What is the typical treatment for familial hyperlipidemia?

Treatment of Familial Hyperlipidemia

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, 2

Distinguishing Familial Hypercholesterolemia vs. Familial Hypertriglyceridemia

The treatment approach differs fundamentally based on the lipid abnormality:

For Familial Hypercholesterolemia (Elevated LDL-C)

Primary Treatment Strategy:

• High-potency statins (atorvastatin, rosuvastatin, or pitavastatin) form the cornerstone of therapy, providing 30-50% LDL-C reduction 1, 3
• Add ezetimibe to statin therapy when initial response is inadequate, providing an additional 15-20% LDL-C reduction 1, 4
• Bempedoic acid may be added if available as an additional adjunctive agent 1

LDL-Cholesterol Treatment Goals:

• <100 mg/dL (<2.5 mmol/L) in the absence of atherosclerotic cardiovascular disease (ASCVD) or other major risk factors 1
• <70 mg/dL (<1.8 mmol/L) with imaging evidence of ASCVD or other major risk factors 1
• <55 mg/dL (<1.4 mmol/L) with clinical ASCVD 1
• <40 mg/dL (<1.0 mmol/L) may be considered for recurrent ASCVD events within 2 years despite maximally tolerated statin therapy 1

Escalation to PCSK9 Inhibitors:

• Add PCSK9-targeted therapy (monoclonal antibodies or inclisiran) when LDL-cholesterol goals are not achieved despite maximally tolerated statin, ezetimibe, and bempedoic acid 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

Additional Adjunctive Therapies:

• Plant sterols/stanols or bile acid sequestrants (colesevelam) may be considered if goals remain unmet 1
• Bile acid sequestrants should be avoided when triglycerides exceed 200 mg/dL 5

For Familial Hypertriglyceridemia (Elevated Triglycerides)

Primary Treatment Strategy:

• Fenofibrate is the first-line pharmacologic agent for severe hypertriglyceridemia (≥500 mg/dL) to reduce pancreatitis risk 5
• Statins should be initiated if 10-year ASCVD risk ≥7.5%, providing 10-30% triglyceride reduction 5
• Target non-HDL-cholesterol <130 mg/dL in patients with triglycerides 200-499 mg/dL 5

Critical Lifestyle Interventions:

• Weight loss of 5-10% reduces triglycerides by 20%, with some patients achieving 50-70% reduction 5
• Restrict added sugars to <6% of total daily calories and limit total fat to 30-35% of calories 5
• Complete alcohol elimination is crucial, as alcohol significantly raises triglyceride levels 5
• 150 minutes per week of moderate-intensity aerobic activity or 75 minutes per week of vigorous-intensity activity 5
• Resistance training with 8-10 exercises, 1-2 sets, 10-15 repetitions at moderate intensity, 2 days per week 5

Secondary Cause Evaluation:

• Screen for uncontrolled diabetes/prediabetes, hypothyroidism, renal disease, liver disease 5
• Review medications that can cause massive triglyceride elevation 5

Combination Therapy Considerations:

• Fenofibrate has a better safety profile than gemfibrozil when combined with statins, though myositis risk remains increased 5
• Monitor creatine kinase levels with combination therapy, particularly in patients >65 years 5

Homozygous Familial Hypercholesterolemia (HoFH)

For severe HoFH with markedly elevated LDL-C from conception:

• Early combination therapy with high-intensity statins, ezetimibe, and PCSK9-directed therapies forms the mainstay, though response depends on residual LDL receptor function 1
• Lomitapide (microsomal triglyceride transfer protein inhibitor) works independently of LDL receptor function 1
• Evinacumab (ANGPTL3 monoclonal antibody) has fewer adverse effects than lomitapide and works independently of LDL receptor function 1
• Lipoprotein apheresis is effective and should be used in countries without access to newer therapies 1
• 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 1

Universal Lifestyle Modifications

All patients with familial hyperlipidemia require:

• Heart-healthy diet with saturated fat <7% of total calories 2, 6
• Regular physical exercise as specified above 1
• Reduction in psychological stress 1
• Moderation in alcohol intake (or complete elimination for hypertriglyceridemia) 1, 5
• Sleep hygiene optimization 1
• Weight management targeting 5-10% loss if overweight 5

Monitoring Strategy

Baseline Laboratory 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 5
• Monitor hepatic aminotransferases in patients at increased risk of hepatotoxicity (liver disease history, excess alcohol, drug interactions) 1
• Measure creatine kinase if musculoskeletal symptoms are reported 1
• Monitor glucose or HbA1c if risk factors for diabetes are present 1
• Annual or biennial monitoring if all values remain optimal 5

Critical Pitfalls to Avoid

Common errors that compromise outcomes:

• Undertreatment with lifestyle modifications alone in high-risk patients—pharmacotherapy is essential for achieving LDL-C goals 2
• 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 5
• Combining gemfibrozil with statins—use fenofibrate instead for better safety profile 5
• Failing to screen family members—reverse-cascade screening identifies other affected individuals who benefit from early treatment 2
• Discontinuing cholesterol-lowering therapy during acute illness—continue unless specifically contraindicated 1

Special Populations

Pediatric Patients (≥10 years old):

• Statins combined with ezetimibe are indicated for heterozygous familial hypercholesterolemia 4, 3
• Early treatment in adolescents with FH has an impressive number needed to treat of only two to prevent one heart attack 1

Patients with Elevated Lipoprotein(a):

• Elevated Lp(a) is an independent risk factor warranting more aggressive LDL-C lowering 2
• Consider low-dose aspirin for primary prevention in asymptomatic patients with marked Lp(a) elevation 1