What is the treatment for familial hyperlipidemia?

Treatment of Familial Hyperlipidemia

First-Line Therapy: High-Potency Statin Plus Ezetimibe

Initiate high-potency statin therapy (atorvastatin, rosuvastatin, or pitavastatin) combined with ezetimibe as first-line treatment for most patients with familial hypercholesterolemia, targeting at least a 50% reduction in LDL-cholesterol from baseline. 1

• High-potency statins provide 30-50% LDL-C reduction and are FDA-approved for both heterozygous and homozygous familial hypercholesterolemia in adults and pediatric patients aged 10 years and older 2
• Adding ezetimibe provides an additional 15-20% LDL-C reduction and is FDA-approved for use in combination with statins for familial hypercholesterolemia 1, 3
• This combination approach is more effective than statin monotherapy and should be initiated early rather than sequentially titrating 1

LDL-Cholesterol Treatment Goals Based on Risk Stratification

The treatment targets differ substantially based on cardiovascular risk status:

• No ASCVD or major risk factors: LDL-C <100 mg/dL (<2.5 mmol/L) 1
• Imaging evidence of ASCVD or other major risk factors: LDL-C <70 mg/dL (<1.8 mmol/L) 1
• Clinical ASCVD present: LDL-C <55 mg/dL (<1.4 mmol/L) 1
• Recurrent ASCVD events within 2 years despite maximally tolerated statin: LDL-C <40 mg/dL (<1.0 mmol/L) may be considered 1

These aggressive targets reflect the cumulative lifetime cholesterol burden in familial hypercholesterolemia patients, who have markedly elevated LDL-C from birth 4

Escalation to PCSK9 Inhibitors

Add PCSK9-targeted therapy (monoclonal antibodies or inclisiran) when LDL-cholesterol goals are not achieved despite maximally tolerated statin plus ezetimibe. 1

• PCSK9 inhibitors should not be delayed when goals are unmet with statin plus ezetimibe, as early aggressive treatment reduces lifetime cardiovascular risk 1
• For extremely high-risk patients (post-myocardial infarction, multivessel coronary disease, or polyvascular disease), consider combination of high-potency statin, ezetimibe, and PCSK9 inhibitor as first-line treatment 1
• The number needed to treat for adolescents with familial hypercholesterolemia to prevent one heart attack is impressively only two, supporting early aggressive intervention 4, 1

Additional Adjunctive Therapies

If LDL-cholesterol goals remain unmet after statin, ezetimibe, and PCSK9 inhibitor:

• Bempedoic acid may be added as an additional adjunctive agent 1
• Plant sterols/stanols or bile acid sequestrants (colesevelam) may be considered 1
• Critical caveat: Bile acid sequestrants should be avoided when triglycerides exceed 200 mg/dL, as they are relatively contraindicated in hypertriglyceridemia 1, 5

Homozygous Familial Hypercholesterolemia (HoFH): Specialized Approach

HoFH requires more aggressive therapy due to markedly elevated LDL-C from conception and accelerated ASCVD:

• Early combination therapy with high-intensity statins, ezetimibe, and PCSK9-directed therapies forms the mainstay, but response depends on residual LDL receptor function 4
• Lomitapide (microsomal triglyceride transfer protein inhibitor) works independently of LDL receptor function and is effective for severe cases 4
• Evinacumab (ANGPTL3 monoclonal antibody) has fewer adverse effects than lomitapide, works independently of LDL receptor function, and is effective in children with HoFH 4
• Lipoprotein apheresis is effective and should be used in countries without access to newer therapies or in combination with pharmacotherapy 4
• Liver transplantation may be offered to young patients with severe HoFH (biallelic null variants) refractory to current therapies, leading to sustained normalization of LDL-cholesterol and regression of coronary atherosclerosis 4

Universal Lifestyle Modifications

All patients require intensive lifestyle intervention alongside pharmacotherapy:

• Heart-healthy diet with saturated fat <7% of total calories 1
• Regular physical exercise: 150 minutes per week of moderate-intensity aerobic activity or 75 minutes per week of vigorous-intensity activity 1
• Weight management targeting 5-10% loss if overweight 1
• Complete elimination of alcohol for patients with concomitant hypertriglyceridemia 5
• Sleep hygiene optimization and reduction in psychological stress 1

Monitoring Strategy

Baseline assessment:

• Measure hepatic aminotransferases, creatine kinase, glucose, and creatinine before starting drug therapy 1
• Obtain fasting lipid profile for treatment decisions, especially with concomitant hypertriglyceridemia 1

Follow-up monitoring:

• Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle modifications or medication changes 1, 5
• Monitor hepatic aminotransferases in patients at increased risk of hepatotoxicity (liver disease history, excess alcohol, drug interactions) 1
• Monitor creatine kinase levels when using combination therapy with fibrates and statins, particularly in patients >65 years of age 5

Critical Pitfalls to Avoid

• Undertreatment with lifestyle modifications alone in high-risk patients—pharmacotherapy is essential for achieving LDL-C goals 1
• Delaying PCSK9 inhibitor therapy when goals are not met with statin plus ezetimibe—early aggressive treatment reduces lifetime cardiovascular risk 1
• Using bile acid sequestrants when triglycerides >200 mg/dL—they are relatively contraindicated 1, 5
• Combining gemfibrozil with statins—use fenofibrate instead for better safety profile if fibrate therapy is needed 1, 5
• Failing to screen family members—reverse-cascade screening identifies other affected individuals who benefit from early treatment 1
• Discontinuing cholesterol-lowering therapy during acute illness—continue unless specifically contraindicated 1

Special Considerations

• Genetic testing may increase the use of statins in children and should be considered to confirm diagnosis 4
• Elevated Lp(a) is an independent risk factor warranting more aggressive LDL-C lowering 1
• Consider low-dose aspirin for primary prevention in asymptomatic patients with marked Lp(a) elevation 1
• For patients with mixed hyperlipidemia (elevated LDL-C and triglycerides), fenofibrate can be combined with ezetimibe per FDA labeling 3