Purpose and Previous U.S. Preventive Services Task Force Recommendation

The purpose of this report is to update prior reviews^1-3 conducted for the U.S. Preventive Services Task Force (USPSTF) on screening for lipid disorders in adults. It will be used by the USPSTF to update its 2008 recommendation.⁴

In 2008, the USPSTF strongly recommended lipid screening in all men age 35 years and older and in women age 45 years and older at increased risk for coronary heart disease (CHD) (A recommendation) based on good evidence that lipid-lowering drug therapy decreases the incidence of CHD events in persons with abnormal lipid levels, resulting in substantial absolute benefits.⁴ The USPSTF recommended screening in men ages 20 to 35 years and women ages 20 to 45 years with risk factors for CHD (B recommendation); due to the lower incidence of CHD events in these populations, screening results in lower expected benefits. The USPSTF made no recommendation for or against lipid screening in men ages 20 to 35 years or in women age 20 years and older not at increased risk (C recommendation) due to small expected benefits.

A difference between this update and prior USPSTF reviews on lipid screening is that it focuses on screening in younger adults (defined in this report as adults ages 21 to 39 years). The USPSTF restricted the scope of this update to younger adults because in older adults, lipid levels are obtained as part of routine cardiovascular risk assessment, and the decision to initiate statin therapy is often based on a global assessment of cardiovascular risk or presence of cardiovascular risk factors in addition to abnormal lipid levels. In younger adults, however, there is more uncertainty about the need to perform cardiovascular risk assessment, and lipid screening might identify those who would benefit from earlier interventions to reduce lipid levels.⁵

A separate evidence review has been commissioned by the USPSTF on the use of statins for the prevention of cardiovascular disease (CVD) in adults age 40 years and older.⁶

Condition Definition

Lipid disorders refer to abnormalities of cholesterol, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. The National Cholesterol Education Project (NCEP) Adult Treatment Panel III (ATP III) defined “optimal” LDL-C levels as less than 100 mg/dL and “high” as 160 mg/dL and greater; “desirable” total cholesterol (TC) levels as less than 200 mg/dL and “high” as 240 mg/dL and greater; “low” HDL-C levels as less than 40 mg/dL; and elevated triglycerides as greater than 150 mg/dL, although thresholds for treatment varied depending on the presence of risk factors for CVD.⁷

Prevalence and Burden of Disease/Illness

The prevalence of lipid disorders is high in the United States, with an estimated 53 percent (105.3 million) of adults affected.⁸ Specifically, 27 percent of Americans (53.5 million) have high LDL-C, 23 percent (46.4 million) have low HDL-C, and 30 percent (58.9 million) have high triglycerides. According to National Health and Nutrition Examination Survey data from 2003 to 2006, 13 percent of adults with high LDL-C, 22 percent of adults with high non–HDL-C, and 8 percent of adults with the combination of high LDL-C, low HDL-C, and high triglycerides were ages 20 to 34 years.⁸ In 2003 to 2004, 64 percent of adults ages 20 to 29 years and 57 percent of adults ages 30 to 39 years met NCEP-recommended lipid levels.⁹

Lipid disorders are associated with CHD, which may lead to sudden coronary death and myocardial infarction. Prevalence of CHD increases with age and is higher in men than in women of the same age.¹⁰ In 2010, the overall prevalence of CHD was 6.0 percent, and among persons ages 18 to 44 years, the age-adjusted prevalence was 1.2 percent.¹⁰ Prevalence of CHD varies by race/ethnicity, affecting 11.6 percent of American Indians/Alaska Natives, 6.5 percent of blacks, 6.1 percent of Hispanics, 5.8 percent of whites, and 3.9 percent of Asian/Pacific Islanders. For young adults ages 20 to 39 years, the prevalence of CVD, including all diseases of the circulatory system and congenital CVD, was 14.9 percent in men and 8.7 percent in women.¹¹

CHD is the leading cause of death in the United States.^12,13 In 2013, the American Heart Association (AHA) estimated that approximately 635,000 Americans would have a new myocardial infarction or CHD death and 280,000 would have a recurrent cardiovascular event, with an additional 150,000 persons having silent myocardial infarctions.¹⁴ The number of myocardial infarctions or fatal CHD events is estimated at 20,000 annually for men ages 35 to 44 years and 5,000 annually for women ages 35 to 44 years.¹⁴ In 2011, CHD caused 12 percent of deaths in persons ages 25 to 44 years.¹³ Estimates based on Framingham Heart Study participants from 1971 to 1996 indicate that the lifetime risks (through age 80 years) of CHD for 40-year-old men with a TC level of 200, 200 to 239, and 240 mg/dL and greater were 31, 43, and 57 percent, respectively, with 10-year cumulative risks of 3, 5, and 12 percent. For younger adults, data from the Chicago Heart Association study (from 1967 to 1973), with mortality followup in 2002, estimated 10-year CHD mortality in the highest-risk decile as 0.58 percent in those ages 18 to 29 years and 1.72 percent in those ages 30 to 39 years.¹⁵

In 2010, heart disease was associated with 972 age-adjusted potential life-years lost per 100,000 persons younger than age 75 years.^16,17 In 2008, heart disease and stroke accounted for nearly $300 billion in health care costs.¹⁸

Etiology and Natural History

Cholesterol is a lipid that is present in all animal cells; it is vital to cell membrane structure and acts as a precursor to vitamin D, adrenal and gonadal steroid hormones, and bile acids.¹⁹ The body is able to absorb dietary cholesterol and also synthesize it de novo. In a typical Western diet, cholesterol intake is about 300 to 450 mg per day and endogenous cholesterol amounts to 800 to 1,400 mg per day. A total of 1,000 to 2,000 mg of cholesterol can be absorbed by the small intestine. Plasma cholesterol levels depend on many factors, including diet and genetics. In the general population, there is great variability in how cholesterol is synthesized and absorbed. Plasma cholesterol levels are the sum of intestinal cholesterol absorption and hepatic cholesterol synthesis balanced by net biliary excretion and cell use.

Cholesterol is transported in the body as particles of lipid and protein (lipoproteins).⁷ There are three classes of lipoproteins: LDL-C, HDL-C, and very low-density lipoprotein cholesterol (VLDL-C). LDL-C makes up 60 to 70 percent of total serum cholesterol, HDL-C contributes 20 to 30 percent, and VLDL-C contributes 10 to 15 percent. LDL-C is the primary atherogenic lipoprotein and is the primary target of cholesterol-lowering therapy, although some forms of VLDL-C are precursors to LDL-C and promote atherosclerosis. HDL-C is inversely related to risk for CHD.

LDL-C is atherogenic when it accumulates in blood vessels, contributing to plaque formation. The fully developed plaque consists of a core of cholesterol, surrounded by a capsule of connective tissue.²⁰ The plaque core is surrounded by foam cells, which are macrophages containing intracytoplasmic cholesterol. These cells produce procoagulant and inflammatory cell mediators. Early-stage plaque formation is not associated with structural damage to the endothelium, but later-stage plaque formation leads to endothelial erosion that exposes the underlying connective tissue and allows platelets to adhere to the site, potentially leading to plaque smooth muscle cell growth through release of growth factor. Further endothelial erosion and disruption contribute to thrombus formation. As the thrombus builds, blood flow sends clumps of platelets into the distal small arteries as emboli and the thrombus may continue to grow until it occludes the artery, resulting in myocardial infarction, cerebrovascular accident (CVA), or another ischemic event. Endothelial erosion and disruption result from enhanced inflammatory activity within the plaque produced by smooth muscle cells and macrophages. Certain plaque characteristics such as a large lipid core, high density of macrophages, and low density of smooth muscle cells in the cap are markers of plaques that are more likely to undergo thrombosis. The risk of a person with coronary artery disease having a future thrombogenic event is more associated with the presence and number of vulnerable plaques than the total number of plaques.

Exposure to nonoptimal lipid levels in young adulthood is associated with atherosclerotic changes later in life. One prospective cohort study of 2,824 persons ages 18 to 30 years with nonoptimal levels of LDL-C (defined as ≥100 mg/dL) at baseline found an association between cumulative exposure to higher LDL-C or lower HDL-C levels and markers of atherosclerosis two decades later.²¹

Persons with familial hypercholesterolemia may have dramatically high levels of LDL-C, which can lead to accelerated atherosclerosis and, if untreated, early cardiovascular death.^22-24 Familial hypercholesterolemia is caused by mutations in the LDL receptor gene, which reduce the number of LDL-C receptors or prevent LDL-C from binding to these receptors, thereby reducing LDL-C removal from the blood. Patients with two mutated copies of the LDL receptor gene have the homozygous form of familial hypercholesterolemia. This condition is rare, with a prevalence of about 1 in 1,000,000.²⁵ The characteristic clinical presentation includes skin and tendon xanthomas, TC levels of 500 to 1,000 mg/dL, and the onset in childhood of symptomatic coronary disease as well as aortic valve and proximal root disease.^26,27 The heterozygous form of familial hypercholesterolemia is more common, with a prevalence of approximately 1 in 500 in the United States and United Kingdom. TC levels in persons with heterozygous familial hypercholesterolemia are less highly elevated than in those with homozygous familial hypercholesterolemia, averaging 325 to 450 mg/dL, but patients are also at increased risk for CHD and death in young adulthood due to prolonged exposure to high lipid levels that often starts in childhood.²³ The estimated proportion of persons with familial hypercholesterolemia who would have an early-onset CHD event in the absence of recognition and treatment is 5 to 15 percent in men younger than age 35 years and 10 to 15 percent in women younger than age 45 years.^28,29 Many patients with severe hypercholesterolemia do not have an identifiable genetic defect.²⁴ Evidence suggests that the clinical consequences of severe hypercholesterolemia are the same regardless of the underlying cause.

Risk Factors

Risk factors for dyslipidemia (high LDL-C, low HDL-C, high triglycerides) include physical inactivity, obesity, abdominal obesity, metabolic syndrome, hypertension, atherogenic diet (high in saturated fatty acids, cholesterol, and sodium), consumption of added dietary sugars, genetic factors (including family history of familial hypercholesterolemia), older age, male sex, and hypothyroidism.^7,8,30,31 Elevated triglycerides are associated with overweight and obesity, physical inactivity, smoking, excess alcohol intake, high carbohydrate diet, other diseases such as diabetes and nephritic syndrome, medications such as corticosteroids or estrogens, and genetic factors.⁷ Hyperlipidemia is also associated with HIV infection, renal transplant, and use of antipsychotic medications and protease inhibitors.^32-34

Dyslipidemia is a risk factor for CHD.⁷ Other modifiable risk factors for CHD include hypertension, smoking, thrombogenic/hemostatic state, diabetes, obesity, physical inactivity, and atherogenic diet. Nonmodifiable risk factors include age (≥45 years in men, ≥55 years in women), male sex, and family history of early-onset CHD.

Non–HDL-C (i.e., TC minus HDL-C) is a measure that includes all potentially atherogenic lipoprotein particles (LDL, VLDL, intermediate-density lipoprotein, and lipoprotein[a]) that may be a more accurate predictor of CHD risk than LDL-C.^32,34,35 Apolipoprotein B is a direct measure of the total number of atherogenic particles, although it is unclear whether it adds to HDL-C and TC as a marker of CHD risk.^34,36-39 In addition, TC and HDL-C are easier and less costly to measure. Other potential risk factors for CVD include alternative measures of lipid status, such as TC-to-HDL-C ratio or other lipoprotein levels, and nonlipid factors, such as inflammatory markers (e.g., C-reactive protein,⁴⁰ homocysteine) and thrombogenic factors (e.g., fibrinogen, antithrombin III, factor V Leiden).⁷

In 2008, the USPSTF recommended screening with a fasting or nonfasting HDL-C level and either TC or a measure of LDL-C.⁴ In 2009, a USPSTF evidence review of nine emerging risk factors, including C-reactive protein, leukocyte count, homocysteine levels, and lipoprotein levels, found that evidence was insufficient to support the use of these risk factors to reclassify persons at intermediate risk for CHD as high risk, although it found that evidence for C-reactive protein was promising.⁴⁰ Clinical practice guidelines continue to predominantly focus on LDL-C as the primary lipid risk factor.

Rationale for Screening/Screening Strategies

Due to the asymptomatic nature of lipid disorders, screening is required for detection. Detection of younger adults with lipid disorders could enable implementation of management strategies such as lifestyle modification or medications that could prevent negative cardiovascular outcomes in persons at immediate risk for an event or decrease risk of future events. Screening could be of particular benefit for identification of young adults with markedly elevated lipid levels due to unrecognized familial hypercholesterolemia.

Screening involves blood tests that may be obtained in a fasting or nonfasting state. Although current recommendations generally recommend testing TC and LDL-C levels, they differ on the inclusion of other lipid components, the age at which to start testing, and the frequency of screening (see the “Recommendations of Other Groups” section).

Interventions/Treatment

Standard treatments for lipid disorders in adults include use of medications, diet, exercise, or a combination of these interventions. Prior to 2013, treatment in the United States generally followed recommendations from the Third Report of the NCEP ATP III, which recommended global cardiovascular risk evaluation, including measurement of lipids starting at age 20 years, to guide decisions regarding use of lipid-lowering therapy.⁷ LDL-C thresholds for initiation of lipid-lowering therapy following lifestyle intervention efforts varied from 130 mg/dL and greater to 190 mg/dL, depending on the assessed risk category (low: 10-year CVD event risk <10%; intermediate: 10% to 20%; high: >20%). Drug options for lipid reduction included statins, bile acid sequestrants, nicotinic acid, and fibrates, although statins were designated as the initial drug of choice given its proven efficacy for reducing LDL-C levels and evidence showing improved clinical outcomes. Statin or other lipid-lowering therapy was targeted to achieve LDL-C levels varying from less than 100 mg/dL to less than 160 mg/dL, depending on the risk category.

Updated guidelines issued in 2013 from the American College of Cardiology (ACC) and the AHA on lipid-lowering therapy differ from those of ATP III in a number of ways. In the new guidelines, statins are the recommended first-line lipid-lowering therapy to reduce CVD risk, as evidence on its effectiveness in improving clinical outcomes is strongest.²⁷ Target populations for statin therapy were redefined as four groups: persons with clinical CVD, persons ages 40 to 75 years with diabetes and LDL-C levels of 70 to 189 mg/dL, persons with LDL-C levels of 190 mg/dL or greater, or persons ages 40 to 75 years with an estimated 10-year CVD risk of 7.5 percent or greater. For patients in the latter group who do not meet criteria for one of the other target populations, a clinician-patient risk discussion is recommended prior to initiation of statin therapy. Rather than managing statin therapy to achieve a target LDL-C level, the ACC/AHA recommends fixed-dose statin therapy, with the intensity (based on the dose and potency of the statin used and, thus, the expected degree of LDL-C reduction) of therapy determined by the risk profile. The updated guidelines also recommend the use of a newly developed global risk calculator to estimate risk.

For patients with familial hyperlipidemia, the National Lipid Association recommends lifestyle modification, moderate- to high-potency statins as first-line drug therapy (alternative drugs or combination therapy is recommended for persons who cannot tolerate statins or do not meet a LDL-C reduction target of ≥50% from baseline), and LDL apheresis in high-risk patients who do not meet lipid targets after lifestyle modification and drug therapy.⁴¹

Current Clinical Practice in the United States

A study based on 1996 to 2006 National Health and Nutrition Examination Survey data from 2,587 adults ages 20 to 45 years found overall lipid screening rates of less than 50 percent.⁴² Screening rates varied based on the presence of cardiovascular risk factors. Lipid testing rates were 68 percent in adults with CHD or CHD equivalents, 47 percent in those with two or more risk factors, 45 percent in those with one risk factor, and 42 percent in those with no known risk factors. The presence of CHD or a CHD equivalent was associated with increased likelihood of screening compared with presence of no risk factors (relative risk, 1.5 [95% confidence interval (CI), 1.1 to 2.2]). In addition, women were more likely to have undergone screening compared with men. Among women with CHD or a CHD equivalent, two or more risk factors, one risk factor, or no risk factors, screening rates were 69, 53, 52, and 49 percent, respectively; corresponding rates for men were 64, 38, 36, and 30 percent, respectively.^4,43 A study based on a 2005 National Ambulatory Medical Care Survey found disparities in rates of lipid screening in adults age 20 years and older, with higher rates in whites (40%) versus blacks (33%) or Hispanics (39%).⁴⁴ Results were not reported separately for younger adults.

Healthy People 2020 has set a target screening rate of 82 percent within the last 5 years for persons older than age 18 years (an increase from 75% in 2008).⁴⁵

Recommendations of Other Groups

Recommendations for lipid screening in young adults without risk factors for CHD vary, with some guidelines recommending screening starting at age 20 years and others not recommending screening until ages 35 to 40 years for men or 40 to 50 years for women. In general, guidelines recommend screening younger adults with CHD, CHD equivalents, or one or more CHD risk factors.

The ATP III guidelines recommend screening all persons age 20 years and older every 5 years with LDL-C, HDL-C, TC, and triglycerides.⁷ It recommends that clinicians perform a lipoprotein analysis and risk factor evaluation to assign risk status as part of the first patient visit for adults age 20 years and older and, depending on the results, initiate efforts to control risk factors, with re-evaluation in 1 to 5 years, or initiate lifestyle changes.⁷

The ACC and AHA guidelines do not specifically address lipid screening but recommend, “as reasonable,” assessment of traditional cardiovascular risk factors every 4 to 6 years starting at age 20 years (grade IIa recommendation).⁵ Although the Pooled Cohort Equations risk calculator developed by the ACC and AHA estimates lifetime risk of atherosclerotic CVD in persons age 20 years and older, the guidelines do not make any recommendation to apply the risk calculator to persons younger than age 40 years.

The American Diabetes Association recommends lipid screening in patients with diabetes at least annually, and every 2 years for adults with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and triglycerides <150 mg/dL).⁴⁶

The European Society of Cardiology and the European Atherosclerosis Society recommend risk-level–based screening depending on various risk factors (e.g., diabetes, established CVD, hypertension, smoking, body mass index >30 kg/m², family history of premature CVD and familial dyslipidemia, chronic inflammatory disease, chronic kidney disease). Assessment of lipid levels may be considered in men older than age 40 years and women older than age 50 years.⁴⁷

The Canadian Working Group on Hypercholesterolemia and Other Dyslipidemias recommends screening in men older than age 40 years, postmenopausal women, women older than age 50 years, and patients with diabetes mellitus, hypertension, smoking, abdominal obesity, strong family history of premature CVD manifestations of hyperlipidemia (e.g., xanthelasma, xanthoma, or arcus corneae), or evidence of symptomatic or asymptomatic atherosclerosis, as well as any patient for whom “lifestyle changes are indicated.” This group further recommends use of the NCEP ATP III risk estimation algorithm, with LDL-C level and TC-to-HDL-C ratio as targets.⁴⁸

The American Academy of Family Physicians concurs with current USPSTF recommendations.⁴⁹

The American College of Physicians Web site refers to an inactive guideline from 1996 recommending screening in men older than age 35 years and women older than age 45 years for TC levels.⁵⁰