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Last Updated: 8/4/2014  

Lipid Disorders (Dyslipidemia)

Screening
  • Screen high-risk adults, all men aged 35 or older, and women aged 45 or older for lipid disorders by checking either a fasting lipid profile or total cholesterol and HDL. Screen low-risk adults every 5 years.

Diagnosis
  • Use history to identify individuals who should be targeted for lipid treatment, determine treatment thresholds and goals for therapy, and classify patients as:

    • CHD or CHD high risk equivalent, and consider very high risk if the patient also has uncontrolled major CV risk factors

    • Intermediate risk, with features suggesting higher than expected short- and long-term CHD risk (e.g., atherosclerosis imaging studies, inflammatory or lipoprotein markers)

    • Low risk

    • Severe lipid (cholesterol) disorder, suggesting high lifetime CHD risk

  • Check a fasting lipid profile to diagnose lipid disorders.

  • Evaluate for diabetes.

  • Calculate CV risk using updated pooled cohort equation or alternative risk tools.

  • Consider additional lab and other studies in select patients at moderate CV risk with either abnormal lipid profiles or unclear need for drug therapy, including:

    • Imaging for atherosclerosis (coronary artery calcium score by CT or carotid intima-media thickness by ultrasound) to help stratify CV risk in moderate-risk individuals

    • Tools such as high-sensitivity C-reactive protein, lipoprotein-(a), lipoprotein phospholipase A2, and others

  • Rule out secondary causes of lipid disorders.

Therapy
  • Initiate dietary therapy with a Mediterranean diet and recommend exercise for all patients, unless they have an overriding medical condition that warrants a different type of diet (e.g., hyperchylomicronemia responds better to a fat-restricted diet).

  • Obtain formal nutrition consultation for individuals with severe hypertriglyceridemia (hyperchylomicronemia).

  • Treat patients requiring drug therapy with statin drugs as the foundation for prevention of atherosclerotic CV disease.

  • Begin statin therapy based on patients' CV risk:

    • In patients with known CV disease, provide a high-intensity statin unless contraindicated or not tolerated.

    • In patients with LDL ≥190 mg/dL, provide a high-intensity statin unless contraindicated or not tolerated.

    • In patients aged 40 to 75 with diabetes, but no known CV disease, provide moderate-intensity or high-intensity statin therapy.

    • Treat other patients according to the calculated risk for CV disease, providing a high-intensity statin to patients aged 40 and 75 with at least a 10% calculated 10-year risk.

  • Use medications to lower triglycerides in patients with severe hypertriglyceridemia/hyperchylomicronemia to prevent pancreatitis, with fibrates and/or high dose omega-3 fatty acids (fish oil).

  • Individualize therapy and consider combination drug therapy (e.g., statin plus nonstatin) in specific patients.

Recommend lifestyle changes that will positively affect the lipid profile and optimize cardiac risk-factor status. 
  • Recognize that lifestyle measures can have a significant impact on CV risk, cardiometabolic risk factors, and lipid/lipoprotein levels.

  • Recommend that patients:

    • Follow a diet balanced in calories and containing <35% of calories from fat, <7% of calories from saturated fat, and <200 mg of cholesterol per day.

    • Eliminate trans fats.

    • Increase intake of vegetables, fruits, and high-fiber foods.

    • Enhance LDL lowering by eating foods enriched with plant stanols (2 g/d) and increased viscous (soluble) fiber (10 to 25 g/d).

    • Exercise aerobically on most and preferably all days of the week for at least 30 minutes per session.

    • Attain and maintain ideal body weight.

    • Avoid all forms of tobacco.

    • Consume no more than one to two alcoholic beverages per day.

Evidence
  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of CV risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruit, vegetables, and whole grains; and which includes low-fat dairy, poultry, fish, nuts, and nontropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times a week (1).

  • A 2006 guideline from the AHA recommended dietary and lifestyle goals, including exercise, not smoking, healthy body weight, and a healthy low-fat diet with fruits and vegetables, a variety of grains, and fatty fish (2).

  • A 2003 guideline from the U.S. Preventive Services Task Force on behavioral dietary counseling in patients with risk factors for CV disease recommended intensive dietary counseling in primary care for patients with hyperlipidemia and other risk factors for CV disease.

  • A 2012 partial update of the 2003 U.S. Preventive Services Task Force guideline addressed behavioral counseling for healthy patients and recommended selective behavioral counseling, noting that the impact of behavioral counseling in healthy patients is small (3).

Rationale
  • Preventing development of nonlipid CV risk factors will keep the patient at lower risk, requiring less aggressive lipid-lowering diet and drug therapy.

  • Increasingly healthy lifestyles should reduce population-wide lipid levels and reduce the need for dietary counseling and drug therapy.

Screen high-risk adults, all men aged 35 or older, and women aged 45 or older for lipid disorders. Screen low-risk adults every 5 years. 
  • Screen for lipid disorders in:

    • Adults at any age who are at risk for CHD, including those with a family history of hyperlipidemia

    • All men aged 35 or older

    • Women aged 45 or older

  • Screen using a fasting lipid panel when possible.

    • If fasting is not feasible, check a nonfasting lipid panel and base treatment decisions on triglycerides and non-HDL cholesterol (total cholesterol minus HDL).

  • Perform screening every 5 years in patients without new risk factors for CHD; consider repeat screening sooner in those who develop new risk factors.

  • Do not perform annual lipid screening in patients not treated for hyperlipidemia unless there is a specific reason to suspect a change.

  • Stop screening in patients with short life expectancy or who would not tolerate drug therapy, including some elderly patients.

  • See module Screening for Dyslipidemia.

Evidence
  • A 2013 guideline from the ACC/AHA on the assessment of CV risk stated that it is reasonable to assess CV risk factors, including cholesterol, every 4 to 6 years in adults aged 20 to 79 who do not have known CV disease (4).

  • A 2008 recommendation statement from the U.S. Preventive Services Task Force recommended screening all men age 35 and older and other adults with risk factors for CHD. The guideline did not recommend routine screening in women at any age without additional risk factors.

  • A 2011 guideline from the National Lipid Association recommended universal screening for familial lipid disorders. The guideline recommended considering cholesterol screening beginning at age 2 for children with a family history of premature CV disease or elevated cholesterol, and advocated screening all individuals by age 20 (5).

  • A 2013 Cochrane review of statins for the primary prevention of CHD included 18 randomized trials. Statins reduced mortality (OR, 0.86 [CI, 0.79 to 0.94]), CHD (OR, 0.73 [CI, 0.67 to 0.80]), and stroke (OR, 0.78 [CI, 0.68 to 0.89]) (6).

  • A 2000 meta-analysis evaluated the effect of lipid-lowering therapies for the primary prevention of CHD and mortality. Drug therapy reduced rates of CHD (OR, 0.70 [CI, 0.62 to 0.79]) but not overall mortality (7).

  • A 1989 reanalysis of cohort studies confirmed that HDL is inversely related to rates of CHD (8).

  • A randomized trial compared risk-factor screening and education to no intervention in a population-based sample. After 1 year, the screened and counseled group had slightly lower cholesterol and BP than control patients and reported higher rates of health-food choices (9).

  • The West of Scotland Coronary Prevention Study (10; 11), the Air Force/Texas Coronary Atherosclerosis Prevention Study (12; 13), and the JUPITER trial (14) were primary prevention studies of statin therapy in asymptomatic, middle-aged men and women with abnormal lipid profiles but relatively normal CV risk (high LDL, low HDL, and normal LDL/elevated high-sensitivity C-reactive protein, respectively). Primary prevention reduced the incidence of symptomatic CHD (angina, MI).

  • Large randomized, controlled trials of elderly hypercholesterolemic patients have shown benefit to treating patients over age 65 (15; 16).

  • Numerous prospective epidemiologic studies have related increased total cholesterol with CHD incidence, including those in young adults (17) and in the elderly (18).

Rationale
  • Elevated total cholesterol and LDL, and low HDL, are risk factors for CHD, with the highest risk in patients with multiple risk factors.

  • A nonfasting specimen can be used when fasting is not practical or safe, but triglycerides have to be interpreted accordingly. Non-HDL cholesterol can be used in a nonfasting specimen to guide therapy when the triglycerides are >150 mg/dL.

Comments
  • For patients with MI, PTCA, or a major surgical event, such as CABG, draw a fasting lipid profile within 24 hours. If this is not possible or if more than 24 hours have elapsed since the event, wait 6 to 8 weeks to draw the lipid profile because HDL can be lower during the acute event and may not reflect the baseline lipid status accurately.

  • In patients with acute cardiac events, if LDL is >100 to 130 mg/dL, start the patient on lipid-lowering therapy before discharge.

Screen patients hospitalized for acute CV events for hyperlipidemia. 
  • Obtain fasting lipid profile within 24 hours of onset of symptoms unless baseline lipid levels are currently established.

  • If lipid values are not drawn in a timely fashion immediately after the acute coronary event, wait at least 6 to 8 weeks to draw fasting lipid profile.

  • Make treatment decisions about hyperlipidemia during hospitalization or soon after discharge.

  • Use the acute care phase to educate patients about health behaviors.

  • Consider initiating high-dose, high-potency statin therapy in patients with acute coronary syndromes and making appropriate dosage adjustments later.

Evidence
  • The 2013 ACCF/AHA guidelines for the management of acute ST-elevation MI recommended starting high-intensity statin therapy during the hospitalization and stated that it was reasonable to check a fasting lipid profile, preferably within 24 hours of presentation (19).

Rationale
  • Lipid levels will not be accurate after 24 hours following an acute coronary event due to the mobilization of free fatty acids, which alter LDL and HDL.

  • Identification of lipid parameters and education about the importance of treatment with statin therapy in the acute care setting can improve adherence to drug therapy.

Comments
  • Adherence to a lipid-lowering drug regimen in patients with CHD may be enhanced by incorporation into an acute care regimen.

Use history to identify the need for therapy. 
  • Obtain a history of atherosclerotic CV disease, including:

    • Coronary disease, including MI, angina, and history of CABG or PTCA

    • Peripheral vascular disease or history of arterial revascularization

    • Stroke or TIA

  • Ask patients about diabetes and consider screening at-risk patients.

  • Assess for the presence of other CHD risk factors, including:

    • Age/sex (male 45 or older; female 55 or older)

    • Family history of premature coronary disease in a first-degree relative (CHD in male first-degree relative under age 55; CHD in female first-degree relative under age 65)

    • Current cigarette smoking

    • Hypertension (BP >140/90 mm Hg or on antihypertensive medications)

    • History of HDL <40 mg/dL

    • History of HDL >60 mg/dL (considered a negative risk factor, allowing the risk factor number to be reduced by one)

  • Use a risk calculator to assess risk in patients aged 40 to 75 without known atherosclerotic disease, using:

  • Classify patients by their need for high- or moderate-intensity statin therapy:

    • Treat patients with high-intensity statin therapy if they:

      • Are under age 75 with CHD, peripheral arterial disease, stroke or TIA

      • Have LDL ≥190 mg/dL

      • Are aged 40 to 75 with diabetes plus calculated 10-year CHD risk ≥7.5%

    • Consider high-intensity statin therapy in some nondiabetic patients with LDL <190 mg/dL and calculated 10-year CHD risk ≥7.5%.

    • Treat patients with moderate-intensity statin therapy if they are:

      • Aged 40 to 75, with diabetes, with calculated 10-year CHD risk <7.5%

      • Nondiabetic with LDL <190 mg/dL and calculated 10-year CHD risk ≥7.5%

      • (Possibly) nondiabetic with LDL <190 mg/dL and calculated 10-year CHD risk ≥5% but <7.5%

  • See table Approach to Statin Therapy in Different Risk Groups.

  • See figure Estimate of 10-Year Risk for Men and Women (Framingham Point Scores).

Evidence
  • A 2013 guideline from the ACC/AHA on the assessment of CV risk recommended using the age- and race-specific pooled cohort equations to estimate each patient's risk for CV disease (4).

  • A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for CV disease recommended high-intensity statin therapy for patients with known CV disease, moderate-intensity statin therapy for patients with diabetes, and therapy based on the calculated risk for CV events in the rest of the population aged 40 to 75 (20).

  • A retrospective study validated the Pooled Risk Equations in patients from a prospective cohort study in whom risk assessment would change statin prescribing. Among patients with estimated 10-year risk for CV disease <5%, the 5-year estimated and observed risks for CV disease were both 1.9/1000 person-years; among patients with estimated 10-year risk for CV disease between 5% and 7.5%, the 5-year estimated and observed risks were both 4.8/1000 person-years; among patients with estimated 10-year risk for CV disease between 7.5% and 10%, the estimated and observed risks were 6.1/1000 person-years and 6.9/1000 person-years, respectively; and among patients with estimated 10-year risk for CV disease 10% or greater, the estimated and observed risks were 12.0/1000 person-years and 15.1/1000 person-years, respectively (21).

  • A study evaluated the accuracy of the Framingham risk score for predicting CHD in six prospectively studied cohorts which included ethnic minority patients. The Framingham risk score was predictive of CHD events in whites and blacks (both men and women), although the standard version of the tool overestimated risk in men of Japanese and Hispanic descent and women of Native American descent (22).

Rationale
  • Absolute risk for coronary events associated with a given lipid profile increases rapidly in the presence of additional CHD risk factors.

Comments
  • Drug therapy for individuals with high or moderate risk should be prescribed. There is an overwhelming level of evidence supporting the use of statin therapy in favor of other nonstatin therapies; however, there are certain conditions and circumstances that would warrant the use of nonstatin therapies to achieve LDL and non-HDL cholesterol goals.

Check a fasting lipid profile to diagnose lipid disorders. 
  • Obtain a lipid profile after an overnight (approximately 12 hours) fast.

  • If the patient is not fasting, consider either a second visit for a lipid profile or check in the nonfasting state. If nonfasting lipids are abnormal, repeat a fasting profile.

  • Calculate the LDL profile using the Friedewald equation (LDL = total cholesterol − HDL − [triglycerides ÷ 5]) if the lab does not provide the result.

    • Recognize that there is more variance between calculated and directly measured LDL when triglycerides are >200 mg/dL and that calculated LDL is not reliable when triglycerides are >400 mg/dL.

  • Calculate the non-HDL cholesterol by subtracting HDL from total cholesterol. This result represents the net cholesterol content found in atherogenic lipoproteins (LDL, IDL, VLDL, and chylomicron remnants).

  • See table Elective Laboratory Elements for Evaluation of Selected Lipid Disorders after Initial Evaluation.

  • See table Approach to Statin Therapy in Different Risk Groups.

Evidence
  • A prospective cohort study evaluated the association between LDL and mortality from CV disease in 13,850 adults with and without preexisting heart disease. In the multivariate model, compared to patients with LDL <130 mg/dL, LDL ≥160 mg/dL was associated with greater risk for CV death in patients with baseline heart disease (adjusted HR, 5.92 [CI, 2.59 to 13.51]) than in those without heart disease at baseline (adjusted HR, 2.43 [CI, 1.15 to 5.13]) (23).

Rationale
  • The fasting lipid profile is the accepted method for detecting hyperlipidemia.

  • Under normal physiologic conditions, chylomicrons are effectively cleared from the circulation after a 12-hour fast.

Consider additional lab and other studies in select patients with either abnormal lipid profiles or unclear need for drug therapy.  
  • Check ALT before starting statin therapy.

  • Consider checking direct LDL in patients with fasting triglycerides >400 mg/dL if type III hyperlipoproteinemia is suspected. Otherwise, base treatment decisions on non-HDL cholesterol.

  • Consider checking apolipoprotein B in patients with elevated triglycerides or low HDL with normal LDL.

  • Consider checking LDL particle number in patients with elevated triglycerides or low HDL with normal LDL.

  • Consider checking apolipoprotein A-1 in patients with low HDL, in consultation with a lipid specialist to guide diagnosis and treatment decisions.

  • Consider checking lipoprotein-(a) in patients with known CHD if the result would affect the decision to use secondary lipid lowering drugs, and/or to evaluate CV risk in an individual who does not have apparent risk factors despite developing premature atherosclerotic CV disease.

  • Consider further testing in patients at intermediate risk (LDL <190 mg/dL and 10-year estimated risk <7.5% without diabetes or known atherosclerotic disease) if results will affect treatment decisions.

    • Consider atherosclerosis imaging with coronary artery calcium scoring by CT or carotid intima media thickness by ultrasound in appropriately selected patients; the choice of test should be dictated by patient characteristics and preferences.

    • Consider checking an ankle-brachial index in older individuals whose apparent risk for CHD events is calculated lower than expected, because a low ankle-brachial index would necessitate treatment as atherosclerotic CV disease.

    • Do not perform further testing in individuals who meet criteria for high-intensity statin therapy.

    • Consider checking C-reactive protein in patients with lipid levels near goal in whom an abnormal result would lead to drug therapy.

  • See table Elective Laboratory Elements for Evaluation of Selected Lipid Disorders after Initial Evaluation.

Evidence
  • A 2013 guideline from the ACC/AHA on the assessment of CV risk recommended looking for secondary causes of hyperlipidemia in patients with LDL ≥190 mg/dL and triglycerides ≥500 mg/dL. The guideline stated that it is reasonable to check C-reactive protein, calcium score, ankle-brachial index, or to ask about family history in patients who do not clearly meet criteria for treatment, and recommended against measuring carotid intimal thickness. The guideline recommended checking ALT before starting statin therapy because patients with unexplained elevations may be at increased risk for hepatic toxicity (4).

  • A 2007 guideline from the AHA/ACCF on the use of coronary artery calcium scoring stated that it is reasonable to use coronary artery calcium scoring before initiating drug therapy in intermediate-risk patients in whom results may change management. The guideline recommended against use of the test in low-risk patients (24).

  • A 2003 statement from the CDC and the AHA on the use of C-reactive protein measurement recommended considering checking C-reactive protein in patients at intermediate risk for CHD in whom the value would alter management (25).

  • A 2004 systematic review of the prognostic significance of coronary artery calcium scoring included four studies. An abnormal calcium score between 1 and 100 was associated with an increased risk for CHD events (RR, 2.1 [CI, 1.6 to 2.9]) (26).

  • A 2007 population-based cohort study measured the predictive value of a variety of cholesterol measurements. An apolipoprotein B:apolipoprotein A-1 was predictive of CHD but did not add predictive value to a standard risk factor-based model (27).

  • A randomized trial found that, compared with placebo, rosuvastatin decreased morbidity in patients with high C-reactive protein and borderline or normal LDL (14).

Rationale
  • Further testing may occasionally change risk assessment and alter management.

Identify triglycerides and HDL as markers of CV risk.  
  • Stratify patients, based on fasting triglycerides, into the following risk groups:

    • Normal (triglycerides <150 mg/dL)

    • Borderline high (triglycerides 150 to 199 mg/dL)

    • High (triglycerides 200 to 499 mg/dL)

    • Very high (triglycerides >500 mg/dL)

  • Recognize low HDL (<40 mg/dL) as a marker of CV risk.

  • Identify non-HDL cholesterol (total cholesterol − HDL) as a marker of CV risk in persons with high triglycerides (≥200 mg/dL).

Evidence
  • A study pooled data from 17 trials to evaluate the independent association between triglycerides and CHD risk in white, mostly male, populations. When controlling for other factors, including LDL and HDL, the pooled RR of CHD was 1.14 for each 1-mmol/L increase in triglycerides in men and 1.37 for each 1-mmol/L increase in women (28).

  • A pooled analysis of 302,430 patients evaluated the prognostic significance of HDL. Higher HDL was associated with lower risk for CHD in the adjusted analysis, with an HR of 0.78 (CI, 0.74 to 0.82) for each standard deviation in HDL measurement (29).

Rationale
  • Elevated triglycerides may identify persons with other metabolic problems in need of intervention (e.g., diabetes, alcoholism, CKD, and nephrotic syndrome).

  • Very high triglycerides (>500 mg/dL) are associated with high risk for pancreatitis due to hyperchylomicronemia, and triglycerides should be lowered to reduce that risk.

Comments
  • In individuals with triglycerides <500 mg/dL, triglycerides are not a target for therapy. The primary goals are LDL and then non-HDL cholesterol levels.

  • Individuals with moderately high triglycerides (<500 mg/dL) tend to have familial abnormalities of triglyceride-rich lipoprotein metabolism in which there is hepatic overproduction of triglyceride-rich lipoproteins or reduced clearance of triglyceride-rich lipoproteins. Persons with elevated triglycerides are more likely to have the metabolic syndrome.

  • If LDL and non-HDL cholesterol goals are met, but triglycerides are still elevated, there may be residual CV risk and other lipoprotein markers should be considered (e.g., LDL particle number or apolipoprotein B) to determine whether there is a role for intensification of therapy.

  • HDL <40 mg/dL identifies a greater risk for CHD in men than in women.

Rule out secondary causes of lipid disorders in patients with triglycerides ≥500 mg/dL and/or LDL ≥190 mg/dL. 
  • Obtain history, physical exam, and appropriate lab tests to identify major secondary causes of the lipid disorder, including:

    • Elevated LDL:

      • Hypothyroidism

      • Obstructive liver disease

      • Nephrotic syndrome

      • Medications: diuretics (not common), cyclosporine, glucocorticoids

      • Menopause

    • Low HDL:

      • Inactivity

      • Type 2 diabetes

      • Medications: androgenic steroids, proestrogens, thiazides, β-blockers (without intrinsic sympathetic activity), combination of fibric acid derivative and thiazolidinedione (rare)

      • Renal failure

      • Smoking

      • Discontinuation of habitual alcohol intake

      • Hematologic malignancies, especially multiple myeloma

      • Ongoing infection or inflammatory disease process (particularly rheumatologic diseases)

      • Acute illness

    • High triglycerides:

      • Medication: retinoic acid derivatives (e.g., Accutane), antiretroviral therapy (protease inhibitors), oral estrogens, corticosteroids, thiazides, β-blockers (other than carvedilol), antipsychotics, and immunosuppressants; bile acid sequestrants in susceptible individuals

      • Uncontrolled diabetes mellitus

      • Nephrotic syndrome

      • Lipodystrophies

      • Alcoholism

      • Hypothyroidism

      • Excessive dietary consumption of high-calorie, sugar-sweetened beverages and other dietary excesses

  • Look for signs of very high lipids on physical exam, including xanthelasmas and xanthomas.

  • See table Differential Diagnosis of Low HDL Cholesterol.

  • See table Differential Diagnosis of Elevated LDL Cholesterol.

  • See table Differential Diagnosis of Elevated Triglycerides.

  • See table Fredrickson-Levy Classification of Elevated LDL Cholesterol.

  • See table Xanthomas, Associated Dyslipidemia, and Associated Diseases.

  • See figure Xanthelasma.

  • See figure Tuberous Xanthoma.

Evidence
  • A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for CV disease identified commonly encountered secondary forms of hyperlipidemia (20).

  • A chart review of 824 patients in a lipid disorders clinic identified secondary causes in 28% of patients. The most common secondary causes were excessive alcohol intake, diabetes, and albuminuria (30).

  • A 1995 narrative review of diabetic dyslipidemias noted that the most common abnormality is hypertriglyceridemia with low HDL (31).

Rationale
  • Secondary causes should be treated and controlled before initiation of drug therapy to modify lipid abnormalities, because the lipid abnormality may disappear with correction of the secondary cause, or lipid-lowering therapies will be generally ineffective in the presence of the abnormality.

Comments
  • Mild hypothyroidism can be associated with elevated LDL, but not typically marked elevation.

  • In the case of obstructive biliary/liver disease, total cholesterol is elevated due to production of lipoprotein X. This lipoprotein is not measured as part of the standard lipid profile and the calculated high cholesterol is erroneously attributed to LDL. The primary issue in this condition is to address the biliary/liver disease which is typically quite severe before cholesterol levels rise.

  • Consider the benefits vs. the harms of existing drugs that could possibly be contributing to the lipid disorder before discontinuing therapy (e.g., CHD patient requiring β-blocker therapy for secondary prevention of cardiac events vs. the potential LDL elevation).

  • Frederickson-Levy classifications have generally been supplemented by pathway-specific diagnoses, but still describe the phenotypic presentation of disorders.

Obtain consultation with a lipid specialist for patients with suspected familial hypercholesterolemia for further testing. 
  • For patients with LDL >190 mg/dL and a positive family history of lipid disorder or early-onset atherosclerosis, screen first-degree relatives with fasting lipid profiles.

  • If fasting triglycerides are >400 mg/dL, consider obtaining direct LDL and VLDL measurements. Type III hyperlipidemia is characterized by a direct VLDL:triglyceride ratio >0.3 and can be distinguished from familial combined hyperlipidemia by this measurement.

Evidence
  • A 1998 narrative review noted that <50% of patients with familial hypercholesterolemia are diagnosed, with even fewer treated and controlled, despite a poor prognosis (average age of MI is 46) and the availability of effective drug therapy (32).

Rationale
  • Lipid specialists are more comfortable than general practitioners with the diagnosis of rare familial lipid disorders.

  • Confirmation of familial hypercholesterolemia has great implications for therapy and for identifying risk in family members.

Comments
  • Both familial combined hyperlipoproteinemia and type III hyperlipidemia have a genetic basis; familial combined hyperlipoproteinemia has an autosomal dominant inheritance (33).

  • A specific diagnosis may allow more targeted therapy, with statin therapy as the foundation for familial combined hyperlipoproteinemia and fibric acid derivatives for type III hyperlipidemia, although alternative drugs and combination drug therapy may be effective for both conditions.

  • Familial hypercholesterolemia occurs at a rate of 1 in 200 to 500 persons in the general population. Genetic studies suggest that this condition may occur as frequently as 1 in 200 and even as frequently as 1 in 100 in specific populations with a significant “founder effect” (e.g., South African Jews of Ashkenazi descent). The homozygous form is a rare condition that occurs in 1 per 1 million by most estimates, but may be far more common (may occur as frequently as 1 in 250,000 by some estimates) when diagnosed with genetic assay rather than reliance on clinical evaluation alone.

  • Type III hyperlipidemia is sensitive to dietary modification and fibrates as primary therapy.

  • Endocrinology consultation may be helpful for suspected diagnoses of Cushing's disease, insulin resistance syndrome, polycystic ovarian syndrome, or hypothyroidism, as patients may require long-term therapy and follow-up for these chronic disorders.

  • Examine patients for eruptive, tuberoeruptive, or palmar xanthomas as clinical evidence of type III hyperlipidemia.

Obtain consultation with a lipid specialist for patients with very low HDL or very high triglycerides. 
  • Consult a lipid specialist in patients with HDL <20 mg/dL.

  • Note that the lipid specialist will:

    • Consider one of the genetic forms of low HDL.

    • Consider obtaining an apolipoprotein A-1 assay to distinguish between the inherited low HDL syndromes.

    • Examine the patient for peripheral manifestations of rare low HDL (<10 mg/dL) syndromes, such as Tangier disease (associated with orange tonsils, and due to deficiency in ABCA1) and fish-eye disease (corneal opacification due to deficiency in lecithin cholesteryl acyl transfer protein), and also for evidence of established CHD.

    • Screen first-degree relatives to establish genetic basis for low HDL.

Evidence
  • Consensus.

Rationale
  • Because risk for CHD is heterogeneous for low HDL syndromes (e.g., apolipoprotein A-1 Milano has low risk), identification of genetic syndromes or assessment of atherosclerotic risk can provide reassurance or a rationale for therapy.

Comments
  • A case series described the genetic defect in a kindred with fish eye disease, corneal opacities, and marked high-density lipoprotein deficiency (34).

Obtain consultation with a lipid specialist for managing patients with specific rare disorders requiring additional or complex treatment; those at very high risk for a vascular event; and those in whom treatment has not been effective. 
  • Obtain consultation with a lipid specialist for patients with familial hypercholesterolemia/combined hyperlipidemia, type III dyslipoproteinemia, very low HDL syndromes (HDL <20 mg/dL), and resistant hypertriglyceridemia (triglycerides >1000 mg/dL).

  • Obtain consultation with a lipid specialist for patients with marked cholesterol and/or triglyceride elevations, or HDL deficiency even if the specific lipoprotein diagnosis is not known.

  • Obtain consultation with a lipid specialist for patients with lipid disorders and vascular disease at a young age (under 45), evidence of disease progression despite treatment, or other risk factors for CV disease.

  • Obtain consultation with a lipid specialist if diet or drug strategies do not reduce LDL to the extent expected.

Evidence
  • Consensus.

Rationale
  • Patients with rare lipid disorders often require either special monitoring or complex regimens that are difficult to initiate in a routine practice.

Comments
  • Patients at very high risk may need multiple interventions to lower their LDL substantially below the usual goal, to raise HDL, or to identify and treat other lipid and nonlipid risk factors.

  • Treatments to lower LDL are efficacious; however, a poor response may prompt an examination of secondary causes, such as unusual lipid and lipoprotein disorders, lack of compliance, or other causes.

  • Additional therapies, such as LDL apheresis or novel therapies that require close supervision and special permission for use, may be available under the guidance of a lipid specialist.

  • Additional diagnostic testing may be warranted, including advanced lipoprotein testing or genetic testing.

  • Cascade screening of families is particularly important in inherited conditions, and privacy laws in the U.S. make this a challenging endeavor.

Obtain consultation with a lipid specialist for management of patients in whom lipid disorder control has not been accomplished due to lack of adherence to diet or drug regimen. 
  • Refer the patient to a multidisciplinary program if there is noncompliance with a diet or drug regimen despite a high risk to the patient.

  • Refer the patient to a multidisciplinary program if there are medication side effects limiting adherence to prescribed therapy.

Evidence
  • Consensus.

Rationale
  • The multidisciplinary team based in a lipid clinic, preventive cardiology clinic, or community-based cardiac rehabilitation program provides a supportive environment, feedback monitoring, and frequent contacts to enhance compliance and adherence to therapy.

Comments
  • Multidisciplinary programs, such as preventive cardiology or cardiac rehabilitation programs, that are multifactorial in their approach to patient education and counseling about risk reduction and lifestyle changes and that use behavioral interventions can be helpful in managing lipid disorders.

  • Most lipid interventions require 6 months or more to affect clinical event rates, and all treatments are usually lifelong.

  • When referring to a cardiac rehabilitation program, be certain that the program offers a multifactorial approach to patient care. It should focus on the modification of coronary risk factors through a fully comprehensive program that offers all facets of cardiac risk-factor modification, including exercise, education, dietary counseling, smoking cessation, and stress management.

  • Although the diagnosis of a lipid disorder is not an insurance-covered diagnosis code for Phase II (outpatient) cardiac rehabilitation, the patient will benefit from attending the maintenance phases of cardiac rehabilitation (Phases III-IV), which are private pay and modestly priced.

Consider referring patients with lipid disorders to a registered dietitian to implement and monitor adherence to a recommended diet. 
  • Refer patients who are unable to achieve a therapeutic diet to a registered dietitian or other qualified nutrition counselor.

Evidence
  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of CV risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruits, vegetables, and whole grains; and which includes low-fat dairy, poultry, fish, nuts, and nontropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times a week (1).

  • The 2000 AHA dietary guidelines provide recommendations for different patient groups (35).

  • A 2003 Cochrane review of the effect of the source of dietary advice on cholesterol included 12 trials. Patients receiving advice from dietitians had greater cholesterol reductions than those receiving advice only from physicians (36).

Rationale
  • Physician and office staff do not have the time, training, or support materials to successfully initiate a large dietary change in their patients.

Hospitalize patients with pancreatitis due to hyperchylomicronemia. 
  • If a patient has pancreatitis, hospitalize for fluid resuscitation and supportive measures.

  • If the pancreatitis is thought to be secondary to hyperchylomicronemia, consider treatment with a fibric acid derivative if triglycerides have not fallen to <2000 mg/dL within 1 or 2 days while fasting, in addition to supportive therapy.

  • Follow these measures for the treatment of the hyperchylomicronemia:

    • Give the patient nothing by mouth.

    • If supportive parenteral nutrition is required, use a reduced lipid solution.

    • Consider parenteral heparin/heparinoids to enable the transient release of lipoprotein lipase and briefly assist with chylomicron clearance.

    • Consider insulin therapy to help normalize triglycerides.

  • In rare cases when the cause of severe hyperchylomicronemia is known to be from apoprotein C2 deficiency, consider an infusion of plasma in the acute care setting.

  • Consider plasma exchange for immediate reduction in chylomicronemia.

Evidence
  • Consensus.

Rationale
  • Approximately 20% of idiopathic pancreatitis is thought to be secondary to hyperchylomicronemia.

Comments
  • Pancreatitis from hyperchylomicronemia is the only acute manifestation of a lipid disorder requiring hospitalization.

Initiate dietary therapy with a Mediterranean or low-fat diet in patients with hyperlipidemia at risk for CHD.  
  • Recommend a diet that is:

    • Low in sweets and sugar-sweetened beverages

    • Low in red meat

    • Low in fat, with <6% of saturated fat calories and <200 mg/d of cholesterol in most patients

    • High in fruits, vegetables, and whole grains

    • Inclusive of low-fat dairy, poultry, fish, nuts, and nontropical vegetable oils

  • Consider a Mediterranean diet supplemented by olive oil or nuts, particularly in patients with additional risk factors for CHD.

  • Consider using one or two servings of stanol-ester foods and two or three servings of high-fiber foods (20 to 30 g/d) to reduce LDL.

  • Advise patients to reduce their consumption of alcohol to one serving daily.

  • Consider consultation with a nutritionist or cardiac risk-factor counselor who is familiar with LDL-lowering diets to facilitate a significant change in diet.

Evidence
  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of CV risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruits, vegetables, and whole grains; and which includes low-fat dairy, poultry, fish, nuts, and nontropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times a week (1).

  • A 2013 Cochrane review of the effect of dietary advice on risk factors for CHD included 44 trials with 18,000 participants. Overall, dietary advice reduced serum total cholesterol (reduction of 0.15 mmol/L [CI, 0.06 to 0.23]) and serum LDL (reduction of 0.16 mmol/L [CI, 0.08 to 0.24]) (37).

  • A 1999 meta-analysis of trials of high-fiber foods found that high-fiber foods lowered total cholesterol by 0.045 mmol/L per gram soluble fiber (CI, 0.035 to 0.054) and lowered LDL by 0.057 mmol/L per gram soluble fiber (CI, 0.044 to 0.070) (38).

  • A randomized trial compared margarine with sitostanol-ester to margarine without the ingredient in 153 patients with mild hyperlipidemia. After 1 year, the group receiving sitostanol margarine had lower total cholesterol (by 24 mg/dL) than those receiving control margarine (39).

  • An observational study based on data from the National Health and Nutrition Examination Surveys III observed dietary changes over time, which were accompanied by similar improvements in cholesterol levels across the U.S. population (40).

  • A 2006 randomized trial compared a Mediterranean diet supplemented by either extra-virgin olive oil or nuts with a low-fat diet in patients with risk factors for CHD but no known disease. Both Mediterranean diets reduced the cholesterol:HDL ratio more than the low-fat diet (41).

Rationale
  • Persons complying with an LDL-lowering diet are more likely to attain LDL goals.

Comments
  • A diet low in saturated fat and cholesterol is safe for all age groups.

  • Stanol-ester foods are expensive. Their short-term safety and efficacy has been established for FDA approval; however, long-term issues of blocking vitamin A absorption have not been totally resolved but do not seem to be major issues.

Recommend weight reduction through caloric restriction and increased physical activity in overweight and obese patients with hyperlipidemia, and recommend exercise in all patients. 
  • Initiate a program of weight loss through reduction in calories from fat and simple carbohydrates.

  • Encourage daily, safe physical activity in all persons, especially those with BMI >25 kg/m2.

  • Work collaboratively with patients to set goals and establish treatment strategies for weight loss and risk-factor control.

  • Schedule periodic weight checks and maintenance counseling, including dietary and behavior therapy, once progress is evident.

  • Be aware that obese patients (BMI >30, or BMI >27 with obesity-related risk factors, such as diabetes, hypertension, or CHD) may require more intensive interventions involving meal replacement systems, weight-reduction drug therapy, and/or bariatric surgery.

Evidence
  • A 2013 guideline from the ACC/AHA on lifestyle management for the reduction of CV risk recommended that patients who would benefit from lowering their LDL adhere to a diet low in sweets, sugar-sweetened drinks, and red meat; high in fruits, vegetables, and whole grains; and which includes low-fat dairy, poultry, fish, nuts, and nontropical vegetable oils. The guideline also recommended low levels of saturated and trans fats and aerobic moderate-intensity exercise for an average of 40 minutes three to four times per week (1).

  • A 2007 meta-analysis of the effect of exercise on HDL included 25 studies. Overall, exercise led to a small but statistically significant increase in HDL (42).

Rationale
  • Weight reduction is a cornerstone of therapy and can help lower triglycerides.

Comments
  • A weight-reduction program will be enhanced greatly if combined with a structured aerobic exercise program using large-muscle groups (e.g., walking, running, cycling, or swimming).

Begin statin therapy in patients at risk for CHD. 
  • Initiate therapy with HMG-CoA reductase inhibitors (statins) in patients at high risk for CHD.

  • Tailor the intensity of statin therapy to the CHD risk.

  • Provide high-intensity statin therapy to:

    • Patients with known atherosclerotic disease (clinical CHD, cerebrovascular disease, or peripheral arterial disease)

    • Patients with LDL ≥190 mg/dL

    • Patients with diabetes, LDL <190 mg/dL, and calculated 10-year CHD risk ≥7.5%

    • Some nondiabetic patients with LDL <190 and calculated 10-year CHD risk ≥7.5%

  • Provide moderate-intensity statin therapy to:

    • Patients with diabetes who are not receiving high-intensity therapy

    • Most nondiabetic patients with LDL <190 mg/dL and calculated 10-year CHD risk ≥7.5%

    • Some nondiabetic patients with LDL <190 mg/dL and calculated 10-year CHD risk ≥5% but <7.5%

  • Always reinforce health, diet, and exercise habits.

  • Consider alternatives, including niacin, bile acid-binding resins, and intestinal cholesterol absorption blockers (ezetimibe), if statins are not tolerated.

  • See table Drug Treatment for Lipid Disorders.

  • See table Approach to Statin Therapy in Different Risk Groups.

  • See table Therapeutic Intensity of Statin Doses.

Evidence
  • A 2013 guideline from the ACC/AHA on the assessment of CV risk recommended using the age- and race-specific pooled cohort equations to estimate each patient's risk for CV disease (4).

  • A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for CV disease recommended high-intensity statin therapy for patients with known CV disease, moderate-intensity statin therapy for patients with diabetes, and therapy based on the calculated risk for CV events in the rest of the population aged 40 to 75 (20).

  • A 2004 guideline from the American College of Physicians on the management of hyperlipidemia in patients with diabetes recommended statins as first-line agents (43).

  • A 2013 Cochrane review of statins for the primary prevention of CHD included 18 randomized trials. Statins reduced mortality (OR, 0.86 [CI, 0.79 to 0.94]), CHD (OR, 0.73 [CI, 0.67 to 0.80]), and stroke (OR, 0.78 [CI, 0.68 to 0.89]) (6).

  • A 2012 meta-analysis of the effect of statins on recurrent CV events in men and women included 11 trials with over 43,000 patients. Statin therapy reduced CV events in men (RR, 0.82 [CI, 0.78 to 0.85]) and women (RR, 0.81 [CI, 0.74 to 0.89]). Statin therapy reduced stroke (RR, 0.81 [CI, 0.72 to 0.92]) and mortality (RR, 0.79 [CI, 0.72 to 0.87]) in men but did not significantly reduce stroke (RR, 0.92 [CI, 0.76 to 1.10]) or mortality (RR, 0.92 [CI, 0.76 to 1.13]) in women (44).

  • A 2000 meta-analysis evaluated the effect of lipid-lowering therapies for the primary prevention of CHD and mortality. Drug therapy reduced rates of CHD (OR, 0.70 [CI, 0.62 to 0.79]) but not overall mortality (7).

  • A 2010 systematic review of the effect of fibrates on CV outcomes included 18 trials with 45,000 participants. Fibrates reduced major CV events (RR, 0.90 [CI, 0.82 to 1.0]) and reduced coronary events (RR, 0.87 [CI, 0.81 to 0.93]) but did not reduce death or stroke (45).

  • A 2012 Cochrane review of the lipid-lowering effect of atorvastatin included 254 trials. Overall, atorvastatin reduced LDL by 36% to 53% depending on dose (46).

  • A 2009 systematic review of the cholesterol-lowering effects of ezetimibe included eight randomized trials. After 12 weeks of therapy, ezetimibe reduced LDL by 18.6% (CI, 19.7 to 17.5) compared with placebo (47).

  • The Post Coronary Artery Bypass Graft trial suggested that lowering LDL to <100 mg/dL reduced events and reduced disease progression more than lowering LDL to 100 to 130 mg/dL (48).

  • A randomized trial compared simvastatin plus ezetimibe to simvastatin alone in 4650 patients with CKD. After 4.9 years of follow-up, the combination group had lower rates of stroke (NNT, 100) but no significant reduction in MI or death from CHD (49).

  • A randomized trial (VA-HIT study) compared gemfibrozil to placebo in 2531 men with known CHD. After 5.1 years, the gemfibrozil group had lower rates of the primary endpoint of MI or CHD death (NNT, 23). HDL was higher in the gemfibrozil group, and LDL did not differ (50).

  • The Helsinki Heart Study was a randomized trial comparing gemfibrozil to placebo in 4081 men with lipid abnormalities but no CHD. After 5 years, the gemfibrozil group had lower rates of cardiac events (RR, 0.66 [CI, 0.47 to 0.92]) (51).

Comments
  • Lipid-lowering therapies other than statins have a smaller impact on clinical outcomes.

Use medications to lower triglycerides in patients with triglycerides >1000 mg/dL. 
  • In patients with severe hypertriglyceridemia (>1000 mg/dL), treat primarily with a drug to lower triglycerides.

  • Select among the following drug classes:

    • Fibrates, which raise HDL slightly

      • Examples include gemfibrozil and fenofibrate

    • Omega-3 polyunsaturated fatty acids (used to reduce triglycerides)

    • Niacin (less impact on lowering triglycerides than fibrates or high-dose fish oil, but also lowers cholesterol, LDL, and lipoprotein-(a) and raises HDL)

  • See table Drug Treatment for Lipid Disorders.

Evidence
  • A randomized trial compared bezafibrate to placebo in patients with elevated triglycerides and metabolic syndrome. After 6.2 years, rates of MI were lower in the bezafibrate group (NNT, 25) (52).

  • A crossover trial compared simvastatin plus omega-3 esters to simvastatin alone in patients with elevated triglycerides who were not at their non-HDL goal. Combination therapy resulted in improved triglycerides (-44% vs. -22%) and improved HDL (16% vs. 11%) (53).

Rationale
  • Severe triglyceride elevations predispose patients to pancreatitis and other complications.

Comments
  • Triglycerides >2000 mg/dL typically suggest that chylomicrons are high enough to precipitate pancreatitis. Treatment goals for triglycerides <1000 or 500 mg/dL are considered reasonable because they enable a therapeutic safety buffer below the pancreatitis threshold.

  • There are no randomized, placebo-controlled clinical trials assessing the role of drug therapy for the prevention of pancreatitis due to hyperchylomicronemia.

Individualize therapy and consider combination drug therapy in patients with familial syndromes or with very high cholesterol. 
  • Consider combination therapy in patients with severe elevations in lipids from disorders such as familial hypercholesterolemia, recognizing that up to three drugs may be required.

  • Be aware of drug interactions, such as those between cytochrome P-4503A4 metabolized drugs like particular statins and gemfibrozil, which may induce myositis and rhabdomyolysis.

  • See table Drug Treatment for Lipid Disorders.

Evidence
  • A 2014 AHRQ Comparative Effectiveness Review of combination therapy compared with intensification of statin monotherapy for patients with hyperlipidemia included 55 randomized trials. Evidence regarding clinical outcomes was insufficient. Bile acid sequestrants combined with monotherapy low-potency statins reduced LDL more than intermediate-potency statins. Intermediate-potency statins plus ezetimibe reduced LDL more than monotherapy with high-potency statins. There was insufficient evidence to assess the effect of combination therapy with fibrates or niacin (54).

  • In the Effect of Combination Ezetimibe and High-dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia trial, ezetimibe was not superior to statin therapy alone on measures of carotid intimal media thickness in a population with well-controlled LDL who had been treated for years before enrollment in the clinical trial (55).

  • The AIM-HIGH study was a randomized trial comparing the addition of extended-release niacin to standard-dose statin therapy (with or without the addition of ezetimibe to achieve the LDL goal) vs. standard-dose statin therapy titrated to goal LDL <80 mg/dL (with or without the addition of ezetimibe to achieve the LDL goal) and placebo in 3400 patients with known CHD. The primary endpoint was a composite of stroke, MI, CHD death, revascularization, or hospitalization for acute coronary syndrome. The trial was stopped early after 3 years of follow-up when rates of the primary endpoint did not differ between the groups (56).

  • A randomized trial (the HPS2-THRIVE study) compared simvastatin and ezetimibe (if needed) plus extended-release niacin and laropiprant (to reduce flushing from niacin) with simvastatin/ezetimibe plus placebo in 25,673 patients with arterial disease. After 4 years, rates of myopathy were higher in the niacin/laropiprant combination group (RR, 4.4 [CI, 2.6 to 7.5]) (57).

Rationale
  • Familial syndromes may require multiple medications to achieve LDL and non-HDL cholesterol levels.

Comments
  • Low HDL is a confirmed marker of increased CV risk. Niacin and other medicines raise HDL slightly and reduce CV risk when taken as monotherapy, but have not been fully evaluated as add-on therapy to statin drugs. Two major niacin add-on studies in individuals with well-treated LDL and non-HDL showed no CV benefit when compared with placebo, with more side effects.

  • Niacin, fibrates, fish oil, ezetimibe, and bile acid sequestrants have not been fully tested for their ability to reduce CV risk as add-on therapy to statin drugs when LDL and non-HDL goals have not been reached with statin monotherapy.

Work with the health care team members to assist patients in the necessary lifestyle changes to decrease cardiac risk. 
  • Recognize that patient information should focus on smoking cessation, weight control, regular aerobic exercise, BP control, a heart-healthy diet, and diabetes management.

Evidence
  • A 2003 Cochrane review of the effect of the source of dietary advice on cholesterol included 12 trials. Patients receiving advice from dietitians had greater cholesterol reductions than those receiving advice only from physicians (36).

  • Non-drug interventions allow lifestyle modifications to improve prognosis. Behavioral interventions increase compliance with non-drug and drug treatments (58).

Rationale
  • A multidisciplinary approach that includes physicians, nurses, dietitians, psychologists, and exercise specialists using proven behavioral techniques fosters patients' compliance and adherence to their medical regimen.

Comments
  • Risk-factor identification and intervention must be individualized for each patient and be outcome driven. Mutually agreed-on goals and outcomes increase the likelihood for successful lifestyle modification.

Recognize that many patients require repeated attempts to modify often lifelong habits. 
  • Provide ongoing support to patients actively engaged in lifestyle modifications, such as dieting and smoking cessation.

  • Use encouragement, empathy, compassion, and a nonjudgmental approach to foster the patient's emotional withdrawal from bad habits.

Evidence
  • Mainly consensus.

  • Community-based intervention programs, such as counseling and follow-up provided by the patient's pharmacist, improve the process of cholesterol management in high-risk patients (59).

Rationale
  • The effectiveness of cardiac risk modification and patients' continued perseverance to alter their lifestyle is significantly influenced by the amount of support and follow-up the multidisciplinary health care team provides.

Comments
  • Telephone calls, progress letters, reminder postcards, flow charts, and a reward system (e.g., T-shirts, congratulation certificates) can be helpful.

Use written or audiovisual patient education materials to reinforce recommendations. 
  • Reinforce recommendations given in the office by providing formal educational materials the patient can review at home.

  • Consider using a decision aid such as the Statin Choice Decision Aid.

  • Provide written information about medications, including:

    • Why the medication is prescribed

    • What benefits should be expected

    • Potential side effects to look out for and when to notify the clinician

    • Frequency of monitoring

Evidence
  • A 1992 meta-analysis of 28 controlled trials of patient education found that cardiac patient education programs improved diet, BP, exercise, and mortality (60).

Rationale
  • Patients who receive clear, concise, and understandable information about prescribed medications are more likely to comply with drug therapy and to take the medication as directed.

Comments
  • Encourage the use of videos, audiotapes, or Internet access to health care-oriented websites.

  • Emphasize compliance and adherence during follow-up visits or telephone calls.

See patients on drug therapy regularly to monitor risk, adjust therapy, reinforce adherence to therapy, and look for potential side effects. 
  • See patients on drug therapy at 4- to 6-month intervals (or more often as needed).

  • Ask patients about:

    • Symptoms of muscle toxicity, such as fatigue and weakness, or muscle pain, stiffness, or cramping

    • Symptoms of hepatotoxicity, such as fatigue, weakness, abdominal pain, anorexia, jaundice, or icterus

  • Monitor lab tests:

    • Check a fasting lipid panel in patients on medication annually

    • Check liver enzymes in patients with any symptoms of liver toxicity

    • Check muscle enzymes in patients with symptoms of myopathy

  • Emphasize the importance of long-term adherence to drug and non-drug treatment.

Evidence
  • A 2013 guideline from the ACC/AHA on the treatment of blood cholesterol to reduce the risk for CV disease stated that it is reasonable to check muscle enzymes (creatine kinase) in patients on statin therapy who develop muscle symptoms or hepatic function in those who develop symptoms of hepatotoxicity, but recommended against routinely checking lab tests. The guideline noted that special caution regarding toxicity should be taken in patients over age 75 or who have had a liver transplant (20).

  • The 2006 report of the National Lipid Association Statin Safety Assessment Task Force found little evidence to support monitoring LFTs in patients on statins but still recommended monitoring after 12 weeks of therapy (with lipid levels) and after changes in therapy. The group recommended considering lowering the dose or stopping a statin in patients with ALT or AST more than 3 times the upper limit of normal if other causes were ruled out (61).

Rationale
  • Adherence to drug regimens is poor at 6 to 12 months after initiation; adverse effects may contribute to noncompliance or nonadherence and, in unusual exceptions, may lead to switching drugs.

Table Grahic Jump Location
 Differential Diagnosis of Low HDL Cholesterol

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DiseaseCharacteristics
Familial hypoalphalipoproteinemiaHDL may be very low (<10 mg/dL)
Many rare genetic defects have been identified (Tangier disease, fish-eye disease, apolipoprotein A-1 Milano)
Not all very low HDL syndromes carry a high CV risk (e.g., apolipoprotein A-1 Milano)
Deleterious forms are associated with family history of early-onset atherosclerosis and/or low HDL
Usually low apolipoprotein A-1
Familial combined hyperlipidemiaCharacterized by high cholesterol and triglycerides because of high LDL and VLDL (Fredrickson classification type IIb) and low HDL inversely related to triglycerides, except in cases of alcoholism and estrogen use
May partially respond to weight loss and drug therapies that reduce triglycerides
Low HDL in presence of low total cholesterol Populations with low total cholesterol and triglycerides (triglycerides <150 mg/dL) may have low HDL but normal apolipoprotein A-1
Probably not related to CHD risk
Can reassure patient if apolipoprotein A-1 is within normal limits of lab tests
Secondary hypoalphalipoproteinemiaMay be secondary to drug therapy (progestogens, anabolic steroids, and β-blockers without intrinsic sympathetic activity), chronic kidney disease, cigarette smoking, obesity, or inflammatory disease, such as rheumatoid arthritis, psoriasis, or lupus; also related to hematologic malignancy, especially multiple myeloma

CHD = coronary heart disease; CV = cardiovascular; HDL = high-density lipoprotein (cholesterol); LDL = low-density lipoprotein (cholesterol); VLDL = -low-density lipoprotein (cholesterol).

Table Grahic Jump Location
 Drug Treatment for Lipid Disorders

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
FirstLineIconHMG-CoA reductase inhibitors (statins)Older agents are more effective if given at bedtimeRhabdomyolysis and acute renal failure, myalgia, myopathy, hepatotoxicity, hyperglycemia/diabetesAvoid with: active hepatic disease, pregnancy. Avoid concomitant use with cyclosporine or gemfibrozil. Use caution with fenofibrate or niacin. For most statins, additional drug interactions exist due to CYP450 hepatic metabolism. Avoid large quantities (>1 quart daily) of grapefruit or pomegranate juice. Elderly may have an increased responseFirst-line agents. Drug interaction profiles vary
Atorvastatin (Lipitor)10-80 mg qdDo not exceed 20 mg qd in patients taking a CYP3A4 inhibitor (e.g., protease inhibitors)
Fluvastatin (Lescol, Lescol XL)Regular-release: 20-40 mg qd, up to 40 mg bid. Extended-release: 80 mg qdCaution with CYP2C9 inhibitors or substrates (e.g., fluconazole, valproic acid, amiodarone)
Lovastatin (Mevacor, Altoprev)Regular-release: 10-80 mg qd with PM meal. Extended-release (Altoprev): 10-60 mg qhsIf CrCl<30, maximum dose 20 mg qd. Do not take a CYP3A4 inhibitor (e.g., protease inhibitor) concomitantly
Pitavastatin (Livalo)1-4 mg qdIf CrCl<60, maximum dose 2 mg qd
Pravastatin (Pravachol)10-80 mg qd. Can be taken in AM or PMStart with 10 mg qd with CKD. Not a CYP3A4 substrate
Rosuvastatin (Crestor)5-40 mg qd. Can be taken in AM or PMIf CrCl<30, maximum dose 10 mg qd. Undergoes minimal hepatic metabolism. Use 5 mg starting dose in Asian patients
Simvastatin (Zocor)5-40 mg qhsIf CrCl<20, start with 5 mg qd. Do not take with a CYP3A4 inhibitor (e.g., protease inhibitor). Caution with >20 mg in Asian patients
FirstLineIconNiacin
Niacin (Niacor, Niaspan)Immediate-release (IR): Initially 250 mg qd after PM meal. Usual dose: 1.5-3 g total daily dose, dosed bid-tid. Maximum 6 g total daily dose. Extended-release (ERN): 500 mg qhs for wks 1-4, then 1000 mg qhs for wks 5-8. Then may increase to 1500 mg qhs for wks 9-12, and then 2000 mg qhs. Usual dose: 1000-2000 mg qhs.
Sustained-release (SRN): can be taken up to 1000 mg bid after meal (available as Slo-niacin)
Peripheral vasodilation (flushing), hyperglycemia, GI side effects, hepatotoxicity, hyperuricemiaAvoid with: hepatic disease, active peptic ulcer disease. Increased risk for rhabdomyolysis if combined with a statinGive noncoated 325 mg aspirin 30 min before niacin to offset flushing. Taking with food also ameliorates flushing. IRN most likely to cause flushing; SRN most likely to cause hepatotoxicity
Bile acid sequestrantsGI side effects, particularly constipation. May increase triglycerides in susceptible individualsAdminister other drugs at least 1 hr before or 4-6 hrs after bile acid sequestrant. Caution with CKDColesevelam (Welchol) is pregnancy category B
Cholestyramine (Prevalite, LoCHOLEST)Initially 4 g qd or bid before meals. Usual dose: 4-16 g total daily dose, dosed bid. Maximum 24 g total daily dose
Colesevelam (Welchol) (tablets: 625 mg, or packets for oral suspension: 1.875 g, 3.75 g)1.875 g bid or 3.75 g qd. Take with a meal. Take tablets with water; dissolve packet in 4-8 ounces water, fruit juice, or diet soda
Colestipol (Colestid)Granules: Initially 5 g qd or bid. Usual dose: 5-20 g total daily dose, dosed bid-qid. Maximum 30 g total daily dose. Tablets: Initially 2 g qd or bid. Maximum 16 g total daily dose
FirstLineIconFibric acid derivativesGI side effects, cholelithiasis, hepatotoxicity, blood dyscrasias, pancreatitis, hypersensitivity reactionsMultiple drug interactions due to inhibition of CYP2C9 (e.g., fluconazole, valproic acid, amiodarone) and other CYP450 isoenzymes. Avoid with: hepatic disease, gallbladder disease. Can increase warfarin INR. Can enhance hypoglycemic effects of antidiabetics. Caution with cyclosporineFirst line for high triglycerides
Gemfibrozil (Lopid)600 mg bid, 30 min before AM and PM mealsAvoid with CrCl<50Avoid concomitant use of a statin
Fenofibrate (Tricor, Lipofen, Antara, Triglide)Tricor: 48-145 mg qd, fenofibrate: 54-160 mg qd with a meal, Triglide: 50-160 mg qd, Antara: 43-130 mg qd, Lipofen: 50-150 mg qd with a mealIf CrCl 30-80, start with lowest dose. Avoid if CrCl<30Can administer cautiously with a low or moderate dose statin
Fenofibric acid (immediate-release: Fibricor, delayed-release: Trilipix)Immediate-release: 35-105 mg qd. Delayed-release: 45-135 mg qdIf CrCl 30-80, start with lowest dose. Avoid if CrCl<30Can administer cautiously with a low or moderate dose statin
Cholesterol absorption inhibitor
Ezetimibe (Zetia)10 mg qdAvoid with moderate hepatic disease (lack of data)Can be used as monotherapy or with a statin or fenofibrate. Second line for high LDL. There is no evidence that monotherapy reduces risk
FirstLineIconFish oil, omega-3 fatty acids
Omega-3 fatty acids (Lovaza, generic)4 g total daily dose, dosed qd or bidGI side effects, elevated hepatic enzymes, elevated LDL, skin rashCaution with anticoagulant therapyFirst line for high triglycerides, usually 2 g bid
Icosapent ethyl (Vascepa)2 g bid with meals is recommendedGI side effects, elevated hepatic enzymes, elevated LDL, skin rashCaution with anticoagulant therapyFirst line for high triglycerides
Combination agentsAdjust the dose of each drug separately before considering a combination agent. Use caution due to risk for myopathy or rhabdomyolysis
Niacin extended-release/statin
Niacin/Lovastatin (Advicor)500/20 mg, 750/20 mg, 1000/20 mg, 1000/40 mg; dosed 1 tablet qhs with a low-fat snack. Maximum dose 2000/40 mg qhs
Niacin/Simvastatin (Simcor)500/20 mg, 500/40 mg, 750/20 mg, 1000/20 mg, 1000/40 mg; dosed 1 tablet qhs with a low-fat snack. Maximum dose 2000/40 mg qhs
Cholesterol absorption inhibitor/statin
Ezetimibe/Simvastatin (Vytorin)10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg; dosed 1 tablet qd in the PM

FirstLineIcon = first-line agent; AM = morning; bid = twice daily; CKD = chronic kidney disease; CrCl = creatinine clearance; CYP = cytochrome P450; GI = gastrointestinal; HMG-CoA = hydroxymethylglutaryl-coenzyme A; HDL = high-density lipoprotein (cholesterol); hr = hour; hs = bedtime; INR = international normalized ratio; LDL = low-density lipoprotein (cholesterol); min = minutes; PM = evening; qd = once daily; qid = four times daily; tid = three times daily.

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Elective Laboratory Elements for Evaluation of Selected Lipid Disorders after Initial Evaluation

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TestIndicationNotes
ChylomicronFasting triglycerides >1000 mg/dLWhole blood in anticoagulant placed vertically overnight in refrigeration, then examined for milky layer. Presence of any chylomicrons after >8 h of fasting is abnormal and identifies a possible problem in postprandial triglyceride-rich lipoprotein clearance (e.g., lipoprotein lipase deficiency)
Direct LDL measurementFasting triglycerides >400 mg/dLAllows identification of LDL abnormality when Friedewald formula is unreliable
Apolipoprotein B“Normal” LDL and elevated triglycerides (>150 mg/dL) or low HDL if results would change managementElevated apolipoprotein B in the presence of “normal” LDL suggests presence of small, dense LDL particles, which are thought to be atherogenic
Apolipoprotein A-1Low HDL <40 mg/dL in patients with low total cholesterol (<200 mg/dL)Normal apolipoprotein A-1 in setting of low HDL suggests adequate reverse cholesterol transport capacity (62).
Apolipoprotein A-1 constitutes 70% of the protein in HDL
Lipoprotein-(a)Evidence of coronary disease in the absence of identifiable risk factors, and a normal lipid profileLipoprotein-(a) measures are poorly standardized. Lipoprotein-(a) >30 mg/dL has been identified in most prospective studies to be independently associated with CHD (63). Consider statin therapy in patients with CHD, abnormal lipoprotein-(a) and LDL at goal
C-reactive proteinUnclear indication for lipid-lowering therapy or unclear goal of therapyMarker of CHD risk. C-reactive protein should not be performed in patients with clear indications for lipid-lowering therapy or in very-low-risk patients with normal lipids
Coronary calcium scoreIntermediate or low risk for CHD with borderline lipids, in whom the result would determine need for therapyCoronary calcium should not be performed in patients with clear indications for lipid-lowering therapy or in very-low-risk patients with normal lipids

CHD = coronary heart disease; HDL = high-density lipoprotein (cholesterol); LDL = low-density lipoprotein (cholesterol).

Table Grahic Jump Location
 Approach to Statin Therapy in Different Risk Groups

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Risk groupRecommended statin intensity
Clinical CHD, stroke or TIA, or peripheral arterial diseaseHigh. Moderate, if high-intensity therapy not tolerated or in some patients over age 75
LDL ≥190 mg/dLHigh. Use maximum tolerated dose for patients who cannot tolerate high-intensity therapy
DiabetesModerate. Consider high intensity if calculated 10-year risk for atherosclerotic events ≥7.5%
No known vascular disease or diabetes, LDL 70-189 mg/dL, with estimated 10-year risk for atherosclerotic events ≥7.5%Moderate to high
No known vascular disease or diabetes, LDL 70-189 mg/dL with estimated 10-year risk for atherosclerotic events ≥5% to <7%Moderate

CHD = coronary heart disease; LDL = low-density lipoprotein (cholesterol); TIA = transient ischemic attack.

Adapted from 20.

Table Grahic Jump Location
 Differential Diagnosis of Elevated LDL Cholesterol

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DiseaseCharacteristicsNotes
Heterozygous familial hypercholesterolemia
(Frederickson-Levy Type IIa)
Markedly elevated LDL (usually >220 mg/dL).
Presence of tendon xanthomas (Presence of tendon xanthomas (15%) or history of elevated total cholesterol or LDL in early childhood confirm the diagnosis.
Family history of first-degree relative with early-onset CHD and/or familial hypercholesterolemia.
Autosomal-dominant inheritance pattern.
Prevalence 1/500 in U.S.
Identifies person with deficiency of LDL receptors best treated with HMG-CoA reductase inhibitors and/or bile acid-binding resins
Familial combined hyperlipidemia
(Frederickson-Levy Type IIb)
Elevated LDL and/or elevated VLDL.
Elevated apo B.
Family history of first-degree relative with early-onset CHD and/or lipid disorder.
Autosomal-dominant inheritance with incomplete penetrance.
Prevalence of gene as high as 25% in U.S.
Associated with metabolic syndrome of low HDL, hypertension, diabetes, hyperuricemia, and central obesity
Identifies person with hepatic overproduction of B-containing lipoproteins who may benefit from niacin therapy
Dysbeta lipoproteinemia
(Fredrickson-Levy Type III)
Elevated total cholesterol and triglycerides due to excess in cholesterol enriched VLDL and chylomicron remnant particles.
Family history of early-onset CHD and/or hyperlipidemia.
Low prevalence of eruptive, tuberoeruptive, or palmar xanthomas.
Associated with apo E-2 homozygosity.
Prevalence 1/1750 in patients with CHD.
Associated with atherosclerotic disease, especially peripheral vascular disease
Broad beta band on lipoprotein electrophoresis, but best confirmed by apo E2/E2 genotype.
Responsive to fibric acids, HMG-CoA reductase inhibitors, and attention to the “second hit” (e.g., dietary modification, hormonal change, insulin resistance/hyperglycemia, or hypothyroidism typically)
Polygenic hypercholesterolemiaElevated LDL.
Variable family history of early onset CHD and/or hyperlipidemia.
Unclear inheritance pattern
Most common pattern in hypercholesterolemia
Secondary hypercholesterolemiaElevated LDL with or without high triglycerides.
Associated with signs and symptoms of hypothyroidism, obstructive liver disease, nephrotic syndrome, or uncontrolled diabetes.
Confirmed by appropriate lab tests (TSH, liver function tests, urine for protein, fasting blood glucose)
Diet and drug therapies are often ineffective.
Correction of underlying secondary cause may normalize lipid profile

apo = apolipoprotein; CHD = coronary heart disease; HDL = high-density lipoprotein (cholesterol); HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LDL = low-density lipoprotein (cholesterol); TSH = thyroid-stimulating hormone; VLDL = -low-density lipoprotein (cholesterol).

Table Grahic Jump Location
 Differential Diagnosis of Elevated Triglycerides

Swipe to view table

DiseaseCharacteristicsNotes
Chylomicronemia due to genetic lipoprotein lipase deficiency
(Fredrickson-Levy Type I)
Severe hypertriglyceridemia (>1000 mg/dL) with normal or low total cholesterol.
Chylomicronemia without elevated VLDL in fasting serum.
Usually presents in childhood.
High risk for pancreatitis.
Usually not associated with CHD risk. Homozygous for recessive lipoprotein lipase deficiency gene. Rare
Triglyceride-reducing drugs do not affect levels.
The only therapy is a very low-fat diet (<15% of the total calories from fat source; under guidance of dietitian).
Lipoprotein Lipase gene therapy approved in Europe, not available in U.S.
Chylomicronemia with elevated VLDL
(Fredrickson-Levy Type V)
Severe hypertriglyceridemia (>1000 mg/dL) with elevated total cholesterol.
Chylomicronemia with cloudy serum (elevated VLDL) in fasting serum.
Increased risk for pancreatitis.
May carry risk for atherosclerosis
Abnormality of exogenous lipid transport pathway but responsive to lipoprotein lipase-inducing drugs (e.g., fibric acid derivatives)
Familial hypertriglyceridemia
(Fredrickson-Levy Type IV)
Moderate (200-499 mg/dL) to severely (>500 mg/dL) elevated fasting triglycerides.
Chylomicrons absent.
Family history of early-onset CHD or lipid disorder.
Associated with risk for atherosclerotic disease
May be a variant of familial combined hyperlipoproteinemia with elevated apolipoprotein B
Familial combined hypercholesterolemia
(Fredrickson-Levy Type IIb)
Variable expression of elevated triglycerides, elevated LDL, or both in some patients
Secondary hypertriglyceridemiaMay be markedly elevated triglycerides (>1000 mg/dL).
Many potential causes, including uncontrolled diabetes, excessive alcohol use, hypothyroidism, thiazide diuretics, β-blockers, oral estrogens, retinoic acid, protease inhibitors, ticlopidine, or bile acid-binding resins
Often resistant to diet or drug therapy unless underlying cause is corrected

CHD = coronary heart disease; LDL = low-density lipoprotein (cholesterol); VLDL = very-low-density lipoprotein (cholesterol).

Table Grahic Jump Location
 Therapeutic Intensity of Statin Doses

Swipe to view table

DrugHigh-intensity dosingModerate-intensity dosingLow-intensity dosing
Atorvastatin40-80 mg10-20 mg
Fluvastatin80 mg (or 40 mg bid)10-20 mg
Lovastatin40 mg20 mg
Pitavastatin2-4 mg1 mg
Pravastatin40-80 mg10-20 mg
Rosuvastatin20-40 mg5-10 mg
Simvastatin*80 mg20-40 mg10 mg

* Not recommended by the FDA.

Adapted from 20.

Table Grahic Jump Location
 Fredrickson-Levy Classification of Hyperlipoproteinemia Phenotypes

Swipe to view table

TypeLipoprotein abnormalityNotes
IElevated chylomicronsTriglycerides >1000 mg/dL; risk for pancreatitis; pediatric condition; most have lipoprotein lipase deficiency (apoprotein C2 deficiency much less common)
IIaElevated LDLMost common is familial hypercholesterolemia; high risk for atherosclerotic heart disease at young age
IIbElevated LDL and VLDLMost common is familial combined hyperlipidemia; high risk for atherosclerotic heart disease at young age; associated with metabolic syndrome
IIIElevated triglyceride-rich remnant particlesAutosomal recessive trait, associated with apolipoprotein E2/E2 genotype; requires a “second hit” from a metabolic stressor to manifest phenotype (e.g., dietary modification, hormonal change, insulin resistance/hyperglycemia, or hypothyroidism)
IVElevated VLDLCommonly seen in metabolic syndrome
VElevated chylomicrons and VLDLCan result from phenotype transformation of type IV and/or type I patients; high risk for pancreatitis

LDL = low-density lipoprotein (cholesterol); VLDL = very-low-density lipoprotein (cholesterol).

Data from 64; 65; 66; 67; 68.

Table Grahic Jump Location
 Xanthomas, Associated Dyslipidemia, and Associated Disease

Swipe to view table

Type of xanthomaClinical presentationAssociated dyslipidemiaImportant associated diseases
XanthelasmaAsymptomatic, flat, yellow-to-orange papules or plaques around eyelidsLDL; 50% of patients have no dyslipidemiaFamilial hypercholesterolemia
Eruptive xanthomasYellow or yellow-orange papules appearing suddenly in crops over buttocks, thighs, arms, forearms, back, or chest; may be pruriticTriglyceridesFamilial lipoprotein deficiency; apoprotein CII deficiency; familial hypertriglyceridemia
Tendon xanthomasLipid deposition within tendons, ligaments, and fasciae; smooth, firm, lobulated nodules over extensor tendons of hands, elbows, knees, and Achilles tendonLDL Familial hypercholesterolemia; cerebrotendinous xanthomatosis; sitosterolemia
Tuberous xanthomasSmall, soft, yellow, orange, or red papules or nodules over extensor surfaces, especially the elbows, knees, and buttocks; often coalesce to form large, lobular massesLDL or triglyceridesFamilial hypercholesterolemia
Plane xanthomasFlat, yellow plaques that most commonly involve the skin folds
Diffuse plane xanthomas (neck, face, upper trunk, arms)NormolipemicMultiple myeloma; paraproteinemia; leukemia; lymphoma
Intertriginous areasLDL Homozygous familial hypercholesterolemia
Palmar xanthomasLDL or triglyceridesDysbetalipoproteinemia

LDL = low-density lipoprotein (cholesterol).

  • Estimate of 10-Year Risk for Men and Women (Framingham Point Scores)
  • Xanthelasma Xanthelasma, asymptomatic, flat, yellow-to-orange papules or plaques around the eyelids, are associated with familial hypercholesterolemia.
  • Tuberous Xanthoma Tuberous xanthoma in a patient with sitosterolemia (an autosomal recessive disorder characterized by hyperabsorption of cholesterol and plant sterols).
Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S76-99. (PMID: 24222015)
 
Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA, et al.; American Heart Association Nutrition Committee. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114:82-96. (PMID: 16785338)
 
Moyer VA; U.S. Preventive Services Task Force. Behavioral counseling interventions to promote a healthful diet and physical activity for cardiovascular disease prevention in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:367-71. [Full Text] (PMID: 22733153)
 
Goff DC, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S49-73. (PMID: 24222018)
 
Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:133-40. (PMID: 21600517)
 
Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;2:CD004816. (PMID: 23440795)
 
Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ. 2000;321:983-6. (PMID: 11039962)
 
Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989;79:8-15. (PMID: 2642759)
 
Murray DM, Luepker RV, Pirie PL, Grimm RH, Bloom E, Davis MA, et al. Systematic risk factor screening and education: a community-wide approach to prevention of coronary heart disease. Prev Med. 1987;15:661-72. (PMID: 3797397)
 
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-7. (PMID: 7566020)
 
The effects of pravastatin on hospital admission in hypercholesterolemic middle-aged men: West of Scotland Coronary Prevention Study. J Am Coll Cardiol. 1999;33:909-15. (PMID: 10091815)
 
Downs JR, Oster G, Santanello NC. HMG CoA reductase inhibitors and quality of life. [Letter] JAMA. 1993;269:3107-8. (PMID: 8505809)
 
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-22. (PMID: 9613910)
 
Ridker PM, MacFadyen JG, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, et al.; JUPITER Study Group. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER). Circ Cardiovasc Qual Outcomes. 2009;2:616-23. (PMID: 20031900)
 
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-30. (PMID: 12457784)
 
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 20026;360:7-22. (PMID: 12114036)
 
Klag MJ, Ford DE, Mead LA, He J, Whelton PK, Liang KY, et al. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med. 1993;328:313-8. (PMID: 8419817)
 
Manolio TA, Pearson TA, Wenger NK, Barrett-Connor E, Payne GH, Harlan WR. Cholesterol and heart disease in older persons and women. Review of an NHLBI workshop. Ann Epidemiol. 1992;2:161-76. (PMID: 1342259)
 
O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, et al.; American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78-140. (PMID: 23256914)
 
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-S45. (PMID: 24222016)
 
Muntner P, Colantonio LD, Cushman M, Goff DC, Howard G, Howard VJ, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA. 2014;311:1406-15. (PMID: 24682252)
 
D’Agostino RB, Grundy S, Sullivan LM, Wilson P; CHD Risk Prediction Group. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001;286:180-7. (PMID: 11448281)
 
Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med. 1990;322:1700-7. (PMID: 2342536)
 
Greenland P, Bonow RO, Brundage BH, Budoff MJ, Eisenberg MJ, Grundy SM, et al.; American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography); Society of Atherosclerosis Imaging and Prevention; Society of Cardiovascular Computed Tomography. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2007;49:378-402. (PMID: 17239724)
 
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, Criqui M, et al.; Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511. (PMID: 12551878)
 
Pletcher MJ, Tice JA, Pignone M, Browner WS. Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis. Arch Intern Med. 2004;164:1285-92. (PMID: 15226161)
 
Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA. 2007;298:776-85. (PMID: 17699011)
 
Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B-12B. (PMID: 9526807)
 
Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, et al.; Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993-2000. (PMID: 19903920)
 
Vodnala D, Rubenfire M, Brook RD. Secondary causes of dyslipidemia. Am J Cardiol. 2012;110:823-5. (PMID: 22658245)
 
Oki JC. Dyslipidemias in patients with diabetes mellitus: classification and risks and benefits of therapy. Pharmacotherapy. 1995;15:317-37. (PMID: 7667166)
 
Grundy SM. Cholesterol management in high risk patients without heart disease. When is lipid-lowering medication warranted for primary prevention? Postgrad Med. 1998;104:117-20, 123-4, 129. (PMID: 9823389)
 
Aouizerat BE, Allayee H, Bodnar J, Krass KL, Peltonen L, de Bruin TW, et al. Novel genes for familial combined hyperlipidemia. Curr Opin Lipidol. 1999;10:113-22. (PMID: 10327279)
 
Dimick SM, Sallee B, Asztalos BF, Pritchard PH, Frohlich J, Schaefer EJ. A kindred with fish eye disease, corneal opacities, marked high-density lipoprotein deficiency, and statin therapy. J Clin Lipidol. 2014;8:223-30. (PMID: 24636183)
 
Krauss RM, Eckel RH, Howard B, Appel LJ, Daniels SR, Deckelbaum RJ, et al. AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation. 2000;102:2284-99. (PMID: 11056107)
 
Thompson RL, Summerbell CD, Hooper L, Higgins JP, Little PS, Talbot D, et al. Dietary advice given by a dietitian versus other health professional or self-help resources to reduce blood cholesterol. Cochrane Database Syst Rev. 2003;(3):CD001366. (PMID: 12917906)
 
Rees K, Dyakova M, Wilson N, Ward K, Thorogood M, Brunner E. Dietary advice for reducing cardiovascular risk. Cochrane Database Syst Rev. 2013;(12):CD002128. (PMID: 24318424)
 
Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr. 1999;69:30-42. (PMID: 9925120)
 
Miettinen TA, Puska P, Gylling H, Vanhanen H, Vartiainen E. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N Engl J Med. 1995;333:1308-12. (PMID: 7566021)
 
Ernst ND, Sempos CT, Briefel RR, Clark MB. Consistency between US dietary fat intake and serum total cholesterol concentrations: the National Health and Nutrition Examination Surveys. Am J Clin Nutr. 1997;66:965S-972S. (PMID: 9322575)
 
Estruch R, Martínez-González MA, Corella D, Salas-Salvadó J, Ruiz-Gutiérrez V, Covas MI, et al.; PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145:1-11. [Full Text] (PMID: 16818923)
 
Kodama S, Tanaka S, Saito K, Shu M, Sone Y, Onitake F, et al. Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis. Arch Intern Med. 2007;167:999-1008. (PMID: 17533202)
 
Snow V, Aronson MD, Hornbake ER, Mottur-Pilson C, Weiss KB; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2004;140:644-9. [Full Text] (PMID: 15096336)
 
Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med. 2012;172:909-19. (PMID: 22732744)
 
Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875-84. (PMID: 20462635)
 
Adams SP, Tsang M, Wright JM. Lipid lowering efficacy of atorvastatin. Cochrane Database Syst Rev. 2012;375:CD008226. (PMID: 23235655)
 
Pandor A, Ara RM, Tumur I, Wilkinson AJ, Paisley S, Duenas A, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med. 2009;265:568-80. (PMID: 19141093)
 
Alaupovic P, Fesmire JD, Hunnighake D, Domanski M, Forman S, Knatterud GL, et al. The effect of aggressive and moderate lowering of LDL-cholesterol and low dose anticoagulation on plasma lipids, apolipoproteins and lipoprotein families in post coronary artery bypass graft trial. Atherosclerosis. 1999;146:369-79. (PMID: 10532693)
 
Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al.; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181-92. (PMID: 21663949)
 
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-8. (PMID: 10438259)
 
Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-45. (PMID: 3313041)
 
Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyko V, Behar S. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med. 2005;165:1154-60. (PMID: 15911729)
 
Maki KC, McKenney JM, Reeves MS, Lubin BC, Dicklin MR. Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. Am J Cardiol. 2008;102:429-33. (PMID: 18678300)
 
Monroe AK, Gudzune KA, Sharma R, Chelladurai Y, Ranasinghe PD, Ansari MT, et al. Combination Therapy Versus Intensification of Statin Monotherapy: An Update. Comparative Effectiveness Reviews, No. 132. Rockville, MD: Agency for Healthcare Research and Quality (US) Report No.: 14-EHC013-EF, 2014. (PMID: 24624458)
 
Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-43. (PMID: 18376000)
 
AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. 2011;161:538-43. (PMID: 21392609)
 
HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279-91. (PMID: 23444397)
 
Carleton RA, Bazzarre T, Drake J, Dunn A, Fisher EB Jr, Grundy SM, et al. Report of the Expert Panel on Awareness and Behavior Change to the Board of Directors, American Heart Association. Circulation. 1996;93:1768-72. (PMID: 8653885)
 
Tsuyuki RT, Johnson JA, Teo KK, Simpson SH, Ackman ML, Biggs RS, et al. A randomized trial of the effect of community pharmacist intervention on cholesterol risk management: the Study of Cardiovascular Risk Intervention by Pharmacists (SCRIP). Arch Intern Med. 2002;162:1149-55. (PMID: 12020186)
 
Mullen PD, Mains DA, Velez R. A meta-analysis of controlled trials of cardiac patient education. Patient Educ Couns. 1992;19:143-62. (PMID: 1299819)
 
McKenney JM, Davidson MH, Jacobson TA, Guyton JR; National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97:89C-94C. (PMID: 16581336)
 
Rader DJ, Hoeg JM, Brewer HB Jr. Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med. 1994;120:1012-25. [Full Text] (PMID: 8185133)
 
Stein JH, Rosenson RS. Treatment of severe hypertriglyceridemia lowers plasma viscosity. Atherosclerosis. 1998;137:401-5. (PMID: 9622283)
 
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276:273-81 concl. (PMID: 5334042)
 
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276:215-25 contd. (PMID: 5333808)
 
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276:148-56 contd. (PMID: 5334266)
 
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276:94-103 contd. (PMID: 5332928)
 
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276:34-42 contd. (PMID: 5333081)
 
ABCA1

adenosine triphosphate binding cassette transporter type A1

ACC

American College of Cardiology

ACCF

American College of Cardiology Foundation

AHA

American Heart Association

AHRQ

Agency for Healthcare Research and Quality

ALT

alanine aminotransferase

AST

aspartate aminotransferase

bid

twice daily

BMI

body mass index

BP

blood pressure

CABG

coronary artery bypass graft(ing)

CDC

Centers for Disease Control and Prevention

CHD

coronary heart disease

CI

confidence interval

CKD

chronic kidney disease

CT

computed tomography

CV

cardiovascular

CVA

cerebrovascular accident

FDA

Food and Drug Administration

GI

gastrointestinal

HDL

high-density lipoprotein (cholesterol)

HMG-CoA

3-hydroxy-3-methylglutaryl coenzyme A

HR

hazard ratio

IDL

intermediate-density lipoprotein (cholesterol)

LDL

low-density lipoprotein (cholesterol)

LFT

liver function test

MI

myocardial infarction

NNT

number needed to treat

OR

odds ratio

PTCA

percutaneous transluminal coronary angiography

qd

once daily

qhs

every night

RR

relative risk

TIA

transient ischemic attack

tid

three times daily

TSH

thyroid-stimulating hormone

VLDL

very-low-density lipoprotein (cholesterol)


Study name acronyms
AIM-HIGH

Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes

HPS2-THRIVE

Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events

JUPITER

Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin

VA-HIT

Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial


DOI: 10.7326/d176
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Disclosures:
Thomas A. Pearson, MD, PhD, FACP is a consultant for Bristol-Myers Squibb, Bayer, J and J Merck, Merck/Schering Plough, Sanofi-Adventis, Forbes/Meditech, received honorarium from Abbott, AstraZeneca, Bayer, Bristol-Myers/Squibb, KOS, Pfizer, Merck/Schering Plough, Merck & Co., received grants from KOS, Merck & Co., Pfizer, Sanofi-Adventis. Laurie A. Kopin, EdD, MS, RN, ANP, FPCNA has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Daniel Soffer, MD received a one-time consulting fee from Aegerion, grant funding from Sanofi/Regeneron, and an educational grant from Roche Genentech.
Deborah Korenstein, MD, FACP, Editor in Chief, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. Richard B. Lynn, MD, FACP, Editor, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.
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