What is the treatment for familial hypercholesterolemia?

Treatment of Familial Hypercholesterolemia

For adults with familial hypercholesterolemia, initiate high-intensity statin therapy immediately upon diagnosis with a goal of achieving ≥50% LDL-C reduction from baseline, adding ezetimibe if LDL-C remains >100 mg/dL despite maximal tolerated statin therapy, and escalating to PCSK9 inhibitors if goals are not met with combination therapy. 1, 2

Initial Treatment Strategy for Adults

Start with high-intensity statin therapy as first-line treatment:

• Atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily should be initiated immediately upon diagnosis 1, 3
• The primary goal is achieving ≥50% reduction in LDL-C from baseline 1, 2
• For patients with severe hypercholesterolemia (LDL-C ≥190 mg/dL), starting at 40 mg atorvastatin daily is reasonable 1
• Obtain baseline liver function tests, creatine kinase, glucose, and creatinine before initiating therapy 2, 3

Implement intensive lifestyle modifications concurrently:

• Restrict saturated fat to <7% of total calories 2
• Target 5-10% weight loss if overweight, which can reduce LDL-C by 20% 4
• Engage in at least 150 minutes per week of moderate-intensity aerobic activity 4
• Eliminate tobacco use completely 2

Escalation Algorithm When Goals Not Met

Add ezetimibe 10 mg daily if LDL-C remains >100 mg/dL after 4-6 weeks on maximal tolerated statin:

• Ezetimibe is well-tolerated, available as a generic, and provides additional 15-25% LDL-C reduction 1
• This combination has demonstrated cardiovascular risk reduction in patients with acute coronary syndrome 1
• Reassess lipid panel 4-6 weeks after adding ezetimibe 2

Consider bile acid sequestrants as third-line therapy:

• Colesevelam 3.75 g daily can provide an additional 18.5% LDL-C reduction when added to statin plus ezetimibe 1
• However, use is limited by gastrointestinal side effects, inconvenient dosing, and drug interactions 1
• Generic formulations are poorly tolerated 1

Add PCSK9 inhibitor therapy if LDL-C remains ≥100 mg/dL despite maximal statin plus ezetimibe:

• Alirocumab 75-150 mg subcutaneously every 2 weeks or evolocumab 140 mg every 2 weeks 5
• PCSK9 inhibitors provide ≥50% additional LDL-C reduction and are well-tolerated 1
• These agents are particularly effective in patients with heterozygous FH on background statin therapy 1, 5

Treatment Goals Based on Risk Stratification

For patients without additional ASCVD risk factors:

• Target LDL-C <135 mg/dL or approximately 50% reduction from baseline 1
• Non-fasting blood samples may be used to monitor LDL-C levels in those receiving stable therapy 1

For patients with additional ASCVD risk factors (diabetes, hypertension, elevated lipoprotein(a), or parental history of premature ASCVD):

• Target LDL-C <100 mg/dL 1, 2
• More aggressive treatment is warranted given the cumulative atherosclerotic burden 2

For patients with established ASCVD:

• Target LDL-C <70 mg/dL 1
• Consider combination therapy as first-line treatment in highest-risk patients 1

Pediatric Patients (Age ≥10 Years) with Heterozygous FH

Initiate statin therapy at age 10 years or older:

• Start with atorvastatin 10 mg daily; dosage range is 10-20 mg daily 1, 3
• Consider earlier initiation (age 8-10 years) if LDL-C >190 mg/dL on two occasions 1
• May also consider earlier treatment if LDL-C >160 mg/dL with multiple ASCVD risk factors or family history of premature ASCVD 1

Treatment goals for pediatric patients:

• Target LDL-C <135 mg/dL or approximately 50% reduction if no additional risk factors 1
• Target LDL-C <100 mg/dL if additional ASCVD risk factors present 1

Add ezetimibe and bile acid sequestrants if statin monotherapy insufficient:

• These agents should be considered in addition to maximal tolerated statin dose 1
• PCSK9 inhibitors may be considered according to clinical indications and regulatory approvals, though long-term safety data in children are limited 1

Homozygous FH Management

Initiate aggressive multi-drug therapy immediately upon diagnosis:

• Treatment should begin at diagnosis, ideally by age 2 years 1
• Start with high-potency statin with rapid up-titration to maximally tolerated doses 1
• Add ezetimibe within 8 weeks, followed by colesevelam if tolerated 1

Add PCSK9 inhibitor within 8 weeks in patients without biallelic LDLR null mutations:

• Continue only if ≥15% additional LDL-C reduction is demonstrated 1
• For highest-risk patients (symptomatic ASCVD or multivessel coronary atherosclerosis), strongly consider combination of high-potency statin, ezetimibe, and PCSK9 inhibitor as first-line treatment 1

Initiate lipoprotein apheresis if pharmacotherapy inadequate:

• Should be offered at age 3 years (no later than age 8 years) when LDL-C goals cannot be achieved with maximal pharmacotherapy 1
• Apheresis is particularly critical for homozygous FH patients 1

Treatment goals for homozygous FH:

• LDL-C <100 mg/dL in absence of ASCVD or major risk factors 1
• LDL-C <70 mg/dL with imaging evidence of ASCVD or additional major risk factors 1
• LDL-C <55 mg/dL with previous ASCVD event 1

Monitoring Strategy

Short-term monitoring:

• Assess lipid panel 4-6 weeks after initiating or adjusting therapy 2
• Monitor liver enzymes periodically while on statin therapy 2, 3
• Check creatine kinase if muscle symptoms develop 2

Long-term monitoring:

• Reassess lipid panel every 6-12 weeks until goals achieved 4
• Once stable, monitor annually or every 2 years if all values remain optimal 4
• Monitor growth and adherence to lifestyle management and medications annually 1

Critical Pitfalls to Avoid

Do not delay pharmacotherapy in favor of lifestyle modifications alone:

• FH patients have lifetime exposure to elevated LDL-C from birth, making early aggressive treatment essential 1, 2
• Lifestyle modifications are adjunctive, not sufficient as monotherapy 2

Do not use bile acid sequestrants when triglycerides >200 mg/dL:

• These agents are relatively contraindicated in hypertriglyceridemia 4

Exercise caution when combining fibrates with statins:

• Increased myositis risk, particularly with gemfibrozil 4
• Fenofibrate has a better safety profile if combination therapy is necessary 4
• Monitor creatine kinase levels, especially in patients >65 years 4

Instruct patients to report muscle symptoms immediately:

• Unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, requires prompt evaluation 3
• Temporarily discontinue statin if acute condition develops that increases rhabdomyolysis risk 3

Do not neglect family screening:

• Perform reverse-cascade screening of family members to identify other affected individuals 2
• Early identification and treatment of relatives can significantly reduce their lifetime cardiovascular risk 2

Address elevated lipoprotein(a) as an independent risk factor:

• Lipoprotein(a) >300 mg/dL warrants more aggressive LDL-C lowering targets 2
• This marker independently increases cardiovascular risk beyond LDL-C elevation 2