HIGH TOTAL BLOOD CHOLESterol

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1 ORIGINAL CONTRIBUTION Trends in High Levels of Low-Density Lipoprotein Cholesterol in the United States, Elena V. Kuklina, MD, PhD Paula W. Yoon, ScD, MPH Nora L. Keenan, PhD HIGH TOTAL BLOOD CHOLESterol is recognized as a major contributing factor for the initiation and progression of atherosclerosis. 1 The evidencebased recommendations for management of lipid disorders in clinical practice in the United States are specified by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). 2 The NCEP ATP III places a primary focus for cholesterol management on elevated levels of low-density lipoprotein cholesterol (LDL-C), the major atherogenic lipoprotein. The guidelines set LDL-C target levels that are based on the history of coronary heart disease (CHD) or risk for developing CHD in the next 10 years. Several studies using National Health and Nutrition Examination Survey (NHANES) data have reported the prevalence of high LDL-C levels among persons aged 20 years or older in the United States. 3-7 Most of these studies focused on people with a high risk for CHD and on pharmacologic management of high LDL-C levels. Results from these studies showed that a large proportion of adults with high LDL-C levels, especially those at high See also pp 2144 and Context Studies show that a large proportion of adults with high levels of lowdensity lipoprotein cholesterol (LDL-C) remain untreated or undertreated despite growing use of lipid-lowering medications. Objective To investigate trends in screening prevalence, use of cholesterollowering medications, and LDL-C levels across 4 study cycles ( , , , and ). Design, Setting, and Participants The National Health and Nutrition Examination Survey (NHANES) is a cross-sectional, stratified, multistage probability sample survey of the US civilian, noninstitutionalized population. After we restricted the study sample to fasting participants aged 20 years or older (n=8018) and excluded pregnant women (n=464) and participants with missing data (n=510), our study sample consisted of 7044 participants. Main Outcome Measure High LDL-C levels, defined as levels above the specific goal for each risk category outlined in guidelines from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). All presented results are weighted and age-standardized to 2000 standard population estimates. Results Prevalence of high LDL-C levels among persons aged 20 years or older decreased from 31.5% in to 21.2% in (P.001 for linear trend) but varied by risk category. By the study cycle, prevalence of high LDL-C was 58.9%, 30.2%, and 11.0% for high-, intermediate-, and low-risk categories, respectively. Self-reported use of lipid-lowering medications increased from 8.0% to 13.4% (P.001 for linear trend), but screening rates did not change significantly, remaining less than 70% (P=.16 for linear trend) during the study periods. Conclusions Among the NHANES population aged 20 years or older, the prevalence of high LDL-C levels decreased from to In the most recent period, the prevalence was 21.2%. JAMA. 2009;302(19): risk for CHD, remain untreated or inadequately treated despite a steadily growing use of lipid-lowering medications. Few studies, however, have described the prevalence of high LDL-C levels and the use of lipidlowering medications across all CHD risk categories. Also, studies to date have not examined health care factors Author Affiliations: Division for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia. Corresponding Author: Elena V. Kuklina, MD, PhD, Division for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, Mailstop K-37, Atlanta, GA (ekuklina@cdc.gov) JAMA, November 18, 2009 Vol 302, No. 19 (Reprinted) 2009 American Medical Association. All rights reserved.

2 such as inadequate screening, diagnosis, and treatment that may contribute to poor control of high LDL-C levels at the population level. The objectives of this study, using NHANES data, were (1) to investigate trends in the prevalence of screening, current use of cholesterollowering medication, and high LDL-C levels; (2) to evaluate trends in prevalence of high LDL-C levels by ATP III CHD risk category; and (3) to describe the distribution of participants who were unscreened, those who were screened but undiagnosed (ie, they were not told whether they had high LDL-C levels), and those participants with high LDL-C levels who were screened and diagnosed but untreated or inadequately treated. METHODS Study Participants NHANES is a continuous survey of the health and nutritional status of the US civilian, noninstitutionalized population; samples of participants are selected through a complex, multistage probability design. 8 Each year, approximately 6000 participants are selected to participate in the study. Persons who agree to participate are first interviewed in their homes about their health, disease history, and diet. After interviews, qualified participants are invited to a local mobile examination center for administration of additional questionnaires, physical examinations, and laboratory tests. NHANES data are released in 2-year increments, and this analysis used data from the last 4 study cycles: , , , and The overall response rate for completed examinations among all selected participants for each study cycle was 76% (9282/12 160), 80% (10 477/13 156), 76% (9643/12 761), and 77% (9950/12 862), respectively. Among study participants invited to the mobile examination center, a subsample of participants was randomly selected and asked to fast for 8 or more hours (up to 24 hours) for laboratory testing (n=13 875). As with Table 1. Low-Density Lipoprotein Cholesterol Goals and Cut Points for Initiating Therapeutic Lifestyle Changes and Drug Therapy by Risk Category a Risk Category High risk: CHD or CHD equivalents (10-y risk 20%) d Intermediate risk: 2 risk factors (10-y risk 20%) e other subsamples in the study, the fasting subsample has its own designated weight, which accounts for the additional probability of selection and nonresponse. After excluding 5857 participants younger than 20 years, our study sample consisted of 8018 persons. Women who had a positive urine pregnancy test or self-reported to be pregnant (n=464) as well as participants with missing lipid profile and blood pressure data (n=510) were excluded, leaving analytical samples for 7044 participants. The study protocols for NHANES received approval from the National Center for Health Statistics institutional review board and included written informed consent. 9 CHD Risk Factors and ATP III CHD Risk Categories We classified the 7044 remaining study participants into 3 ATP III CHD risk categories: high, intermediate, and low (TABLE 1). Participants with a selfreported history of CHD, angina, myocardial infarction, stroke, and diabetes mellitus or participants with a fasting blood glucose level of 126 mg/dl or LDL-C Goal Therapeutic Lifestyle Changes b Drug Therapy c 100 mg/dl 100 mg/dl 100 mg/dl ( 100 mg/dl: consider drug options) 130 mg/dl 130 mg/dl 10-y risk 10%-20%: 130 mg/dl ( mg/dl: consider drug options); 10-y risk 10%: 160 mg/dl Low risk: 1 risk factor f 160 mg/dl 160 mg/dl 190 mg/dl ( mg/dl: LDL-C lowering drug optional) Abbreviations: CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol. SI conversion factor: To convert LDL-C to mmol/l, multiply by a Risk categories according to National Cholesterol Education Program Adult Treatment Panel III. 9 b For persons at high or moderately high risk with lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglyceride, low levels of high-density lipoprotein cholesterol [HDL-C], or metabolic syndrome), regardless of LDL-C levels. c Drug therapy should be sufficient to achieve a 30% to 40% reduction in LDL-C levels. d CHD includes history of myocardial infarction, unstable angina, stable angina, coronary artery procedures (angioplasty or bypass surgery), or evidence of clinically significant myocardial ischemia. CHD equivalents include clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease [transient ischemic attacks or stroke of carotid origin or 50% obstruction of a carotid artery]), diabetes mellitus, and 2 or more risk factors with 10-year risk for CHD greater than 20%. e Risk factors include cigarette smoking, hypertension (blood pressure 140/90 mm Hg or taking antihypertensive medication), low HDL-C level ( 40 mg/dl), family history of premature CHD (CHD in male first-degree relative younger than 55 years, CHD in female first-degree relative younger than 65 years), and older age (men 45 years or older, women 55 years or older). Electronic 10-year risk calculators are available at f Most persons with 1 or no risk factor have a 10-year risk less than 10%, indicating that a 10-year risk assessment for such persons is unnecessary. greater were placed in the high ATP III risk category. Noncoronary forms of atherosclerotic disease (peripheral arterial disease [PAD] and abdominal aortic aneurysm) are also considered a CHD equivalent in the NCEP ATP III guidelines. However, the NHANES examination includes neither a test for aortic aneurysms nor a history of this condition or of aortic surgery. Also, we did not use the ankle-brachial pressure index in our study because this measure was discontinued in However, we determined that the estimated prevalence of PAD calculated by the ankle-brachial pressure index from the data for contributed little (about 6%-9%) to the overall prevalence of CHD or CHD equivalent. After participants with high risk were identified, the remaining participants were assessed according to the number of major CHD risk factors they had. These risk factors included cigarette smoking (self-reported smoking every day or some days), hypertension (an average of 3 blood pressure measurements 140/90 mm Hg, determined by NHANES physical examination, or self American Medical Association. All rights reserved. (Reprinted) JAMA, November 18, 2009 Vol 302, No

3 reported current use of antihypertensive medication), high-density lipoprotein cholesterol (HDL-C) level less than 40 mg/dl, family history of premature CHD (angina or heart attack) in a firstdegree relative younger than 50 years, and older age (men 45 years and women 55 years). In accord with the ATP III guidelines, 2 if a person had an HDL-C level of 60 mg/dl or greater, 1 risk factor was subtracted from the person s total number of risk factors. (To convert total cholesterol, HDL-C, and LDL-C to mmol/l, multiply by ) For participants with 2 or more risk factors, we calculated a 10-year CHD risk score using the Framingham risk equation, an assessment tool used in the NCEP. 10 Based on categorical values for age, total cholesterol level, systolic blood pressure, HDL-C level, and smoking status, points were assigned and then totaled to calculate an absolute 10-year CHD risk for each participant. Those participants with a 10-year CHD risk greater than 20% were placed in the high ATP III risk category, and those with 20% or lower risk were placed in the intermediate category. Participants with 1 or no major CHD risk factor were placed in the low ATP III risk category without Framingham scoring because of their low 10-year CHD risk. Lipid Measurements and Definition of High LDL-C Levels We further categorized LDL-C levels according to the ATP III risk categories and goals for therapeutic lifestyle changes and drug therapy (Table 1). High LDL-C levels were defined as LDL-C levels greater than the specific goal for each risk category. Participants with high LDL-C levels included those eligible for therapeutic lifestyle changes or drug therapy. For all lipid analyses, frozen venous serum samples were shipped on dry ice to the Lipoprotein Analytical Laboratory at Johns Hopkins University Hospital, Baltimore, Maryland. 11 Methods for determining total cholesterol, HDL-C, and triglyceride levels for NHANES have been described. 11 Values for LDL-C were calculated from measured values of total cholesterol, triglycerides, and HDL-C according to the Friedewald calculation. 11 All lipid measurements were standardized through the Lipid Standardization Program maintained by the Centers for Disease Control and Prevention in collaboration with the National Heart, Lung, and Blood Institute. 12 Assessment and Definition of Screening Status Participants were asked whether they had ever had their blood cholesterol checked and how long it had been since their last cholesterol test. Screening was categorized as those screened during the last 5 years and told by health professionals that they had high blood cholesterol, those screened during the last 5 years and not told by health professionals that they had high blood cholesterol, and those never screened or screened more than 5 years ago. Current use of a cholesterol-lowering drug was identified by self-reported taking of prescribed medication to decrease blood cholesterol levels. Participants with high LDL-C levels were defined as unscreened if they were never screened or not screened during the last 5 years; undiagnosed if they were screened during the last 5 years but never told they had high blood cholesterol; and untreated or inadequately treated if they had been screened and told they had high blood cholesterol, but their cholesterol was not controlled. Data Analysis Estimated population prevalence and means with 95% confidence intervals were calculated using SUDAAN statistical software (Research Triangle International, Research Triangle Park, North Carolina) to account for nonresponse and complex sampling design. 13 The prevalence and means estimates were age-standardized to the 2000 US standard population. 14 We used orthogonal polynomial coefficients calculated recursively according to the method of Fisher and Yates for linear trend testing. 13 Significance was set at P.05. RESULTS The weighted age-standardized estimates of CHD, CHD equivalents, CHD risk factors, and ATP III risk categories are presented in TABLE 2 for each study cycle. No significant changes were observed in the prevalence of CHD or CHD equivalents from to Among participants without CHD or CHD equivalents, prevalences of hypertension and low HDL-C levels decreased significantly from 15.7% to 10.2% (P.001) and from 19.3% to 9.4% (P.001), respectively. Self-reported use of lipidlowering medications increased significantly (P.001), but no changes were observed in the screening rates (P=.16). Our results assessing the distribution and trends in the screening groups among persons with high levels of LDL-C during the period of study are reported in TABLE 3. No significant changes were observed in the weighted age-standardized screening rates from to Among participants with high LDL-C levels, 35.5% were unscreened, 24.9% undiagnosed, and 39.6% untreated or inadequately treated in Our analysis showed that 78.0% of participants in the high-risk category had total cholesterol levels of 200 mg/dl or greater or HDL-C levels less than 40 mg/ dl; thus, according to current guidelines, they would be recommended for further complete lipid profile testing (data are not shown). The weighted age-standardized prevalence of high LDL-C levels among all participants and among participants in each ATP III risk category decreased significantly during the study periods (TABLE 4). Overall prevalence for high LDL-C levels decreased from 31.5% to 21.2% (P.001). However, this prevalence varied substantially by risk category. The highest prevalence of high LDL-C levels was observed in the high-risk ATP III category with 69.4% and 58.9% during the first and last cycles, respectively. During the last study period, the prevalence of high LDL-C was 30.2% and 11.0% for the intermediate- and low-risk categories, re JAMA, November 18, 2009 Vol 302, No. 19 (Reprinted) 2009 American Medical Association. All rights reserved.

4 Table 2. Weighted Age-Standardized Prevalence of ATP III Risk Factors and Risk Categories, NHANES, a (n = 1646) Prevalence, % (95% CI) (n = 1930) (n = 1744) (n = 1724) P Value b CHD or CHD equivalents History of CHD 2.8 ( ) 3.6 ( ) 3.7 ( ) 3.7 ( ).98 Angina 3.2 ( ) 2.9 ( ) 2.7 ( ) 2.9 ( ).26 Myocardial infarction 3.4 ( ) 3.5 ( ) 3.3 ( ) 3.7 ( ).73 Stroke 2.0 ( ) 2.3 ( ) 3.0 ( ) 2.9 ( ).17 Diabetes mellitus c 7.8 ( ) 9.7 ( ) 9.6 ( ) 10.3 ( ).06 Total with 1 condition 13.4 ( ) 15.6 ( ) 15.2 ( ) 16.0 ( ).16 CHD risk factors, excluding CHD/CHD equivalents Cigarette smoking 20.4 ( ) 20.6 ( ) 21.2 ( ) 21.4 ( ).68 Hypertension d 15.7 ( ) 14.4 ( ) 12.8 ( ) 10.2 ( ).001 Older participants (men 45 y, women 55 y) 29.3 ( ) 28.6 ( ) 28.6 ( ) 28.8 ( ).66 Family history e 11.9 ( ) 10.6 ( ) 13.1 ( ) 11.4 ( ).98 HDL-C 40 mg/dl 19.3 ( ) 16.5 ( ) 11.7 ( ) 9.4 ( ).001 HDL-C 60 mg/dl 22.5 ( ) 22.4 ( ) 28.9 ( ) 30.6 ( ).001 ATP III risk categories High risk f 13.9 ( ) 16.5 ( ) 15.9 ( ) 17.3 ( ).11 Intermediate risk g 22.7 ( ) 20.8 ( ) 19.4 ( ) 14.7 ( ).001 Low risk h 63.5 ( ) 62.6 ( ) 64.8 ( ) 68.1 ( ).06 Current use of lipid-lowering drug, self-reported 8.0 ( ) 10.2 ( ) 13.3 ( ) 13.4 ( ).001 Screened, total i 64.5 ( ) 61.4 ( ) 63.4 ( ) 67.3 ( ).16 Abbreviations: ATP III, Adult Treatment Panel III; CHD, coronary heart disease; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; NHANES, National Health and Nutrition Examination Survey. SI conversion factor: To convert HDL-C to mmol/l, multiply by a Direct age standardization is based on 2000 standard population for adults aged 20 years and older using age groups 20 to 39 years, 40 to 59 years, and 60 years and older. b P value for linear trend is assessed by calculating orthogonal polynomial coefficients according to the method of Fisher and Yates. c Self-reported or fasting blood glucose 126 mg/dl or greater. d Systolic blood pressure greater than 140 mm Hg, diastolic blood pressure greater than 90 mm Hg, or reporting taking a prescription medication for treatment of hypertension. e Heart attack or angina at younger than 50 years. f CHD or CHD equivalent or 2 or more major CHD risk factors and 10-year Framingham risk greater than 20%. CHD risk factors assessed in the study were cigarette smoking, hypertension (blood pressure 140/90 mm Hg or receiving antihypertensive medication), low HDL-C level ( 40 mg/dl), family history of premature CHD (CHD in first-degree relative younger than 50 years), and older age (men 45 years, women 55 years). g Two or more major CHD risk factors and 10-year Framingham risk 20% or lower. h One or no major CHD risk factor. i Screened within the last 5 years. spectively. In the high-risk category, about one-fifth of participants were eligible for lipid-lowering drug therapy but were not receiving it in Among all participants, mean LDL-C level decreased from mg/dl in to mg/dl in (P.001). The decrease in mean LDL-C level was also observed in all risk categories. The mean LDL-C level decreased from mg/dl to mg/dl (P.001), from mg/dl to mg/dl (P.001), and from mg/dl to mg/dl (P.001) in the high-, intermediate-, and low-risk categories, respectively. COMMENT According to NHANES data, the prevalence of high LDL-C Table 3. Estimated Weighted Age-Standardized Prevalence for Screening Among Participants With High Levels of LDL-C, NHANES, a Screening Prevalence, % (95% CI) P High LDL-C Levels (n = 537) (n = 604) (n = 487) (n = 412) Value b Screened, total c 64.4 ( ) 68.5 ( ) 68.1 ( ) 64.5 ( ).99 Screened, told 40.2 ( ) 34.6 ( ) 42.3 ( ) 39.6 ( ).61 (untreated or inadequately treated) c,d Screened, never told 24.2 ( ) 33.9 ( ) 25.8 ( ) 24.9 ( ).57 (undiagnosed) c,e Unscreened c 35.6 ( ) 31.5 ( ) 31.9 ( ) 35.5 ( ).99 Abbreviations: CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; NHANES, National Health and Nutrition Examination Survey. a Direct age standardization is based on 2000 standard population for adults aged 20 years or older using age groups 20 to 39 years, 40 to 59 years, and 60 years and older. b P value for linear trend is assessed by calculating orthogonal polynomial coefficients according to the method of Fisher and Yates. c Screening within the last 5 years. d Participants responded yes when asked, Have you ever been told by a doctor or other health professional that your blood cholesterol level was high? e Participants responded no or don t know or refused to respond when asked, Have you ever been told by a doctor or other health professional that your blood cholesterol level was high? 2009 American Medical Association. All rights reserved. (Reprinted) JAMA, November 18, 2009 Vol 302, No

5 levels among persons aged 20 years or older decreased by approximately onethird from to Screening rates for high blood cholesterol did not change, remaining less than 70% during the study periods. The goal of improving screening rates may be hindered by lack of consensus regarding the age at which screening should start. The US Preventive Services Task Force and the American College of Physicians American Society of Internal Medicine recommend initiating high blood cholesterol screening at age 35 years in healthy men and at age 45 years in women. 15 The NCEP ATP III, convened by the National Heart, Lung, and Blood Institute and the American Heart Association, recommends that screening start at 20 years of age. 15 Clinicians play an additional role in decisions about screening; the clinician s choice of specific guidelines is often determined by the patient s insurance policy. 15 Consensus exists among different guidelines concerning the need to screen all adults at high risk for developing CHD in the next 10 years, including adults with a history of CHD, vascular disease, or diabetes. 15 However, according to our study, one-third of participants with high LDL-C levels were Table 4. Estimated Weighted Age-Standardized Prevalence of High Levels of LDL-C and Mean Levels of LDL-C by ATP III Risk Categories, NHANES, a (n = 1646) (n = 1930) (n = 1744) (n = 1724) P Value b Total NHANES Participants High LDL-C prevalence, % (95% CI) c Total d 31.5 ( ) 28.4 ( ) 23.8 ( ) 21.2 ( ).001 Eligible for TLC e 19.7 ( ) 17.9 ( ) 13.6 ( ) 13.4 ( ).001 Currently receiving drug 1.0 ( ) 1.7 ( ) 1.8 ( ) 2.2 ( ).04 Not currently receiving drug 10.8 ( ) 8.8 ( ) 8.4 ( ) 5.7 ( ).001 LDL-C level, mean (95% CI) ( ) ( ) ( ) ( ).001 High ATP III Risk Category g High LDL-C ( 100 mg/dl) prevalence, % (95% CI) Total d 69.4 ( ) 70.4 ( ) 60.1 ( ) 58.9 ( ).06 Eligible for TLC e 28.9 ( ) 33.5 ( ) 28.4 ( ) 29.1 ( ).82 Currently receiving drug h 1.9 ( ) i 5.9 ( ) i 6.8 ( ) 10.0 ( ) i.03 Not currently receiving drug 38.6 ( ) 31.1 ( ) 24.8 ( ) 19.8 ( ).001 LDL-C level, mean (95% CI) ( ) ( ) ( ) ( ).001 Intermediate ATP III Risk Category j High LDL-C ( 130 mg/dl) prevalence, % (95% CI) Total d 51.3 ( ) 45.4 ( ) 41.5 ( ) 30.2 ( ).001 Eligible for TLC e 31.1 ( ) 30.3 ( ) 22.6 ( ) 20.7 ( ).002 Currently receiving drug h 0.6 ( ) i 1.7 ( ) i 3.1 ( ) i 3.0 ( ) i.04 Not currently receiving drug 19.7 ( ) 13.3 ( ) 15.8 ( ) 6.5 ( ).002 LDL-C level, mean (95% CI) ( ) ( ) ( ) ( ).001 Low ATP III Risk Category k High LDL-C ( 160 mg/dl) prevalence, % (95% CI) Total d 15.5 ( ) 13.5 ( ) 9.2 ( ) 11.0 ( ).02 Eligible for TLC e 11.9 ( ) 10.4 ( ) 6.7 ( ) 9.4 ( ).07 Currently receiving drug h 0.6 ( ) i 0.7 ( ) i 0.0 ( ) i 0.0 ( ) i.03 Not currently receiving drug 3.0 ( ) 2.4 ( ) 2.5 ( ) 1.7 ( ).14 LDL-C level, mean (95% CI) ( ) ( ) ( ) ( ).001 Abbreviations: ATP III, Adult Treatment Panel III; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; NHANES, National Health and Nutrition Examination Survey; TLC, therapeutic lifestyle changes. SI conversion factor: To convert LDL-C to mmol/l, multiply by a Direct age standardization is based on 2000 standard population for adults aged 20 years and older using age groups 20 to 39 years, 40 to 59 years, and 60 years and older. b P value for linear trend is assessed by calculating orthogonal polynomial coefficients according to the method of Fisher and Yates. c LDL-C levels 100, 130, and 160 mg/dl for high, intermediate, and low ATP III risk categories, respectively. d Includes persons eligible for therapeutic lifestyle changes and drug therapy. e LDL-C levels , 130, , and mg/dl for high, intermediate with a 10-year Framingham risk 20% to 10%, intermediate with a 10-year Framingham risk less than 10%, and low ATP III risk categories, respectively. f LDL-C levels 130, 160, and 190 mg/dl for high or intermediate with a 10-year Framingham risk 20% to 10%, intermediate with a 10-year Framingham risk less than 10%, and low ATP III risk categories, respectively. g Includes persons with coronary heart disease (CHD) or CHD equivalent or 2 or more major CHD risk factors and 10-year Framingham risk greater than 20%. CHD risk factors assessed in the study were cigarette smoking, hypertension (blood pressure 140/90 mm Hg or receiving antihypertensive medication), low high-density lipoprotein cholesterol level less than 40 mg/dl, family history of premature CHD (CHD in first-degree relative 50 years of age), and age (men 45 years, women 55 years). h Confidence intervals are estimated using the Clopper-Pearson method; all other CIs in the table are estimated by the Wald method. i Estimate is statistically unreliable (relative standard error 30%). j Two or more major CHD risk factors and 10-year Framingham risk 20% or less. k One or no major CHD risk factor JAMA, November 18, 2009 Vol 302, No. 19 (Reprinted) 2009 American Medical Association. All rights reserved.

6 unscreened and thus missed an opportunity to improve their LDL-C levels. Differences in clinicians practices, their awareness of and adherence to the NCEP ATP III guidelines, and health care disparity issues 16 may contribute to screening rates below the Healthy People 2010 target of 80% for adults. 17 Using the 2001 NCEP ATP III guidelines, we estimated that one-fourth of participants with high LDL-C levels were screened but never told about having high blood cholesterol by their clinicians. Several factors may contribute to this nondiagnosis. Our classification was based on the question, Have you ever been told by a doctor or other health professional that your blood cholesterol level was high? Information about when the participant was tested as well as their fasting status and completeness of the lipid profile is not available in the NHANES questionnaires. Thus, a deterioration of lipid profile since the last screening is possible in some participants but is unlikely to contribute substantially to our estimate. Clinicians awareness of and adherence to the NCEP ATP III guidelines probably play a key role. We found that assessing only total cholesterol and HDL-C levels instead of taking a complete fasting lipid profile as recommended in the NCEP ATP III guidelines would misclassify approximately 22% of participants as having optimal LDL-C levels when they really would be in the high-risk category with high LDL-C levels. In a study of 500 randomly selected US physicians, almost half failed to classify their patients risk levels correctly according to Framingham scores. 18 Lack of screening and diagnosis can result in inappropriate treatment. Secondary prevention has been proven to be cost-effective in reducing illness and death associated with CHD. 19 However, our study found that almost two-thirds of participants who were at high risk for developing CHD within 10 years and who were eligible for lipid-lowering drugs were not receiving medication. Our estimates would be even higher had we used the modification of the LDL-C goal for high-risk patients of less than 70 mg/dl recommended by the updated 2004 NCEP ATP III report. 20 A better understanding of factors leading to the nondiagnosis of high LDL-C levels is needed. Meanwhile, clinicians compliance with cardiovascular disease prevention guidelines can be improved through ongoing education. 21 Even when a clinician has opportunities to initiate therapeutic lifestyle changes (eg, diet, exercise, and weight control) or drug therapy according to the NCEP ATP III guidelines, management of high LDL-C levels may still be challenging, especially in high-risk patients. A recent study using data on patients from a health maintenance organization administrative claims database showed that LDL-C goal attainment was not achieved among 61% of patients who received lipid drug treatment during the first 6 months after an initial diagnosis of CHD or diabetes. 22 Moreover, among those who continued treatment for high LDL-C, half of the patients were unable to reach their LDL-C goal regardless of diagnosis (CHD vs diabetes), sex, statin titration, lipid-modifying drug switching, or treatment with a highpotency dosage of LDL-C lowering drug. In a study of therapeutic lifestyle interventions that used 24-hour dietary recall data in 555 patients with CHD, only a small proportion (5%- 12%) met the recommended consumption of vegetables, fruit, cereal fiber, and trans-fat intake 1 year after diagnosis of CHD. 23 Two large (about participants in each) prospective observational studies found that high baseline LDL-C values, pretreatment with certain statins, high glycated hemoglobin A 1c (HbA 1c ) levels in patients with diabetes, and high body mass index were associated with uncontrolled hyperlipidemia. 24 In our study, during approximately 2% of participants in the low-risk category had LDL-C levels appropriate for initiation of drug therapy, and approximately 9% had levels appropriate for the initiation of therapeutic lifestyle changes. However, use of drug therapy in young or low-risk adults remains controversial. The combination of low-fat diet, increased physical activity, and weight control may decrease cholesterol levels by 20% to 30% without drug therapy. 2 Results of 2 recent clinical trials show that a diet low in saturated fat along with plant sterols and viscous fibers, soy protein, and nuts 25 or, alternatively, therapeutic lifestyle changes combined with ingestion of red yeast rice and fish oil supplements, may be comparable with statin use in lipid-lowering effects. 26 The results of this analysis should be interpreted in light of the following study limitations. First, the prevalence of high LDL-C levels in the US population may be underestimated because persons residing in long-term care facilities are not included in the NHANES. Second, a misclassification bias is possible in our study: the proportion of participants in the highrisk category may be underestimated due to lack of data on peripheral vascular disease. In addition, the NHANES question on family history of heart attack or angina asks about firstdegree relatives younger than 50 years regardless of sex instead of using younger than 55 years for men and younger than 65 years for women, which are the ages considered to assess family risk factor in the NCEP ATP III guidelines. 2 Thus, some participants may be placed in the low-risk group instead of the intermediate- or high-risk category if the recommended age criteria by sex had been used. Third, although the collection of examination and laboratory data was standardized, self-reported data from interviews and questionnaires may be subject to misunderstanding and recall bias. Finally, although these analyses show a striking decrease in the prevalence of LDL-C levels over 8 years, the cause of the decline in LDL-C levels cannot be determined. There were 2009 American Medical Association. All rights reserved. (Reprinted) JAMA, November 18, 2009 Vol 302, No

7 4 different surveys over the 8-year span, but each one was a separate crosssectional study and precludes determining causality. In addition, even though temporal changes in potential contributing factors, such as improvement in treatment of LDL-C levels, can be documented, the missing or limited information on the duration of treatment, dose titration, and changes in type of medication used threatens the validity of such analyses. In conclusion, among the NHANES population aged 20 years or older, the prevalence of high LDL-C levels decreased from to In the most recent period, the prevalence was 21.2%. Author Contributions: Dr Kuklina had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kuklina, Yoon, Keenan. Acquisition of data: Kuklina. Analysis and interpretation of data: Kuklina, Yoon, Keenan. Drafting of the manuscript: Kuklina. Critical revision of the manuscript for important intellectual content: Kuklina, Yoon, Keenan. Statistical analysis: Kuklina. Administrative, technical, or material support: Kuklina. Study supervision: Yoon, Keenan. Financial Disclosures: None reported. Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent official views of the Centers for Disease Control and Prevention. Additional Contributions: Darwin Labarthe, MD, MPH, PhD, director of the Division for Heart Disease and Stroke Prevention, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, provided insightful and critical review of the manuscript. REFERENCES 1. Choi BG, Vilahur G, Yadegar D, Viles-Gonzalez JF, Badimon JJ. The role of high-density lipoprotein cholesterol in the prevention and possible treatment of cardiovascular diseases. Curr Mol Med. 2006;6 (5): Grundy SM. 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