Trends in High Levels of Low-Density Lipoprotein Cholesterol in the United States, 1999-2006 FREE

High total blood cholesterol is recognized as a major contributing factor for the initiation and progression of atherosclerosis.¹ The evidence-based 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 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 lipid-lowering medications across all CHD risk categories. Also, studies to date have not examined health care factors 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 1999-2006 NHANES data, were (1) to investigate trends in the prevalence of screening, current use of cholesterol-lowering 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.

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: 1999-2000, 2001-2002, 2003-2004, and 2005-2006. 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 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 1999-2006 NHANES received approval from the National Center for Health Statistics institutional review board and included written informed consent.⁹

We classified the 7044 remaining study participants into 3 ATP III CHD risk categories: high, intermediate, and low (Table 1). Participants with a self-reported history of CHD, angina, myocardial infarction, stroke, and diabetes mellitus or participants with a fasting blood glucose level of 126 mg/dL or 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 2005. However, we determined that the estimated prevalence of PAD calculated by the ankle-brachial pressure index from the data for 1999-2004 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-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 first-degree 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 0.0259.)

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.

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 1999-2006 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

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.

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.

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 1999-2000 to 2005-2006. 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 lipid-lowering 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 1999-2000 to 2005-2006. Among participants with high LDL-C levels, 35.5% were unscreened, 24.9% undiagnosed, and 39.6% untreated or inadequately treated in 2005-2006. 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, respectively. In the high-risk category, about one-fifth of participants were eligible for lipid-lowering drug therapy but were not receiving it in 2005-2006. Among all participants, mean LDL-C level decreased from 126.1 mg/dL in 1999-2000 to 114.8 mg/dL in 2005-2006 (P < .001). The decrease in mean LDL-C level was also observed in all risk categories. The mean LDL-C level decreased from 121.2 mg/dL to 109.7 mg/dL (P < .001), from 133.2 mg/dL to 113.2 mg/dL (P < .001), and from 125.9 mg/dL to 116.9 mg/dL (P < .001) in the high-, intermediate-, and low-risk categories, respectively.

According to 1999-2006 NHANES data, the prevalence of high LDL-C levels among persons aged 20 years or older decreased by approximately one-third from 1999-2000 to 2005-2006. 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 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 issues¹⁶ 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 11 552 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 high-potency 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 19 000 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 2005-2006 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 nuts²⁵ 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 high-risk 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 first-degree 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 4 different surveys over the 8-year span, but each one was a separate cross-sectional 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 1999-2000 to 2005-2006. In the most recent period, the prevalence was 21.2%.