What is the initial management and treatment approach for familial hyperlipidemia?

Workup and Initial Management of Familial Hyperlipidemia

Diagnostic Workup

Begin with a fasting lipid panel to measure total cholesterol, LDL-C, HDL-C, triglycerides, and calculate non-HDL-C. 1, 2 This distinguishes familial hypercholesterolemia (elevated LDL-C) from familial hypertriglyceridemia (elevated triglycerides).

Key Laboratory Tests

• Baseline hepatic aminotransferases, creatine kinase, glucose, and creatinine before initiating drug therapy 1
• Lipoprotein(a) measurement, as elevated Lp(a) is an independent risk factor requiring more aggressive LDL-C lowering 1, 3
• Genetic testing to confirm familial hypercholesterolemia diagnosis and guide family screening 4, 3, 5

Clinical Assessment

• Document family history of premature cardiovascular disease (men <55 years, women <65 years) 4
• Screen for secondary causes: hypothyroidism, diabetes mellitus, nephrotic syndrome, obstructive liver disease 6
• Identify medications that worsen lipids: estrogen therapy, thiazide diuretics, beta-blockers 6
• Assess for existing atherosclerotic cardiovascular disease (ASCVD) through clinical history and consider imaging 4, 1

Risk Stratification for Treatment Goals

The LDL-C target depends on ASCVD risk level 1, 2:

• <100 mg/dL (<2.5 mmol/L) without ASCVD or major risk factors 1
• <70 mg/dL (<1.8 mmol/L) with imaging evidence of ASCVD or major risk factors 1
• <55 mg/dL (<1.4 mmol/L) with clinical ASCVD 1
• <40 mg/dL (<1.0 mmol/L) with recurrent ASCVD events within 2 years despite maximally tolerated statin therapy 1

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Initial Treatment Approach

Immediate Lifestyle Modifications (All Patients)

Implement a heart-healthy diet with saturated fat <7% of total calories, cholesterol <100-200 mg/day, and total fat 20-30% of calories. 1, 7, 8 Dietary therapy is essential and provides 15-21% LDL-C reduction when combined with pharmacotherapy 7, 8.

• Regular physical exercise: 150 minutes/week moderate-intensity or 75 minutes/week vigorous-intensity aerobic activity 1
• Weight management: Target 5-10% loss if overweight 1
• Complete alcohol elimination if hypertriglyceridemia present; moderation otherwise 1
• Smoking cessation and optimization of sleep hygiene 1, 2

Pharmacotherapy for Familial Hypercholesterolemia

Initiate high-potency statin therapy (atorvastatin, rosuvastatin, or pitavastatin) combined with ezetimibe as first-line treatment, targeting at least 50% reduction in LDL-C from baseline. 1, 2 This combination provides 45-70% LDL-C reduction and forms the cornerstone of therapy 4, 1.

Step 1: High-Potency Statin + Ezetimibe

• High-potency statins provide 30-50% LDL-C reduction 1
• Ezetimibe 10 mg daily adds 15-25% additional LDL-C reduction 1, 3
• Reassess lipid panel in 6-12 weeks after initiating therapy 1

Step 2: Add Bempedoic Acid if Goals Not Met

• Bempedoic acid provides additional LDL-C lowering without muscle-related side effects of statins 1, 3
• Particularly useful in statin-intolerant patients 3

Step 3: Escalate to PCSK9 Inhibitors

Add PCSK9-targeted therapy (evolocumab, alirocumab, or inclisiran) when LDL-C goals are not achieved despite maximally tolerated statin, ezetimibe, and bempedoic acid. 1, 3 PCSK9 inhibitors provide an additional 50-60% LDL-C reduction 4.

• For extremely high-risk patients (post-MI, multivessel coronary disease, polyvascular disease), consider combination of high-potency statin, ezetimibe, and PCSK9 inhibitor as first-line treatment 1, 2
• The number needed to treat for adolescents with familial hypercholesterolemia to prevent one heart attack is only two, emphasizing the importance of early aggressive treatment 4, 1

Additional Adjunctive Therapies

• Plant sterols/stanols (2-3 g/day) provide 7-15% additional LDL-C reduction 4, 1
• Bile acid sequestrants (colesevelam) may be considered if goals remain unmet, but avoid when triglycerides exceed 200 mg/dL 1, 6

Pharmacotherapy for Familial Hypertriglyceridemia

If triglycerides >500 mg/dL, immediately start fenofibrate to prevent acute pancreatitis, which represents a medical emergency. 3, 6 Fenofibrate is preferred over gemfibrozil when planning combination therapy due to lower drug interaction risk 3.

• Fenofibrate dosing: 54-160 mg daily with meals, individualized based on response 6
• Strict dietary restriction: Eliminate simple sugars, restrict alcohol completely, adopt moderate-carbohydrate diet 3
• Primary goal: Reduce triglycerides below 500 mg/dL to eliminate pancreatitis risk; long-term goal <150 mg/dL 3

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Special Populations

Homozygous Familial Hypercholesterolemia (HoFH)

Early combination therapy with high-intensity statins, ezetimibe, and PCSK9-directed therapies forms the mainstay of treatment, but response depends on residual LDL receptor function. 4, 1

• Lomitapide (microsomal triglyceride transfer protein inhibitor) works independently of LDL receptor function 4, 1
• Evinacumab (ANGPTL3 monoclonal antibody) has fewer adverse effects than lomitapide and works independently of LDL receptor function 4, 1
• Lipoprotein apheresis is effective and should be used in countries without access to newer therapies 4, 1
• Liver transplantation may be offered to young patients with severe HoFH (biallelic null variants) refractory to current therapies 4

Children and Adolescents

Consider drug therapy in children ≥10 years of age (usually wait until menarche for females) after a 6-12 month trial of dietary management. 4

• Initiate drug therapy if:
  • LDL ≥190 mg/dL (4.90 mmol/L), OR
  • LDL ≥160 mg/dL (4.10 mmol/L) with positive family history of premature cardiovascular disease or ≥2 other risk factors 4
• Statins improve vascular function (flow-mediated dilatation) to normal levels in children with familial hypercholesterolemia 4

Renal Impairment

Initiate fenofibrate at 54 mg/day in patients with mild to moderately impaired renal function and increase only after evaluating effects on renal function and lipid levels. 6 Avoid fenofibrate in severe renal impairment 6.

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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 4, 1
• Using bile acid sequestrants when triglycerides >200 mg/dL—they are relatively contraindicated 1, 6
• Combining gemfibrozil with statins—use fenofibrate instead for better safety profile 3
• Failing to screen first-degree relatives—reverse-cascade screening identifies other affected individuals who benefit from early treatment 1, 3
• Discontinuing cholesterol-lowering therapy during acute illness—continue unless specifically contraindicated 1
• Ignoring elevated Lp(a)—warrants more aggressive LDL-C lowering and consideration of low-dose aspirin for primary prevention 1, 3

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Monitoring Strategy

• Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle modifications or changing pharmacotherapy 1
• Monitor hepatic aminotransferases in patients at increased risk of hepatotoxicity (liver disease history, excess alcohol, drug interactions) 1
• Withdraw therapy in patients who do not have an adequate response after two months of treatment with the maximum recommended dose 6
• Consider reducing dosage if lipid levels fall significantly below the targeted range 6