Hypercholesterolemia

Although elevated blood cholesterol level is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD) and very likely to be causal in the development of ASCVD, recommendations for how and when to treat hypercholesterolemia for primary prevention of ASCVD continue to evolve. In this section, we will cover:

• Hyperlipidemia

• Hypertriglyceridemia

Hyperlipidemia

Guidelines and Treatment Thresholds

Prior to 2013, cholesterol treatment guidelines were based on low-density lipoprotein (LDL)-cholesterol levels and other risk factors to determine risk categories and recommended treatment depending on LDL-cholesterol goals. Guidelines since then — including the American College of Cardiology (ACC) and the American Heart Association (AHA) 2018 guidelines on management of blood cholesterol and 2019 guidelines on prevention of cardiovascular disease (CVD) — have shifted the focus away from LDL-cholesterol targets to a focus on risk stratification (of which the lipid panel is a component) and appropriate intensity of statin therapy based on risk profiles to reduce LDL cholesterol. This change reflects stronger evidence from randomized clinical trials (RCTs). Based on these data, statins are strongly preferred over other lipid-lowering drugs and treatment is heavily based on ASCVD risk and intensity of statin therapy.

The ACC has an online risk estimator to calculate 10-year ASCVD risk using the Pooled Cohort Risk Assessment Equations model released with the guideline. Untreated LDL cholesterol ≥190 mg/dL suggests genetic hyperlipidemia. Other risk factors to consider include: family history (ASCVD onset in first-degree male relatives aged <55 or first-degree female relatives aged <65), high-sensitivity C-reactive protein level ≥2 mg/liter, coronary artery calcification Agatston score ≥300, or ankle-brachial index <0.9.

The following table describes the major groups for whom statins are recommended by the AHA/ACC:

United States Preventive Services Task Force (USPSTF): In August 2022, the USPSTF issued updated guidelines on statin use for the primary prevention of CVD in adults. The USPSTF recommends use of statin therapy for primary prevention of CVD for adults ages 45 to 75 years who have one or more CVD risk factors (e.g., dyslipidemia, hypertension, diabetes, smoking) and an estimated 10-year ASCVD risk greater than 10% using the ACC/AHA ASCVD risk estimator (grade B recommendation). Statins should be selectively used for primary prevention of CVD in those with one or more CVD risk factors and estimated 10-year ASCVD risk between 7.5% to 10% (grade C recommendation).

Screening

Lipid-screening recommendations differ across organizations as follows:

• ACC/AHA: The 2018 and 2019 guidelines recommend screening adults aged 21-75 every 4-6 years and cascade screening of family members and those younger than 21 years with a strong family history.

• USPSTF: The 2022 recommendations advise screening adults aged 40-75 every 5 years. The interval may vary based on individual risks. The authors found insufficient evidence for or against screening those aged <40.

• UK NICE: Last updated in 2016, the UK National Institute for Health and Care Excellence (NICE) recommends screening adults aged >40 on an ongoing basis with no specific intervals.

The lipid panel: The 2018 ACC/AHA guideline prefers obtaining a fasting lipid panel with the rationale that an elevated nonfasting triglyceride level will artificially lower LDL cholesterol, which is typically calculated by the Friedewald equation (LDL = total cholesterol [mg/dL] - (triglyceride [mg/dL]/5) - HDL [mg/dL]). Some laboratories can directly measure LDL cholesterol, obviating the need for fasting. Research suggests that routine fasting is unnecessary except when the triglyceride level is very high (see the NEJM Journal Watch summary).

Secondary causes: Evaluate for secondary causes of hyperlipidemia in the initial workup, including hypothyroidism, uncontrolled diabetes, excessive alcohol use, smoking, obstructive liver disease, nephrotic syndrome, chronic kidney disease, and certain medications (e.g., thiazides, beta-blockers, glucocorticoids).

Medications and Management

Statin Drugs

The following statins and dosing, categorized by intensity, are available as treatment options for the major groups for whom statins are recommended.

Statin therapy is tailored to an anticipated relative reduction of the LDL cholesterol level (rather than a specific LDL cholesterol goal) as follows:

• ≥50% LDL cholesterol reduction with high-intensity statin use

• 30%-50% reduction with moderate-intensity statin use

If the effect is not adequate:

• Reinforce lifestyle changes and adherence.

• Reevaluate for secondary hyperlipidemia.

• Increase statin dose or consider nonstatin drugs (see below) for patients with very high ASCVD risk, such as prior clinical ASCVD or familial hypercholesterolemia. Note: No nonstatin drug has shown a clear benefit for primary prevention.

Nonstatin Drugs

Ezetimibe: Ezetimibe is a generic medication that lowers blood cholesterol level by inhibiting intestinal absorption and is FDA-approved for the treatment of primary hyperlipidemia and familial hypercholesterolemia. In the landmark IMPROVE-IT trial (view a NEJM Quick Take video summary and read the NEJM Journal Watch summary), patients who, after a hospitalization for acute coronary syndrome, were randomized to combination simvastatin-ezetimibe had fewer cardiovascular outcomes than those randomized to simvastatin-placebo. The benefit of ezetimibe (absolute risk difference, 2.0 percentage points in the primary outcome) was small, but ezetimibe is one of the few nonstatin agents to demonstrate a hard outcome benefit and is the statin adjunct of choice for high-risk patients who do not achieve adequate LDL cholesterol reduction.

PCSK9 inhibitors: In 2015, the FDA approved alirocumab (Praluent) and evolocumab (Repatha), two drugs in this new class of lipid-lowering agents. These drugs augment the uptake of circulating LDL in the liver by inhibiting proprotein convertase subtilisin-kexin type 9 (PCSK9), which normally binds LDL receptors for degradation and leads to decreased cellular ability to clear circulating LDL cholesterol. They are FDA-approved for adjunctive use in patients with clinical ASCVD or familial hypercholesterolemia who have had an inadequate response to maximal statin therapy. The available efficacy data for alirocumab and evolocumab show that PCSK9 inhibitors can significantly lower LDL cholesterol (up to 60%) and evolocumab and alirocumab trials demonstrate a reduction in the incidence of cardiovascular events in patients with ASCVD. Due to the results of the FOURIER trial (read the NEJM Journal Watch summary), evolocumab gained FDA indication to prevent cardiovascular events in patients with existing ASCVD. Ezetimibe should be added to maximal statin therapy prior to initiation of a PCSK9-inhibitor.

Statin Intolerance

Although statins are generally well tolerated, the incidence of muscle symptoms can range from 5% in randomized trials to 20% in clinical practice. Rarer but serious adverse effects include rhabdomyolysis and statin-associated autoimmune myopathy. Not all myalgia is necessarily caused by statins, and inappropriately stopping them can lead to worse outcomes, especially in those with a prior myocardial infarction.

Evaluation of statin intolerance: The ACC has a mobile-friendly tool for guiding an evaluation of statin intolerance. Myalgia from statins typically is bilateral and involves large muscle groups, such as the thigh, shoulder girdle, back, and buttock. Onset is usually within weeks of starting the medication and should resolve within weeks of cessation. Review drug-drug interactions that can inhibit statin metabolism and assess for other musculoskeletal illnesses.

Laboratory tests include:

• Creatine kinase: Recent exercise can cause asymptomatic elevation; it should be normal to slightly elevated with simple myopathy.

• Basic metabolic panel: Renal function and electrolytes can help assess for rhabdomyolysis.

• Thyroid-stimulating hormone: Hypothyroidism can cause myopathy with or without creatine kinase elevation and predispose to statin myopathy.

• Vitamin D: Deficiency is associated with statin myopathy, but studies are not conclusive.

Management: If a patient is not tolerating the prescribed statin, consider the following next steps:

• Hold the statin until symptoms resolve and then rechallenge the patient with a lower dose of the same statin or a different statin (pravastatin and fluvastatin may have lower risks of myopathy).

• Every-other-day dosing can be considered with atorvastatin and rosuvastatin (both have long half-lives).

• Correct for hypothyroidism and vitamin D deficiency.

• If repeated statin challenges fail, consider ezetimibe or a PCSK9 inhibitor, or both, for patients with strong indications for treatment.

Hypertriglyceridemia

Hypertriglyceridemia is a common clinical problem and an important marker of elevated risk of ASCVD. Severe hypertriglyceridemia may cause pancreatitis. A minority of patients with hypertriglyceridemia have a monogenic cause (e.g., familial chylomicronemia syndrome), but most people have polygenic hypertriglyceridemia with expression in the presence of other secondary factors.

Guidelines and Management

The 2018 ACC/AHA guideline classifies moderate hypertriglyceridemia as 175−499 mg/dL and severe hypertriglyceridemia as >500 mg/dL. In patients with hypertriglyceridemia, secondary factors should be investigated and managed accordingly. Adults with moderate or severe hypertriglyceridemia with an ASCVD risk of ≥7.5% and for whom therapeutic lifestyle changes and secondary causes have been addressed, initiation or intensification of statin therapy should be strongly considered, especially if the fasting triglyceride level is >500 mg/dL. Adults with severe hypertriglyceridemia (≥1000 mg/dL or 11.3 mmol/L) should undergo intensive lifestyle modification (very-low-fat diet, avoid refined carbohydrates and alcohol) and consideration of fibrate or omega-3 fatty acid therapy to prevent acute pancreatitis.

Emerging treatments: Icosapent ethyl (Vascepa) is currently approved by the U.S. Food and Drug Administration (FDA) to reduce triglycerides in patients with triglycerides above 500 mg/dL, and to reduce cardiovascular risk in patients at high risk for CVD with a triglyceride level ≥150 mg/dL. The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) randomized 8179 statin-treated patients with elevated cardiovascular risk to receive icosapent ethyl (2 grams twice daily) or placebo. All patients had either established cardiovascular disease or diabetes plus at least one additional cardiovascular risk factor. After a median of 4.9 years, the primary endpoint (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) occurred in significantly fewer patients who received icosapent ethyl than placebo (17.2% vs. 22.0%; hazard ratio, 0.75), suggesting that icosapent ethyl lowered the risk of major ischemic events in patients with elevated triglyceride levels who were receiving statin.