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Evidence suggests C-reactive protein (CRP) may be more than a simple markerof inflammation. Some experts say it also is a key risk factor for acutecardiovascular events among individuals with insulin resistance that warrantswidespread monitoring and, when elevated, a comprehensive managementapproach.
But others caution that it is premature to test for elevated CRP in theclinical setting, as there are no therapies that selectively reduce CRPwithout affecting other, related risk factors.
A recent study evaluating CRP levels in patients with acute coronarysyndrome (ACS) found the interaction of CRP with glucose to be an independentpredictor of cardiovascular risk.
Subjects were 662 adults without diabetes and 267 with diabetes. Among thenondiabetic subjects, average blood glucose level was 106.2 mg/dl, and averageCRP level was 5.2 mg/l. Among the diabetic subjects, average blood glucoselevel was 174.6 mg/dl, and average CRP level was 6.6 mg/l.
Investigators learned that diabetic subjects whose elevated CRP and bloodglucose levels were among the highest one-third of all subjects were more thantwice as likely to have a heart attack or die as diabetic subjects whose CRPlevels were not elevated and whose blood glucose levels were among the lowestone-third of subjects.
"There was an interaction between high glucose and high CRP beyondwhat you would expect for each risk factor alone—that is, amultiplicative effect rather than an additive effect," says Kausik K.Ray, MD, of Brigham and Women's Hospital in Boston.
He explains the significance of this effect: "If your CRP is abovethe median, each 18-unit rise in glucose carries a 60% increased risk, versusonly a 16% increase in risk if your CRP is below average."
Ray presented these results at the 2005 Annual Scientific Session of theAmerican College of Cardiology in May, and the abstract was published in theJournal of the American College ofCardiology.1
Other data suggest that the inflammation associated with diabetes actuallybegins at an earlier stage among otherwise healthy individuals with insulinresistance. Investigators divided 100 healthy adults aged 20–55 yearsinto four groups based on their CRP levels. Subjects' glucose and seruminsulin levels (as a marker of insulin sensitivity) were measured in thefasting state and at 2 hours after a 75-g oral glucose load. With each rise inCRP level (subjects' four levels were 0.8–3.5 mg/l up to 6.4–15.4mg/l), insulin levels also rose.
Ritesh Panwar, MD, a fellow in clinical endocrinology at Lady HardingeMedical College in New Delhi, India, shared these findings at the AmericanAssociation of Clinical Endocrinologists 14th Annual Meeting and ClinicalCongress in May 2005.
"We haven't established exactly why insulin resistance is associatedwith elevated CRP," Ray says. But he asserts that CRP may be a"global barometer" of risk factor burden.
"It should become a core tool for disease diagnostic criteria,"Ray says. "CRP seems to measure totality of risk associated with each ofthese risk factors [elevated body mass index, elevated blood pressure,elevated glucose, high triglycerides, low levels of HDL cholesterol, andsmoking]."
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A DIFFERENT VIEW
Michael Miller, MD, and colleagues recently analyzed data from more than15,000 adults and concluded that CRP appears to be linked to traditional riskfactors for heart disease but is not an independent riskfactor.2
"We have no justification presently to support CRP as a clinical toolfor cardiovascular screening," says Miller, director of preventivecardiology at the University of Maryland (UM) Medical Center in Baltimore andassociate professor at the UM School of Medicine. "Rather, it shouldremain within the confines of clinical research and investigation."
Miller concedes, however, that evaluating high CRP levels independentlyfrom other risk factors is sometimes advisable. "In highlyproinflammatory settings such as acute coronary syndromes, the higher the CRP,the greater the likelihood of cardiovascular morbidity andmortality."
Currently, no therapies selectively reduce CRP or systemic inflammationwithout affecting other cardiovascular risk factors, specifically LDLcholesterol or glucose levels, Miller points out.
But measuring CRP does have benefits, Ray maintains. "CRP gives you anumber and a bit more information. It adds to the information you get from ablood pressure and a cholesterol reading," he says. Plus, he adds,"You can use it to motivate people to change their behavior."
SCREENING
Increasingly, recommendations on how and whom to screen for elevated CRPtend to favor testing in at least subsets of at-risk patients.
In 2003, a panel convened by the American Heart Association (AHA) and theCenters for Disease Control and Prevention (CDC) issued the first guidelineson using CRP to gauge patients' cardiovascularrisk.3 The panelsupports using CRP as an adjunct to other measurements when assessingcardiovascular disease risk in patients at "inter-mediate risk" ofcardiovascular events, i.e., those who score 5–20% on the FraminghamRisk evaluation tool (designed to estimate risk in adults 
20 years of agewho do not have heart disease ordiabetes).
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Some experts think that's not enough.
"More recent data support screening in almost all middle-agedindividuals as an adjunct to cholesterol evaluation," says Paul M.Ridker, MD, director of the Center for Cardiovascular Disease Prevention atBrigham and Women's Hospital in Boston. "It may be just as important forthe CRP to come down as it is for the LDL to come down."
As for how to measure CRP, both AHA and CDC recommend measuringhigh-specificity CRP levels and, because they can fluctuate, doing so twiceand using the average to arrive at an accurate estimate (see table on page10). In a stable person, levels of 1–3 mg/l are considered average;levels >3 mg/l are high. Importantly, persons with levels >10 mg/lshould be tested again several weeks later, as elevations of that degreelikely represent acute inflammatory processes, such as viralillnesses.3
STRATEGIES FOR LOWERING CRP
A Cleveland Clinic study demonstrated that intensive statin therapy (80 mgof atorvastatin daily) reduced CRP levels36%.4 A moremoderate regimen of 40 mg of pravastatin lowered CRP by just 5%. Theresearchers emphasized that CRP reductions were independent of, and not merelya consequence of, lower cholesterol levels.
But the effort to lower CRP levels shouldn't end with statin use, Ray says."Even if you put someone on high doses of statins, if they don't adhereto lifestyle management recommendations, their CRP will remain high," hesays.
Diet can have a significant impact on both CRP levels and insulinresistance, as a recent JAMA studydemonstrated.5 In arandomized, single-blind trial, researchers assessed the effects of aMediterranean-style diet (rich in whole grains, fruits, vegetables, nuts, andolive oil) on vascular inflammatory markers in patients with so-calledmetabolic syndrome. They compared subjects who adopted a Mediterranean dietfor 3 years with a placebo group that followed a "prudent" dietcontaining 50–60% carbohydrates, 15–20% proteins, and <30%total fat. Subjects who ate the Mediterranean diet had significantly reducedserum concentrations of high-sensitivity CRP (40% reduction) and decreasedinsulin resistance. At a 2-year follow-up, only 40 of the original 90 subjectsin the intervention group still had features of metabolic syndrome, comparedwith 78 of the 90 control subjects.
Then there's exercise. "Weight reduction, via the regular practice ofexercise, may translate to lower CRP levels due to reduced inflammation, thusproviding benefits beyond solely decreasing glucose levels or obesityprevalence," says Ana Cristina Santos, MPH, of University of PortoMedical School in Porto, Portugal, lead investigator of a study that foundcentral obesity to be a strong predictor of elevatedCRP.6
"Once considered a passive storage of fat, adipose tissue is nowrecognized for its active role in the inflammation process. In vivostudies showed that about 25% of the pro-inflammatory cytokine interleukin 6(IL-6) is produced in the adipose tissue," Santos says.
In addition to diet modification and exercise, experts also advocatesmoking cessation to lower CRP.
"When you think you've done everything, it makes sense to askyourself, `What else can the patient do? What else can I do?'" Ray says.
References
2. Miller M, Zhan M, Havas S: High attributable risk of elevatedC-reactive protein level to conventional coronary heart disease risk factors:The Third National Health and Nutrition Examination Survey. ArchIntern Med 165:2063–2068, 2005.
3. Pearson TA, Mensah GA, Alexander RW, et al.: Markers ofinflammation and cardiovascular disease: Application to clinical and publichealth practice: A statement for healthcare professionals from the Centers forDisease Control and Prevention and the American Heart Association.Circulation 107:499–511, 2003.
4. Nissen SE, Tuzcu EM, Schoenhagen P, et al.: Statin therapy, LDLcholesterol, C-reactive protein, and coronary artery disease. NEngl J Med 352:29–38, 2005.
5. Esposito K, Marfella R, Ciotola M, et al.: Effect of aMediterranean-style diet on endothelial dysfunction and markers of vascularinflammation in the metabolic syndrome: A randomized trial.JAMA 292:1440–1446, 2004.
6. Santos AC, Lopes C, Guimaraes JT, et al.: Central obesity as amajor determinant of increased high-sensitivity C-reactive protein inmetabolic syndrome. Int J Obes 29: 1452–1456, 2005.[Medline]
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