Prevalence of Low Low-Density Lipoprotein Cholesterol With Elevated High Sensitivity C-Reactive Protein in the U.S.

Transcription

1 Journal of the American College of Cardiology Vol. 53, No. 11, by the American College of Cardiology Foundation ISSN /09/$36.00 Published by Elsevier Inc. doi: /j.jacc 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, Roger S. Blumenthal, MD Baltimore, Maryland Objectives Background Methods Results Conclusions We assessed the prevalence of low-density lipoprotein-cholesterol (LDL-C) 130 mg/dl with elevated highsensitivity C-reactive protein (hscrp) in the National Health And Nutrition Examination Survey (NHANES), weighted to be representative of the general U.S. population. 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. 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. 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. Extrapolating JUPITER eligibility to NHANES, an estimated 6.5 million additional adults could be potential candidates to initiate statin therapy. (J Am Coll Cardiol 2009;53:931 5) 2009 by the American College of Cardiology Foundation 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 From the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 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. Manuscript received October 8, 2008; revised manuscript received December 3, 2008, accepted December 8, 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 highsensitivity 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. Methods 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

2 932 Michos and Blumenthal JACC Vol. 53, No. 11, 2009 Applying JUPITER Eligibility Criteria to NHANES March 17, 2009:931 5 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 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 lipidlowering 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. The JUPITER Study Eligibility Criteria Table 1 The JUPITER Study Eligibility Criteria Inclusion Exclusion Men age 50 yrs, women age 60 yrs Fasting LDL-C 130 mg/dl hscrp 2 mg/l Lipid-lowering, oral hormone, or immunosuppressant therapy Prior cardiovascular or cerebrovascular event or CHD risk equivalent including diabetes Alanine transaminase 2, creatinine kinase 3, or thyroidstimulating hormone 1.5 upper limit of normal, creatinine 2 mg/dl, triglycerides 500 mg/dl Systolic blood pressure 190 or diastolic 100 mm Hg Malignancy within past 5 years except nonmelanoma skin cancer Chronic inflammatory condition such as severe arthritis, lupus, or inflammatory bowel disease Data from Ridker et al. (5). CHD coronary heart disease; hscrp high-sensitivity C-reactive protein; JUPITER Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin; LDL-C low-density lipoprotein cholesterol. Population Age JUPITER >60Study Years Estimates Eligibility in Millions of Men by(95% hscrp Age CI) >50 and Meeting and LDL-C Women the Levels Population Estimates of Men Age >50 and Women Table 2 Age >60 Years in Millions (95% CI) Meeting the JUPITER Study Eligibility by hscrp and LDL-C Levels hscrp, mg/l Sample <2 2 to 3 >3 Number of Cases All LDL 130 mg/dl 6.2 ( ) 2.4 ( ) 4.1 ( ) 531 LDL 130 mg/dl 6.6 ( ) 2.6 ( ) 5.6 ( ) 579 Women LDL 130 mg/dl 1.6 ( ) 1.0 ( ) 1.6 ( ) 196 LDL 130 mg/dl 2.1 ( ) 1.1 ( ) 2.5 ( ) 240 Men LDL 130 mg/dl 4.6 ( ) 1.4 ( ) 2.5 ( ) 335 LDL 130 mg/dl 4.5 ( ) 1.5 ( ) 3.2 ( ) 339 CI confidence interval; JUPITER Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin; LDL low-density lipoprotein; other abbreviations as in Table 1. 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. Results 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). 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. 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

3 JACC Vol. 53, No. 11, 2009 March 17, 2009:931 5 Michos and Blumenthal Applying JUPITER Eligibility Criteria to NHANES 933 Population (95% CI) Meeting Estimates JUPITER of Adults Study Age Eligibility >20 Years by hscrp in Millions and LDL-C Levels Population Estimates of Adults Age >20 Years in Millions Table 3 (95% CI) Meeting JUPITER Study Eligibility by hscrp and LDL-C Levels hscrp, mg/l <2 2 to 3 >3 Sample Number of Cases All LDL 130 mg/dl 47.6 ( ) 11.7 ( ) 24.9 ( ) 2,379 LDL 130 mg/dl 23.9 ( ) 8.3 ( ) 19.1 ( ) 1,549 Women LDL 130 mg/dl 21.9 ( ) 6.2 ( ) 16.0 ( ) 1,277 LDL 130 mg/dl 8.3 ( ) 4.2 ( ) 10.0 ( ) 738 Men LDL 130 mg/dl 25.8 ( ) 5.6 ( ) 8.9 ( ) 1,102 LDL 130 mg/dl 15.6 ( ) 4.1 ( ) 9.0 ( ) years below their treatment threshold have hscrp 2 mg/l (Table 5). Discussion 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. Population Years in Millions Estimates (95% of CI) Men at NCEP/ATP-III Age >50 Years Goals and With Women hscrp Age >2>60 mg/l Table 4 Abbreviations as in Tables 1 and 2. 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 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). ATP-III Risk Category Low Moderate Moderately High High Below LDL-C goal* 4.1 ( ) 1.5 ( ) 2.2 ( ) 0.3 ( ) At or above LDL-C goal* 1.2 ( ) 1.8 ( ) 2.9 ( ) 0.8 ( ) Below NCEP cutpoint to consider drug therapy* 5.0 ( ) 2.5 ( ) 2.2 ( ) 0.3 ( ) At or above NCEP cutpoint to consider drug therapy* 0.3 ( ) 0.7 ( ) 2.9 ( ) 0.8 ( ) Below NCEP optional cutpoint for drug therapy* 4.1 ( ) 2.5 ( ) 0.8 ( ) 0.01 ( ) At or above NCEP optional cutpoint for drug therapy* 1.2 ( ) 0.7 ( ) 4.4 ( ) 1.1 ( ) *LDL-C goals (mg/dl) and cutpoints to consider drug therapy by risk category: low-risk: goal 160, cutpoint 190, optional cutpoint 160; moderate-risk: goal 130, cutpoint 160; moderately high: goal 130, cutpoint 130, optional cutpoint 130; high: goal 100 (optional goal 70), cutpoint 100, optional cutpoint 70. ATP Adult Treatment Panel; CI confidence interval; NCEP National Cholesterol Education Program; other abbreviations as in Table 1.

4 934 Michos and Blumenthal JACC Vol. 53, No. 11, 2009 Applying JUPITER Eligibility Criteria to NHANES March 17, 2009:931 5 Population Estimates of Adults Age >20 Years in Millions (95% CI) at NCEP/ATP-III Goals With hscrp >2 mg/l Table 5 Population Estimates of Adults Age >20 Years in Millions (95% CI) at NCEP/ATP-III Goals With hscrp >2 mg/l ATP-III Risk Category Low Moderate Moderately High High Below LDL-C goal* 37.8 ( ) 5.8 ( ) 2.5 ( ) 0.5 ( ) At or above LDL-C goal* 6.3 ( ) 5.4 ( ) 4.0 ( ) 1.7 ( ) Below NCEP cutpoint to consider pharmacotherapy* 42.4 ( ) 9.0 ( ) 2.5 ( ) 0.5 ( ) At or above NCEP cutpoint to consider therapy* 1.7 ( ) 2.2 ( ) 4.0 ( ) 1.7 ( ) Below NCEP optional cutpoint for therapy* 37.8 ( ) 9.0 ( ) 0.8 ( ) 0.03 ( ) At or above NCEP optional cutpoint for therapy* 6.3 ( ) 2.2 ( ) 5.7 ( ) 2.2 ( ) *See Table 4 for LDL-C goals (mg/dl) and cut points to consider drug therapy by risk category. Abbreviations as in Tables 1 and 4. 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. Conclusions 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. Acknowledgments The authors thank Judith Hsia and Eileen Ming of Astra- Zeneca for critical discussions. Reprint requests and correspondence: Dr. Erin D. Michos, Division of Cardiology, Johns Hopkins School of Medicine, Carneige 568, 600 North Wolfe Street, Baltimore, Maryland edonnell@jhmi.edu. REFERENCES 1. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347: Grundy SM. National Cholesterol Education Program (NCEP) The National Cholesterol Guidelines in 2001, Adult Treatment Panel (ATP)-III. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol 2002;90:11i 21i. 3. Akosah KO, Schaper A, Cogbill C, et al. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel-III guidelines perform? J Am Coll Cardiol 2003;41: Nasir K, Michos ED, Blumenthal RS, Raggi P. 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5 JACC Vol. 53, No. 11, 2009 March 17, 2009:931 5 Michos and Blumenthal Applying JUPITER Eligibility Criteria to NHANES Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-reactive protein within 14 days: an effect independent of lowdensity lipoprotein cholesterol reduction. Circulation 2002;106: Lakoski SG, Cushman M, Blumenthal RS, et al. Implications of C-reactive protein or coronary artery calcium score as an adjunct to global risk assessment for primary prevention of CHD. Atherosclerosis 2007;193: Goodson NJ, Symmons DP, Scott DG, et al. Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum 2005;52: Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004;291: Key Words: JUPITER y C-reactive protein y LDL cholesterol y prevention y rosuvastatin.