What is the management of familial hypercholesterolemia?

Management of Familial Hypercholesterolemia

All patients with familial hypercholesterolemia require immediate initiation of high-intensity statin therapy upon diagnosis, with aggressive escalation to combination therapy including ezetimibe and PCSK9 inhibitors as needed to achieve LDL-cholesterol goals based on risk stratification. 1

Initial Diagnostic Confirmation and Risk Assessment

• Confirm the diagnosis using Dutch Lipid Clinic Network or Simon Broome criteria in adults, incorporating elevated LDL-cholesterol levels, family history of premature cardiovascular disease, and physical stigmata such as tendon xanthomas. 2
• Perform genetic testing in all suspected cases to identify pathogenic variants in LDLR, APOB, or PCSK9 genes, which provides the most accurate diagnosis and enables cascade testing of family members. 2
• Stratify cardiovascular risk by assessing non-cholesterol risk factors (age, sex, smoking, hypertension, diabetes, obesity), lipoprotein(a) levels, family history of premature atherosclerotic cardiovascular disease (ASCVD) in first-degree relatives, and presence of tendon xanthomas. 3
• Do not use general population cardiovascular risk calculators (Framingham, Pooled Cohort Equation, SCORE-2, QRISK-3) in FH patients, as these underestimate risk; instead consider FH-specific calculators like SAFEHEART or FH Risk Score. 3

Treatment Goals Based on Risk Stratification

Adults with Heterozygous FH

• Target LDL-cholesterol <100 mg/dL (<2.5 mmol/L) in patients without ASCVD or major risk factors, with a minimum 50% reduction from baseline. 1, 4
• Target LDL-cholesterol <70 mg/dL (<1.8 mmol/L) in patients with imaging evidence of ASCVD or major risk factors. 1, 4
• Target LDL-cholesterol <55 mg/dL (<1.4 mmol/L) in patients with established clinical ASCVD. 1, 4
• Consider LDL-cholesterol <40 mg/dL (<1.0 mmol/L) in patients with recurrent ASCVD events within 2 years despite maximal statin therapy. 4

Pediatric Patients (Age 8-10 Years and Older) with Heterozygous FH

• Target LDL-cholesterol <135 mg/dL (<3.5 mmol/L) or approximately 50% reduction in children without additional ASCVD risk factors. 3, 1
• Target LDL-cholesterol <100 mg/dL (<2.5 mmol/L) in children with additional risk factors such as diabetes, hypertension, elevated lipoprotein(a), or parental history of ASCVD in the second or third decade. 3, 1

Homozygous FH (All Ages)

• Target LDL-cholesterol <100 mg/dL in the absence of ASCVD or major risk factors. 1
• Target LDL-cholesterol <70 mg/dL with imaging evidence of ASCVD or additional major risk factors. 1
• Target LDL-cholesterol <55 mg/dL with previous ASCVD events. 1

Stepwise Treatment Algorithm for Adults with Heterozygous FH

Step 1: Lifestyle Modifications and Initial Pharmacotherapy

• Initiate high-intensity statin therapy immediately upon diagnosis: atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily. 1, 5
• Counsel all patients on a heart-healthy, low saturated fat diet (<10% of total calories), high-fiber intake, regular physical exercise, weight reduction if applicable, smoking cessation, and blood pressure control. 3, 1
• Obtain baseline liver function tests, creatine kinase, glucose, and creatinine before initiating statin therapy. 1
• Reassess LDL-cholesterol at 4-6 weeks after initiation to evaluate response. 1, 5

Step 2: Add Ezetimibe if Goals Not Met

• Add ezetimibe 10 mg daily if LDL-cholesterol remains >100 mg/dL after 4-6 weeks on maximal tolerated statin therapy, as this provides an additional 15-25% LDL-cholesterol reduction. 1
• Reassess LDL-cholesterol 4-6 weeks after adding ezetimibe. 1

Step 3: Consider Bile Acid Sequestrants

• Add colesevelam 3.75 g daily if LDL-cholesterol goals remain unmet, which provides an additional 18.5% reduction when combined with statin plus ezetimibe. 1
• Do not use bile acid sequestrants when triglycerides exceed 200 mg/dL due to risk of further triglyceride elevation. 1

Step 4: Add PCSK9 Inhibitor Therapy

• Add PCSK9 inhibitor (evolocumab or alirocumab) if LDL-cholesterol remains ≥100 mg/dL despite maximal tolerated statin plus ezetimibe, as this provides ≥50% additional LDL-cholesterol reduction. 1
• PCSK9 inhibitors are effective in patients with residual LDL receptor function but require longer-term safety data, particularly in younger patients. 3

Exception: Aggressive First-Line Therapy for Extremely High-Risk Patients

• Initiate triple therapy immediately (high-intensity statin + ezetimibe + PCSK9 inhibitor) in patients with recent myocardial infarction, multivessel coronary atherosclerosis, or polyvascular disease. 4

Treatment Algorithm for Pediatric Patients with Heterozygous FH

Timing of Initiation

• Offer pharmacological treatment at age 8-10 years if LDL-cholesterol >190 mg/dL (>4.9 mmol/L) on two fasting occasions. 3, 1
• Consider treatment at age 8-10 years if LDL-cholesterol >160 mg/dL (>4.0 mmol/L) with multiple ASCVD risk factors or family history of premature ASCVD. 3, 1
• Initiation before age 8 years may be considered if LDL-cholesterol >190 mg/dL on two occasions. 3

Medication Selection and Escalation

• Start with atorvastatin 10 mg daily as the initial medication of choice, as this is FDA-approved for pediatric use. 3, 5
• Uptitrate to atorvastatin 20 mg daily if LDL-cholesterol remains >130 mg/dL after 4 weeks. 5
• Add ezetimibe and bile acid sequestrants to maximal tolerated statin dose if treatment goals are not achieved. 3
• PCSK9 inhibitors may be considered in children and adolescents with additional risk factors for ASCVD, noting limited long-term safety data. 3

Treatment Algorithm for Homozygous FH

Immediate Aggressive Multi-Drug Therapy

• Begin treatment at diagnosis, ideally by age 2 years, with high-potency statin and rapid up-titration to maximally tolerated doses. 1, 4
• Add ezetimibe within 8 weeks if LDL-cholesterol goals are not achieved. 1, 4
• Add colesevelam as needed for additional LDL-cholesterol reduction. 1

LDLR-Dependent vs LDLR-Independent Therapies

• Add PCSK9 inhibitor therapy within 8 weeks in patients without biallelic LDLR null mutations, as efficacy depends on residual LDLR function. 3, 1
• Consider lomitapide (microsomal triglyceride transfer protein inhibitor) or evinacumab (ANGPTL3 monoclonal antibody) in patients with absent LDLR function, as these work independently of LDLR. 3
• Evinacumab has fewer adverse effects than lomitapide but requires confirmation of long-term efficacy and safety. 3

Lipoprotein Apheresis

• Initiate lipoprotein apheresis if pharmacotherapy is inadequate, particularly in homozygous FH or treatment-resistant heterozygous FH with established ASCVD. 1
• The use of apheresis before, after, or in combination with LDLR-independent therapies depends on availability, expertise, and patient response. 3

Monitoring Strategy

• Assess lipid panel 4-6 weeks after initiating or adjusting therapy, then every 6-12 weeks until goals are achieved, followed by every 3-12 months once stable. 1, 4
• Monitor liver enzymes periodically in patients at increased risk of hepatotoxicity while on statin therapy. 1, 4
• Check creatine kinase if muscle symptoms develop and instruct patients to report muscle symptoms immediately. 1, 4
• Monitor glucose/HbA1c if diabetes risk factors are present. 4
• Use non-fasting lipid profiles for monitoring stable therapy; use fasting LDL-cholesterol for treatment decisions. 4

Cardiovascular Imaging for Risk Stratification

• Consider coronary artery calcium scoring (CACS), CT coronary angiography, or carotid ultrasonography in asymptomatic adults with heterozygous FH to document presence and severity of subclinical atherosclerosis. 3, 2
• Do not use CACS to monitor treatment effectiveness; use it only for initial risk assessment. 2
• Perform Doppler echocardiographic evaluation of the heart and aorta annually in homozygous FH patients, and CT coronary angiography every 5 years or less if clinically indicated. 2

Cascade Testing and Family Screening

• Offer cascade genetic testing for the specific pathogenic variant to all first-degree relatives after identifying a mutation in the proband, then extend to second-degree and third-degree relatives as needed. 2
• Provide pre-test and post-test genetic counseling to all patients and at-risk relatives as an integral component of testing. 2
• Use standardized processes for consenting, testing, and reporting results, with digital tools and practical resources to facilitate counseling and risk communication. 3
• Children born to a parent with homozygous FH and a parent without FH are obligate heterozygotes and should be formally diagnosed and offered treatment by age 8 years. 3

Special Considerations for Pregnancy

• Provide pre-conception counseling to women with FH about pregnancy risks, including cardiovascular assessment if clinically indicated, and discuss contraception options. 3
• Discontinue statins, ezetimibe, and PCSK9 inhibitors during pregnancy and lactation due to lack of safety data, recognizing this results in prolonged exposure to elevated LDL-cholesterol. 3
• Optimize lifestyle and non-cholesterol risk factors before conception to minimize cardiovascular risk during the period off lipid-lowering therapy. 3
• Counsel couples about LDL-cholesterol testing of the partner and consider prenatal and pre-implantation genetic testing with counseling in couples known to have FH. 3

Critical Pitfalls to Avoid

• Do not delay pharmacotherapy in favor of lifestyle modifications alone, as FH patients have lifetime exposure to elevated LDL-cholesterol from birth, making early aggressive treatment essential. 3, 1
• Do not use general population risk calculators in FH patients, as these significantly underestimate cardiovascular risk. 3
• Do not combine fibrates with statins without careful monitoring due to increased myositis risk. 1
• Do not use bile acid sequestrants when triglycerides exceed 200 mg/dL. 1
• Do not rely solely on total cholesterol for treatment decisions; always use LDL-cholesterol as the primary target. 4
• Do not underestimate the importance of elevated lipoprotein(a) as an independent risk factor; more aggressive LDL-cholesterol lowering targets are warranted if lipoprotein(a) exceeds 300 mg/dL. 1
• Do not fail to screen family members, as cascade testing is highly cost-effective and identifies affected individuals who benefit from early treatment. 2