CLINICAL RESEARCH: CRP AND CAD
Prevalence of Low Low-Density Lipoprotein Cholesterol With Elevated High Sensitivity C-Reactive Protein in the U.S.Implications of the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) Study
Erin D. Michos, MD, MHS* and
Roger S. Blumenthal, MD
Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Manuscript received October 8, 2008;
revised manuscript received December 3, 2008,
accepted December 8, 2008.
* Reprint requests and correspondence: Dr. Erin D. Michos, Division of Cardiology, Johns Hopkins School of Medicine, Carneige 568, 600 North Wolfe Street, Baltimore, Maryland 21287 (Email: edonnell{at}jhmi.edu).
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Abstract
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Objectives: We assessed the prevalence of low-density lipoprotein-cholesterol (LDL-C) <130 mg/dl with elevated high-sensitivity C-reactive protein (hsCRP) in the National Health And Nutrition Examination Survey (NHANES), weighted to be representative of the general U.S. population.
Background: Rosuvastatin therapy in the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) study reduced cardiovascular events among older adults with LDL-C <130 mg/dl and hsCRP  2 mg/l.
Methods: Using 1999 to 2004 NHANES data, we categorized men age 50 years and women age 60 years by fasting LDL-C and hsCRP levels, excluding individuals with prevalent coronary heart disease, coronary heart disease equivalent (including diabetes), and other JUPITER exclusions.
Results: A total of 3.9 million men age 50 years and 2.6 million women age 60 years meeting JUPITER eligibility criteria had fasting LDL-C <130 mg/dl and hsCRP 2 mg/l. In addition, 6.7 million older adults with elevated hsCRP 2 mg/l have LDL-C levels that exceed their National Cholesterol Education Program goals.
Conclusions: Extrapolating JUPITER eligibility to NHANES, an estimated 6.5 million additional adults could be potential candidates to initiate statin therapy.
Key Words: JUPITER • C-reactive protein • LDL cholesterol • prevention • rosuvastatin
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Abbreviations and Acronyms
| | ATP = Adult Treatment Panel | | CHD = coronary heart disease | | CVD = cardiovascular disease | | FRS = Framingham Risk Score(s) | | hsCRP = high-sensitivity C-reactive protein | | LDL-C = low-density lipoprotein cholesterol | | NCEP = National Cholesterol Education Program | | NHANES = National Health And Nutrition Examination Survey |
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Plasma lipoprotein levels can identify individuals at risk for cardiovascular disease (CVD) events; however, lipid screening incompletely identifies individuals likely to benefit from statin therapy (1). The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)-III uses Framingham Risk Scores (FRS) to establish treatment guidelines based on 10-year global risk (2). However, the effectiveness of these guidelines to identify asymptomatic individuals at presumptively low-risk for CVD events is unclear. Limitations of NCEP/ATP-III thresholds for instituting lipid-lowering therapy have been highlighted in previous reports (3,4), underscoring potential missed opportunities for implementing preventive therapies.
The JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) study enrolled adults without known coronary heart disease (CHD) or CHD equivalent with low-density lipoprotein cholesterol (LDL-C) <130 mg/dl but high-sensitivity C-reactive protein (hsCRP) 2 mg/l (5). In this population, which did not qualify for statin therapy based on NCEP/ATP-III, rosuvastatin reduced major CVD events by 44% (5). Using National Health And Nutrition Examination Survey (NHANES) data, we estimated the additional number of U.S. adults who might now be considered for statin therapy.
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Methods
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NHANES is a nationwide probability sample of noninstitutionalized U.S. civilians conducted by the National Center for Health Statistics (6). The National Center for Health Statistics Institutional Review Board approved the overall design; participants provided written informed consent. We restricted our analyses to adults age 20 years who had a physical examination and fasting blood samples collected from 1999 to 2004 (6). hsCRP was measured by nephelometry (Dade Behring Diagnostics Inc., Somerville, New Jersey) (6).
Population estimates of adults meeting the JUPITER study eligibility criteria (Table 1) were determined by hsCRP and LDL-C levels. Those with prior myocardial infarction, stroke, or diabetes mellitus (fasting glucose >126 mg/dl or use of hypoglycemic agents); those using lipid-lowering medications, estrogen, or immunosuppressants; or those with serum creatinine >2 mg/dl, triglycerides >500 mg/dl, elevated liver enzymes (alanine aminotransferase >2 upper limit of normal), uncontrolled hypertension (systolic blood pressure >190 or diastolic >100 mm Hg), or cancer diagnosis within 5 years (except nonmelanoma skin cancer) were excluded from analysis.
The 10-year risk of developing myocardial infarction or CHD death was predicted by FRS (2). Participants were classified as low risk (<10% 10-year risk and 0 to 1 risk factors), moderate risk (<10% 10-year risk but 2 risk factors), moderately-high risk (10% to 20% 10-year risk), and high risk (>20% 10-year risk). The number of participants with elevated hsCRP who were either below or at/above their LDL-C goal based on their NCEP/ATP-III risk level (2) was determined.
Population estimates were determined both for older adults (men age 50 years, women age 60 years as per the JUPITER trial) and for all adults age 20 years. Analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina), and estimates were weighted to the civilian noninstitutionalized U.S. population and to account for the unequal probabilities of selection, oversampling, and nonresponse.
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Results
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Population estimates of men age 50 years and women age 60 years with no JUPITER trial exclusion criteria are summarized by LDL-C and hsCRP levels (Table 2). An estimated 3.9 million men and 2.6 million women have LDL-C <130 mg/dl and hsCRP 2 mg/l, including 57% whites, 15% blacks, 26% Hispanics, and 2% other race/ethnicities. Among adults age 20 years, an estimated 14.5 million men and 22.2 million women have LDL-C <130 mg/dl and hsCRP 2 mg/l (Table 3).
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Table 2 Population Estimates of Men Age 50 and Women Age 60 Years in Millions (95% CI) Meeting the JUPITER Study Eligibility by hsCRP and LDL-C Levels
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Table 3 Population Estimates of Adults Age 20 Years in Millions (95% CI) Meeting JUPITER Study Eligibility by hsCRP and LDL-C Levels
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To assess the potential population affected if hypercholesterolemic patients initiated statin therapy due to identification of elevated hsCRP, we estimated the number of adults with LDL-C levels exceeding NCEP/ATP-III goals by risk category and hsCRP level (Table 4
for older adults, Table 5
for all adults). Across risk categories, 6.7 million older adults and 17.4 million adults age 20 years have LDL-C above goal and also have hsCRP 2 mg/l.
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Table 4 Population Estimates of Men Age 50 Years and Women Age 60 Years in Millions (95% CI) at NCEP/ATP-III Goals With hsCRP 2 mg/l
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We further assessed how many "normolipidemic" individuals (those below their recommended NCEP/ATP-III lipid goals) would be newly eligible to start statin therapy because of an elevated hsCRP 2 mg/l. Approximately 10 million older adults not eligible for statins per NCEP/ATP-III (because they were below the LDL-C cutpoint to consider pharmacotherapy) might now be considered for statins because of elevated hsCRP (Table 4). While not all were eligible per the JUPITER trial, 54.4 million adults age 20 years below their treatment threshold have hsCRP 2 mg/l (Table 5).
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Discussion
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The JUPITER study showed the benefit of statin therapy in individuals with normal-to-low LDL-C but with an elevated marker of inflammation (5). From NHANES, we estimate 37 million adults age 20 years without known CHD or equivalent have low-to-normal LDL-C and elevated hsCRP, individuals who may benefit at least from more aggressive lifestyle changes. This is higher than 1999 to 2000 estimates, which showed that approximately 12 million U.S. adults considered "normolipidemic" have elevated hsCRP (7); however, that analysis used a CRP cutoff of >3 mg/l and considered individuals "normolipidemic" based on risk-factor determined LDL-C thresholds, which may be higher than the 130 mg/dl threshold used in the JUPITER study. We determined that 6.5 million adults with LDL-C <130 mg/dl and hsCRP 2 mg/l not currently on therapy met the "older" age requirement for the JUPITER study and, thus, might now be considered statin candidates.
We also estimated that 17.4 million adults age 20 years have LDL-C above the NCEP/ATP-III goal and elevated hsCRP, confirming the need for improved adherence to guidelines. The JUPITER study might serve as an incentive to patients and providers to achieve their recommended LDL-C goals.
Because the NCEP/ATP-III criteria for LDL-C treatment thresholds are based on the FRS, many other risk factors such as obesity, sedentary lifestyles, inflammation, family history of premature CHD, subclinical atherosclerosis, and chronic renal insufficiency are not taken into account (4,5). The Cardiovascular Prevention Guidelines for Women (8) have moved away from FRS categories, focusing on "at-risk" women because the presence of even 1 major risk factor before the age of 50 years confers a higher lifetime risk for CVD and shorter median survival. Women, on average, have higher hsCRP levels than men, and perhaps there should be sex-specific hsCRP cutoffs (9).
hsCRP is strongly associated with the metabolic syndrome and obesity (10). With the current epidemic of obesity (11), the prevalence of elevated hsCRP will likely increase as well. Elevated hsCRP has consistently provided incremental prognostic value for cardiovascular risk prediction beyond traditional risk factor assessment (1,12). Weight loss (13) and physical activity (14) can lower hsCRP levels, and lifestyle changes are first-line therapy to lower CVD risk. Statins lower hsCRP levels (15). When lifestyle changes alone are not effective in reducing hsCRP, statins may be considered in those with elevated risk.
Among those without clinical CVD, 1.5 million "intermediate-risk" adults with elevated hsCRP (>75th age/sex percentile) would now move into the "high-risk" category if elevated hsCRP directed treatment strategies (16).
The JUPITER study evaluated the benefits of rosuvastatin in older individuals (men age 50 and women 60 years) considered at "lower risk" on the basis of having low-to-normal LDL-C. Our study showed that, of older adults considered "low risk" by NCEP/ATP-III but with elevated hsCRP, 1.2 million have an LDL-C at/exceeding goal and 4.1 million have LDL-C below goal. Whether this same benefit of statin therapy seen in the JUPITER trial of older adults would translate to younger individuals is still unknown. The JUPITER study determined that the number needed to treat at 5 years is 25 (5); with 6.5 million U.S. adults eligible, this strategy could potentially prevent 260,000 events at 5 years.
Study limitations.
Data for all of the JUPITER study inclusion/exclusion criteria were not available in NHANES including thyroid stimulating hormone levels, prior coronary revascularization, and chronic inflammatory conditions. Elevated hsCRP, even in the setting of chronic inflammatory conditions, confers cardiovascular risk (17). Women taking estrogen were excluded from our population estimates. Estrogen use has fallen 66% since 2002 (18), and, consequently, these estimates may be lower than seen in more contemporary patterns of estrogen use.
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Conclusions
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The JUPITER trial results increase the range of individuals potentially benefiting from statin therapy to include those at risk for CVD as identified by hsCRP 2 mg/l. Extrapolating the JUPITER study eligibility to NHANES (weighted to be representative of the general U.S. population), we estimate that an additional 3.9 million men age 50 years and 2.6 million women age 60 years could now be potential candidates for statin therapy. Another potential public health effect would be to encourage untreated or undertreated hypercholesterolemic adults who are still above their NCEP/ATP-III lipid thresholds and with inflammation to initiate statin therapy.
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Acknowledgments
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The authors thank Judith Hsia and Eileen Ming of AstraZeneca for critical discussions.
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Footnotes
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The statistical analysis was funded by AstraZeneca. The National Center for Health Statistics is the source of data analyzed. Dr. Michos is supported by a Johns Hopkins Clinician Scientist Award and American College of Cardiology/Pfizer Career Development Award. Dr. Michos had full access to the study data and takes responsibility for data integrity and accuracy. All analyses, interpretations, and conclusions are made by the authors and do not represent the views of the National Center for Health Statistics or funding organizations.
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Abstract
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