What is the best approach to managing a patient with familial hypercholesterolemia?

Approach to Managing Familial Hypercholesterolemia

Start all patients with FH on maximally tolerated high-potency statin therapy (rosuvastatin or atorvastatin) combined with ezetimibe 10 mg daily, targeting at least a 50% reduction in LDL-C from baseline, with specific LDL-C goals determined by cardiovascular risk level. 1, 2

Initial Diagnostic Workup

Before initiating therapy, obtain the following baseline assessments:

• Fasting lipid panel measuring total cholesterol, LDL-C, HDL-C, triglycerides, and non-HDL-C 2
• Lipoprotein(a) measurement, as elevated Lp(a) ≥125 nmol/l (≥60 mg/dl) is an independent risk factor requiring more aggressive LDL-C lowering 3, 2
• Baseline laboratory monitoring: hepatic aminotransferases, creatine kinase, glucose, and creatinine before starting drug therapy 2, 4
• Genetic testing to confirm FH diagnosis and guide family screening—this is crucial for identifying the specific mutation and enabling cascade screening of first-degree relatives 2
• Document family history of premature cardiovascular disease (men <55 years, women <65 years) 2
• Assess for existing atherosclerotic cardiovascular disease (ASCVD) through clinical history and consider imaging studies 2

Risk Stratification and LDL-C Treatment Goals

Set LDL-C targets based on ASCVD risk after achieving approximately 50% reduction from baseline 1:

• LDL-C <2.5 mmol/l (<100 mg/dl) in patients without ASCVD or other major ASCVD risk factors 3, 1
• LDL-C <1.8 mmol/l (<70 mg/dl) in patients with imaging evidence of ASCVD or other major ASCVD risk factors 3, 1
• LDL-C <1.4 mmol/l (<55 mg/dl) in patients with clinical ASCVD 3, 1

First-Line Pharmacotherapy Algorithm

Step 1: Initiate High-Potency Statin + Ezetimibe

• Start rosuvastatin 20-40 mg daily or atorvastatin 40-80 mg daily combined with ezetimibe 10 mg daily 1, 4, 5
• For Asian patients, initiate rosuvastatin at 5 mg once daily due to higher risk of myopathy 4
• For patients with severe renal impairment (not on hemodialysis), initiate rosuvastatin at 5 mg once daily and do not exceed 10 mg daily 4
• Ezetimibe provides an additional 15-25% LDL-C reduction and is well-tolerated 5

Step 2: Reassess at 6-12 Weeks

• Obtain fasting lipid panel to assess response 2
• If LDL-C goals not achieved, proceed to Step 3 1

Step 3: Add PCSK9 Inhibitor

• Add PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) if LDL-C goals not achieved despite maximally tolerated statin and ezetimibe therapy 1, 2
• PCSK9 inhibitors provide an additional 50-60% LDL-C reduction 2
• For patients without biallelic LDLR null mutations, add PCSK9 inhibitor within 8 weeks and continue only if achieving ≥15% additional LDL-C reduction 3

Step 4: Consider Bempedoic Acid

• Add bempedoic acid if LDL-C goals still not achieved, particularly useful in patients with statin intolerance as it lacks muscle-related side effects 1, 6

Step 5: Lipoprotein Apheresis

• Initiate lipoprotein apheresis in adults with phenotypic heterozygous FH and progressive ASCVD who do not achieve LDL-C goals despite combined treatment with high-potency statin, ezetimibe, and PCSK9 inhibitor, especially those with Lp(a) ≥125 nmol/l 3
• Perform weekly or fortnightly in specialized settings, treating 1-2 plasma volumes 3
• Continue all diet and drug therapy during apheresis treatment 3

Special Population: Homozygous FH (HoFH)

HoFH requires immediate aggressive treatment starting at diagnosis, ideally by age 2 years 3:

• Sequential medication approach: Start high-potency statin with rapid up-titration to maximally tolerated doses, add ezetimibe within 8 weeks, possibly add colesevelam if tolerated 3, 1
• Add PCSK9 inhibitor within a further 8 weeks in patients without biallelic LDLR null mutations 3
• For highest-risk patients (symptomatic ASCVD or multivessel coronary atherosclerosis), strongly consider combination of high-potency statin, ezetimibe, and PCSK9-targeted therapy as first-line treatment 3
• Lipoprotein apheresis should be offered at age 3 years (no later than 8 years) when LDL-C goals not achieved with maximally tolerated medications 3
• Consider lomitapide or evinacumab in patients with markedly elevated LDL-C despite conventional therapy or rapidly progressive ASCVD, especially if apheresis unavailable 3
• Liver transplantation should be considered in patients with rapidly progressive ASCVD who do not attain guideline-recommended LDL-C goals despite all available treatments 3

Special Population: Pediatric Patients

Heterozygous FH (HeFH):

• Ages 8 to <10 years: 5-10 mg rosuvastatin daily 4
• Ages ≥10 years: 5-20 mg rosuvastatin daily 4
• Ezetimibe approved for ages ≥10 years in combination with statin 5

Homozygous FH (HoFH):

• Ages ≥7 years: 20 mg rosuvastatin daily 4
• Ezetimibe approved for ages ≥10 years 5

Monitoring Strategy

• Reassess fasting lipid panel 6-12 weeks after implementing lifestyle modifications or changing pharmacotherapy 2
• Non-fasting lipid profiles can be used to monitor treatment in stable patients 1
• Monitor hepatic aminotransferases as clinically indicated, particularly in patients at increased risk of hepatotoxicity 2, 4
• Monitor creatine kinase if myopathy suspected—instruct patients to report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever 4

Critical Safety Considerations

Myopathy and Rhabdomyolysis Risk Factors:

• Age ≥65 years, uncontrolled hypothyroidism, renal impairment, higher statin dosage 4
• Asian patients at higher risk for myopathy 4
• Discontinue statin if markedly elevated CK levels occur or myopathy diagnosed 4
• Temporarily discontinue in patients experiencing acute conditions at high risk of developing renal failure secondary to rhabdomyolysis 4

Hepatic Monitoring:

• Perform liver enzyme testing as clinically indicated 5
• Consider withdrawal if ALT or AST ≥3× ULN persist 5
• If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia occurs, promptly discontinue statin 4

Comprehensive Cardiovascular Risk Management

Beyond lipid lowering, address all modifiable risk factors 1:

• Smoking cessation (absolute priority)
• Blood pressure control to guideline targets
• Diabetes management if present
• Weight management and treatment of metabolic syndrome
• Regular physical exercise and stress reduction
• Consider low-dose aspirin for primary prevention in asymptomatic patients at higher risk of ASCVD, particularly those with elevated Lp(a), diabetes, or adverse cardiovascular imaging findings 1

Lifestyle Modifications

Implement heart-healthy diet and lifestyle changes concurrently with pharmacotherapy 3, 1:

• Fat-modified, heart-healthy diet with reduced saturated fat intake
• Regular physical exercise
• Moderate alcohol intake
• Sleep hygiene optimization
• Psychological stress reduction

Family Screening

Cascade screening of first-degree relatives is essential as FH is autosomal dominant with 50% transmission risk 2:

• Screen all first-degree relatives once index case identified
• Genetic testing facilitates identification of affected family members
• Early detection enables preventive treatment before ASCVD develops

Common Pitfalls to Avoid

• Do not delay combination therapy—starting statin monotherapy and waiting months before adding ezetimibe wastes valuable time; initiate both simultaneously 1
• Do not use low or moderate-potency statins—only high-potency statins (rosuvastatin 20-40 mg or atorvastatin 40-80 mg) provide adequate LDL-C reduction 1, 4
• Do not accept suboptimal LDL-C control—if goals not met at 6-12 weeks, escalate therapy immediately rather than continuing inadequate treatment 1, 2
• Do not forget lipoprotein(a) measurement—elevated Lp(a) is an independent risk factor requiring more aggressive LDL-C lowering targets 3, 2
• Do not neglect family screening—failure to screen relatives misses opportunity for early intervention in affected family members 2