduced coronary events
in a large randomized clinical
trial.55
Etanercept, a TNF- agonist, produced significant reductions in
CRP compared with placebo (-2.4 vs. 0.5 mg/l, P < 0.001)
and improved other inflammatory markers (including fibrinogen, IL-6, and
adiponectin) in patients with the metabolic syndrome in a recent randomized
trial.56
Results of recent studies also suggest a potential association between
lower CRP levels and improved clinical outcomes with statin
therapy.57,58
In the Heart Protection Study and the Anglo-Scandinavian Cardiac Outcomes
Trial—Lipid-Lowering Arm, patients with baseline levels of LDL
cholesterol in the intermediate range (mean 130 mg/dl) showed further
reduction of risk with statin
therapy.59,60
Statins, which may have anti-inflammatory effects, under various clinical
conditions have produced significant reductions in CRP
levels.6 In the
Cholesterol and Recurrent Events trial of secondary prevention, patients
treated with pravastatin who had higher hs-CRP levels at baseline appear to
have experienced a much greater reduction in relative risk of recurrent
clinical events than those with lower hs-CRP levels (54 vs. 25%,
respectively), although the two groups had similar baseline lipid
profiles.14 In the
Air Force/Texas Coronary Atherosclerosis Prevention Study of primary
prevention, lovastatin therapy was effective in reducing cardiovascular events
in patients with hs-CRP levels above the median, even in those with LDL
cholesterol levels below the
median.61 In both
trials, reductions in levels of hs-CRP appeared to be independent of
reductions in levels of LDL cholesterol. The above-mentioned findings, while
intriguing, must be interpreted with caution because the data were derived
from post hoc analyses and also involve rather small numbers of cardiovascular
events.
The Justification for the Use of Statins in Primary Prevention: an
Intervention Trial Evaluating Rosuvastatin
(JUPITER)62 is an
ongoing, randomized, placebo-controlled trial that seeks to evaluate whether
long-term aggressive therapy with rosuvastatin, 20 mg/day, for 3-4 years can
prevent first major cardiovascular events in an apparently healthy population
of adult men and women with unremarkable levels of LDL cholesterol (< 130
mg/dl) but with potentially increased risk for CHD due to elevated levels of
hs-CRP ( 2 mg/l). JUPITER investigators will enroll 15,000
middle-aged men and women. The JUPITER trial has been designed to test the
potential utility of rosuvastatin therapy to diminish the occurrence of type 2
diabetes. If positive, the findings are likely to elevate the role of CRP both
as a risk factor and, more importantly, a treatment target in the presence of
average concomitant serum levels of LDL cholesterol. Moreover, a positive
outcome in this important clinical trial would likely require an urgent
reassessment of risk stratification, use of statin therapy, and treatment
goals for LDL cholesterol and other lipoprotein lipid end points. In all
likelihood, a demonstration of the need for intensification of therapy for
patients previously considered to be at lower CHD risk will result.
|
Conclusions |
|---|
Current opinion varies widely on the additive value of CRP testing for cardiovascular risk assessment. Debates continue for and against the use of CRP measurements as a part of screening for global risk assessment. A Scientific Statement from the AHA/Centers for Disease Control and Prevention recommended use of such testing in certain population groups but stated that the benefits of a treatment strategy based on such measurements remain uncertain.
However, with the metabolic syndrome and diabetes, the role of inflammation and of CRP as a marker of inflammation appear less controversial. There is increasing evidence that inflammation underlies both the metabolic syndrome and diabetes and may predict both. The role of lowering CRP in reducing the risk for and improving the prognosis of diabetes is undergoing assessment.
The results of ongoing clinical trials will continue to provide data on the additive value of testing levels of CRP and other inflammatory markers for cardiovascular risk assessment and should delineate the clinical utility of such testing in various disease states.
|
Footnotes |
|---|
David M. Capuzzi, MD, PhD, is director of the Cardiovascular Disease Prevention Center at the Lankenau Institute for Medical Research and the Lankenau Hospital in Wynnewood, Pa. Jeffrey S. Freeman, DO, is director of the Division of Endocrinology and Metabolism at the Philadelphia College of Osteopathic Medicine in Philadelphia, Pa.
Note of disclosure: Drs. Capuzzi and Freeman have received educational grant support from AstraZeneca, which manufactures rosuvastatin and supports the ongoing JUPITER study.
|
REFERENCES |
|---|
1 Tillet WS, Francis T: Serological reaction in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 52:561 -571, 1930[Abstract]
2 MacLeod CM, Avery OT: The occurrence during acute infections of a protein not normally present in the blood. II. Isolation and properties of the reactive protein. J Exp Med 73:183 -191, 1943
3 Lofstrom G: Comparison between the reaction of acute phase serum with pneumococcus Cpolysaccaride and with pneumococcus type 27. Br J Exp Pathol 25: 21-26,1944
4 Shrive AK, Metcalfe AM, Cartwright JR, Greenhough TJ: C-reactive protein and SAP-like pentraxin are both present in Limulus polyphemus haemolymph: crystal structure of Limulus SAP. J Mol Biol290 : 997-1008,1999[Medline]
5 Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I: Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 106:1439 -1441, 2002
6 Yeh ETH, Palusinski RP: C-reactive protein: the pawn has been promoted to queen. Curr Atheroscler Rep 5:101 -105, 2003[Medline]
7 Ross R:
Atherosclerosis: an inflammatory disease. N Engl J Med340
: 115-126,1999
8 Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 105:1135 -1143, 2002
9 Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliott HL, Connell JMC: Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clin Sci 98:531 -535, 2000
10 Armani A, Becker RC: The biology, utilization, and attenuation of C-reactive protein in cardiovascular disease. Part II. Am Heart J149 : 977-983,2005[Medline]
11 Verma S, Wang C-H, Li S-H, Dumont AS, Fedak PWM, Badiwala MV, Dhillon B, Weisel RD, Li R-K, Mickle DAG, Stewart DJ: A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 106:913 -919, 2002
12 Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folson AR, Heiss G, Sharrett AR: Lipoprotein-associated phospholipase A2, highsensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation 109:837 -842, 2004
13 Crea F, Monaco C, Lanza GA, Maggi E, Ginnetti F, Cianflone D, Niccoli G, Cook T, Bellomo G, Kjekshus J: Inflammatory predictors of mortality in the Scandinavian Simvastatin Survival Study. Clin Cardiol25 : 461-466,2002[Medline]
14 Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E, for the Cholesterol and Recurrent Events (CARE) Investigators: Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation98 : 839-844,1998
15 Ridker PM, Rifai
N, Rose L, Buring JE, Cook NR: Comparison of C-reactive protein and
low-density lipoprotein cholesterol levels in the prediction of first
cardiovascular events. N Engl J Med347
: 1557-1565,2002
16 Ridker PM, Rifai
N, Cook NR, Bradwin G, Buring JE: Non-HDL cholesterol, apolipopro-teins A-I
and B100, standard lipid measures, lipid ratios, and CRP as risk factors for
cardiovascular disease in women. JAMA294
: 326-333,2005
17 Stern MP: Diabetes and cardiovascular disease: the "common soil" hypothesis. Diabetes 44:369 -374, 1995[Abstract]
18 Ridker PM, Cushman
M, Stampfer MJ, Tracy RP, Hennekens CH: Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men. N Engl J
Med 336: 973-979,1997
19 Ridker PM, Rifai N, Stampfer MJ, Hennekens CH: Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767 -1772, 2000
20 Ridker PM,
Hennekens CH, Buring JE, Rifai N: C-reactive protein and other markers of
inflammation in the prediction of cardiovascular disease in women.
N Engl J Med 342:836
-843, 2000
21 Dekker JM, Girman C, Rhodes T, Nijpels G, Stehouwer CDA, Bouter LM, Heine RJ: Metabolic syndrome and 10-year cardiovascular risk in the Hoorn Study. Circulation 112:666 -673, 2005
22 Bonora E, Kiechl
S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, Muggeo M: Carotid
atherosclerosis and coronary heart disease in the metabolic syndrome:
prospective data from the Bruneck Study. Diabetes Care26
: 1251-1257,2003
23 Ford ES: Body mass
index, diabetes, and C-reactive protein among U.S. adults. Diabetes
Care 22:1971
-1977, 1999
24 Festa A, D'Agostino R Jr, Howard G, Mykkänan L, Tracy RP, Haffner SM: Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102:42 -47, 2000
25 Campos SP, Baumann
H: Insulin is a prominent modulator of the cytokine-stimulated expression of
acute-phase plasma protein genes. Mol Cell Biol12
: 1789-1797,1992
26 Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R: Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 111:1448 -1454, 2005
27 Han TS, Sattar N,
Williams K, Gonzalez-Villalpando C, Lean MEJ, Haffner SM: Prospective study of
C-reactive protein in relation to the development of diabetes and metabolic
syndrome in the Mexico City Diabetes Study. Diabetes
Care 25:2016
-2021, 2002
28 Ridker PM, Buring JE, Cook NR, Rifai N: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation107 : 391-397,2003
29 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 106:3143 -3421, 2002
30 Marchesini G, Forlani G, Cerrelli F, Manini R, Natale S, Baraldi L, Ermini G, Savorani G, Zocchi D, Melchionda N: WHO and ATP III proposals for the definition of the metabolic syndrome in patients with type 2 diabetes. Diabet Med 21: 383-387,2004[Medline]
31 Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, Hellman R, Jellinger PS, Kendall D, Krauss RM, Neufeld ND, Petak SM, Rodbard HW, Seibel JA, Smith DA, Wilson PW: American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract9 : 237-252,2003[Medline]
32 Kahn R, Buse J,
Ferrannini E, Stern M: The metabolic syndrome: time for a critical appraisal.
Joint statement from the American Diabetes Association and the European
Association for the Study of Diabetes. Diabetes Care28
: 2289-2304,2005
33 Grundy SM, Cleeman JI, Daniels SR, Dona- to KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F: Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation112 : 2735-2752,2005
34 Hak AE, Stehouwer
CDA, Bots ML, Polderman KH, Schalkwijk CG, Westendorp ICD, Hofman A, Witteman
JCM: Associations of C-reactive protein with measures of obesity, insulin
resistance, and subclinical arteriosclerosis in healthy, middle-aged women.
Arterioscler Thromb Vasc Biol19
: 1986-1991,1999
35 Grundy SM: The
metabolic syndrome still lives. Clin Chem51
: 1352-1357,2005
36 Ford ES: The metabolic syndrome and C-reactive protein, fibrinogen, and leukocyte count: findings from the Third National Health and Nutrition Examination Survey. Atherosclerosis 168:351 -358, 2003[Medline]
37 Pradhan AD, Manson
JE, Rifai N, Buring JE, Ridker PM: C-reactive protein, interleukin 6, and risk
of developing type 2 diabetes mellitus. JAMA286
: 327-334,2001
38 Festa A, Haffner SM: Inflammation and cardiovascular disease in patients with diabetes: lessons from the Diabetes Control and Complications Trial. Circulation 111:2414 -2415, 2005
39 Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A: The receptor RAGE as a progression factor amplifying arachidonatedependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation108 : 1070-1077,2003
40 Barzilay JI,
Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP: The
relation of markers of inflammation to the development of glucose disorders in
the elderly: the Cardiovascular Health Study. Diabetes50
: 2384-2389,2001
41 King DE, Mainous
AG III, Buchanan TA, Pearson WS: C-reactive protein and glycemic control in
adults with diabetes. Diabetes Care26
: 1535-1539,2003
42 Thorand B,
Löwel H, Schneider A, Kolb H, Meisinger C, Fröhlich M, Koenig W:
C-reactive protein as a predictor for incident diabetes mellitus among
middle-aged men: results from the MONICA Augsburg Cohort Study, 1984-1998.
Arch Intern Med 163:93
-99, 2003
43 Best LG, Zhang Y, Lee ET, Yeh J-L, Cowan L, Palmieri V, Roman M, Devereux RB, Fabsitz RR, Tracy RP, Robbins D, Davidson M, Ahmed A, Howard BV: C-reactive protein as a predictor of cardiovascular risk in a population with a high prevalence of diabetes: the Strong Heart Study. Circulation112 : 1289-1295,2005
44 Tracy RP, Kuller
LH: C-reactive protein, heart disease risk, and the popular media.
Arch Intern Med 165:2058
-2060, 2005
45 Vigushin DM, Pepys MB, Hawkins PN: Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest 91:1351 -1357, 1993[Medline]
46 Yue CC,
Muller-Greven J, Dailey P, Lozanski G, Anderson V, Macintyre S: Identification
of a C-reactive protein binding site in two hepatic carboxylesterases capable
of retaining C-reactive protein within the endoplasmic reticulum. J
Biol Chem 271:22245
-22250, 1996
47 Ledue TB, Rifai N:
Preanalytic and analytic sources of variations in C-reactive protein
measurement: implications for cardiovascular disease risk assessment.
Clin Chem 49:1258
-1271, 2003
48 Miller M, Zhan M,
Havas S: High attributable risk of elevated C-reactive protein level to
conventional coronary heart disease risk factors: the Third National Health
and Nutrition Examination Survey. Arch Intern Med165
: 2063-2068.2005
49 Danesh J, Wheeler
JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GDO, Pepys MB,
Gudnason V: C-reactive protein and other circulating markers of inflammation
in the prediction of coronary heart disease. N Engl J
Med 350:1387
-1397, 2004
50 Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F: Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107:499 -511, 2003
51 Grundy SM, Cleeman
JI, Bairey Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC,
Smith SC Jr, Stone NJ, for the Coordinating Committee of the National
Cholesterol Education Program: Implications of recent clinical trials for the
National Cholesterol Education Program Adult Treatment Panel III Guidelines.
J Am Coll Cardiol 44:720
-732, 2004
52 Caballero AE: Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes Res 11:1278 -1289, 2003[Medline]
53 Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation106 : 679-684,2002
54 Wang G, Wei J,
Guan Y, Jin N, Mao J, Wang X: Peroxisome preliferator-activated
receptor-
agonist rosiglitazone reduces clinical inflammatory
responses in type 2 diabetes with coronary artery disease after coronary
angioplasty. Metab Clin Exp 54:590
-597, 2005
55 Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti MM, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J, on behalf of the PROactive investigators: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet366 : 1279-1289,2005[Medline]
56 Bernstein LE,
Berry J, Kim S, Canavan B, Grinspoon SK: Effects of etanercept in patients
with the metabolic syndrome. Arch Intern Med166
: 902-908,2006
57 Nissen SE, Tuzcu
EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD,
O'Shaughnessy C, Ganz P, for the Reversal of Atherosclerosis with Aggressive
Lipid Lowering (REVERSAL) Investigators: Statin therapy, LDL cholesterol,
C-reactive protein, and coronary artery disease. N Engl J
Med 352: 29-38,2005
58 Ridker PM, Cannon
CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald D, for the
Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in
Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators: C-reactive protein
levels and outcomes after statin therapy. N Engl J Med352
: 20-28,2005
59 Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7 -22, 2002[Medline]
60 Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Östergren J, for the ASCOT investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet361 : 1149-1158,2003[Medline]
61 Ridker PM, Rifai
N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr, for the Air
Force/Texas Coronary Atherosclerosis Prevention Study Investigators:
Measurement of C-reactive protein for the targeting of statin therapy in the
primary prevention of acute coronary events. N Engl J
Med 344:1959
-1965, 2001
62 Ridker PM, on behalf of 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. Circulation109 : 2292-2297,2003
Related Article:
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
Clin. Diabetes 2007 25: 1-2.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |