What is the appropriate treatment plan for a patient with familial hypercholesterolemia to reduce the risk of premature cardiovascular disease?

Treatment of Familial Hypercholesterolemia

Initiate high-intensity statin therapy immediately upon diagnosis of familial hypercholesterolemia, targeting ≥50% LDL-C reduction from baseline, with sequential addition of ezetimibe if LDL-C remains >100 mg/dL and PCSK9 inhibitors if goals are still not met, as this stepwise approach reduces premature cardiovascular disease and mortality. 1

Immediate First-Line Treatment

Start high-intensity statin therapy on the day of diagnosis without waiting for lifestyle modifications, as FH patients have had lifetime exposure to elevated LDL-C from birth, making delay unacceptable. 1

• Atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily should be initiated as first-line therapy. 1
• For patients with severe hypercholesterolemia, starting at atorvastatin 40 mg daily is reasonable, with uptitration as tolerated. 1, 2
• Obtain baseline liver function tests, creatine kinase, glucose, and creatinine before initiating therapy. 1

Treatment Goals Based on Risk Stratification

The target LDL-C varies based on the presence of additional risk factors and established disease:

• No additional ASCVD risk factors: Target LDL-C <135 mg/dL or ≥50% reduction from baseline. 1
• Additional ASCVD risk factors present: Target LDL-C <100 mg/dL. 1
• Established ASCVD: Target LDL-C <70 mg/dL. 1

Additional ASCVD risk factors include poorly controlled hypertension, current smoking, low HDL-C (<40 mg/dL men, <50 mg/dL women), elevated lipoprotein(a), CKD, diabetes, or family history of premature cardiovascular disease. 3

Sequential Escalation Algorithm

Reassess lipid panel 4-6 weeks after initiating or adjusting therapy. 1

Step 2: Add Ezetimibe

• Add ezetimibe 10 mg daily if LDL-C remains >100 mg/dL after 4-6 weeks on maximal tolerated statin. 1, 4
• Ezetimibe provides an additional 15-25% LDL-C reduction and has demonstrated cardiovascular risk reduction in the IMPROVE-IT trial (6% relative/2% absolute risk reduction over 7 years). 3, 1

Step 3: Consider Bile Acid Sequestrants

• Colesevelam 3.75 g daily can provide an additional 18.5% LDL-C reduction when added to statin plus ezetimibe. 1
• Do not use bile acid sequestrants when triglycerides >200 mg/dL, as they can worsen hypertriglyceridemia. 1
• Gastrointestinal side effects and drug interactions limit their use. 1

Step 4: Add PCSK9 Inhibitors

• Add PCSK9 inhibitor therapy if LDL-C remains ≥100 mg/dL (or ≥70 mg/dL with established ASCVD) despite maximal statin plus ezetimibe. 1, 5
• PCSK9 inhibitors provide ≥50% additional LDL-C reduction and are well-tolerated. 1
• Options include evolocumab, alirocumab, or inclisiran (dosed every 6 months after loading doses). 5

Pediatric Patients (Age ≥10 Years) with Heterozygous FH

Initiate statin therapy at age 10 years or older in children with heterozygous FH. 1

• Start with atorvastatin 10 mg daily, uptitrating to 20 mg if LDL-C remains >130 mg/dL after 4 weeks. 3, 2
• Consider earlier initiation if LDL-C >190 mg/dL on two occasions or if multiple ASCVD risk factors are present. 1
• Treatment goals: LDL-C <135 mg/dL (or ≥50% reduction) if no additional risk factors; <100 mg/dL if additional ASCVD risk factors present. 1
• Ezetimibe can be added in pediatric patients 10 years and older with HeFH if statin monotherapy is inadequate. 4

Homozygous FH Management

Initiate aggressive multi-drug therapy immediately upon diagnosis, ideally by age 2 years. 1

• Start with high-potency statin and rapid uptitration to maximally tolerated doses. 1
• Add ezetimibe and colesevelam as needed. 1
• Add PCSK9 inhibitor therapy within 8 weeks in patients without biallelic LDLR null mutations. 1
• Initiate lipoprotein apheresis if pharmacotherapy is inadequate to achieve goals. 1
• Treatment goals: LDL-C <100 mg/dL without ASCVD; <70 mg/dL with imaging evidence of ASCVD or major risk factors; <55 mg/dL with previous ASCVD event. 1

Monitoring Strategy

• Lipid panel at 4-6 weeks after initiating or adjusting therapy. 1
• Lipid panel every 6-12 weeks until goals are achieved. 1
• Monitor liver enzymes periodically while on statin therapy. 1
• Check creatine kinase if muscle symptoms develop and instruct patients to report muscle symptoms immediately. 1, 2
• Non-fasting blood samples may be used to monitor LDL-C levels in patients receiving stable therapy. 1

Critical Pitfalls to Avoid

Do not delay pharmacotherapy in favor of lifestyle modifications alone, as this wastes critical time in patients who have had elevated LDL-C since birth. 1

• Do not use fibrates with statins except in specific circumstances, as this increases myositis risk. 1
• Do not use niacin preparations added to statin therapy, as they have been associated with no benefit and potential harms. 3
• Address elevated lipoprotein(a) as an independent risk factor with more aggressive LDL-C lowering targets if lipoprotein(a) >300 mg/dL. 1
• Perform family screening to identify other affected individuals through cascade testing. 1

Specialist Referral

All patients with suspected FH should be referred to or discussed with a lipid specialist to plan further management, including genetic confirmation, complex treatment decisions, and consideration of advanced therapies. 6

• National and regional centers with expertise in lipidology, genetics, and ASCVD prevention should accept referrals for complex cases. 6
• A multidisciplinary team approach ensures comprehensive management including genetic counseling, advanced treatment options, and management of treatment-resistant cases. 6