What are the first-line treatment recommendations for managing Familial Hypercholesterolemia (FH)?

First-Line Treatment for Familial Hypercholesterolemia

The first-line treatment for familial hypercholesterolemia is maximally tolerated high-potency statin therapy combined with a heart-healthy, low saturated fat diet, with ezetimibe added if LDL-cholesterol goals are not achieved. 1, 2

Initial Treatment Algorithm

Step 1: Lifestyle Modifications + High-Potency Statin

• Initiate dietary counseling immediately at diagnosis: restrict saturated fat to <10% of total calories (or <7% for more aggressive control), cholesterol <300 mg/day (or <200 mg/day for intensive therapy), eliminate trans fats, and increase fiber intake 1
• Start maximally tolerated high-potency statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) as the foundation of pharmacotherapy 1, 2
• High-potency statins are FDA-approved for both heterozygous FH (HeFH) and homozygous FH (HoFH) in adults and children ≥10 years old 3, 4

Step 2: Add Ezetimibe Within 8 Weeks if Not at Goal

• Add ezetimibe 10 mg daily if LDL-cholesterol goals are not achieved with statin monotherapy after 8 weeks 1, 2
• Ezetimibe is FDA-approved for use in combination with statins for both HeFH and HoFH in adults and pediatric patients ≥10 years old 4
• Administer ezetimibe either ≥2 hours before or ≥4 hours after bile acid sequestrants if using combination therapy 4

Step 3: Consider Additional Agents

• Bile acid sequestrants (e.g., colesevelam) may be added if tolerated, though they are less commonly used due to gastrointestinal side effects 1
• Bempedoic acid should be considered in adults as an additional agent when statin plus ezetimibe is insufficient 1, 2
• PCSK9 inhibitors should be added within a further 8 weeks in patients not achieving goals despite maximal statin plus ezetimibe therapy 1, 2

LDL-Cholesterol Treatment Goals

The target LDL-cholesterol level depends on the presence and severity of atherosclerotic cardiovascular disease (ASCVD):

• LDL-C <2.5 mmol/L (<100 mg/dL) in patients without ASCVD or other major risk factors 1, 2
• LDL-C <1.8 mmol/L (<70 mg/dL) in patients with imaging evidence of ASCVD or additional major risk factors 1, 2
• LDL-C <1.4 mmol/L (<55 mg/dL) in patients with clinical ASCVD events 1, 2
• Aim for approximately 50% reduction in LDL-C from baseline as an initial target 2

Special Considerations for Homozygous FH

HoFH requires more aggressive treatment starting at diagnosis, ideally by age 2 years 1:

• Begin with high-potency statin with rapid up-titration to maximally tolerated doses 1, 2
• Add ezetimibe within 8 weeks, and possibly colesevelam if tolerated 1
• Add PCSK9 inhibitor within a further 8 weeks in patients without biallelic LDLR null mutations, continuing only if ≥15% additional LDL-C reduction is achieved 1
• Lipoprotein apheresis should be offered by age 3 years (no later than age 8 years) when goals are not achieved with maximal medication 1, 2
• Consider lomitapide or evinacumab in patients with markedly elevated LDL-C despite conventional therapy or rapidly progressive ASCVD 1

Pediatric Treatment Approach

For children with HeFH, pharmacological treatment should be offered at age 8-10 years when LDL-C >4.9 mmol/L (>190 mg/dL) on two occasions 1:

• Start with lifestyle modifications and dietary counseling at diagnosis 1
• Initiate statin therapy as first-line pharmacological treatment 1
• Add ezetimibe if LDL-C goals not achieved with statin alone 1
• Target LDL-C <3.5 mmol/L (<135 mg/dL) or approximately 50% reduction in patients without additional risk factors 1
• PCSK9 inhibitors may be considered in children with additional ASCVD risk factors, noting limited long-term safety data 1

Monitoring and Follow-Up

• Measure liver enzymes, creatine kinase, glucose, and creatinine before starting statin therapy 1
• Monitor liver and muscle enzymes and glucose as clinically indicated during treatment 1
• Assess LDL-C as early as 4 weeks after initiating or adjusting therapy 4
• Use non-fasting lipid profiles for monitoring in stable patients 2
• Use fasting LDL-C when making treatment decisions, especially in patients with hypertriglyceridemia 2
• Monitor growth and adherence to lifestyle and medications annually or as clinically indicated 1

Critical Pitfalls to Avoid

• Do not delay statin initiation while attempting lifestyle modifications alone in patients with markedly elevated LDL-C, as atherosclerotic burden accumulates from birth 1, 5
• Do not down-titrate statin therapy simply because an arbitrary LDL-C goal has been achieved; maintain maximally tolerated doses 6
• Do not use fibrates other than fenofibrate in combination with ezetimibe until adequately studied 4
• Address all cardiovascular risk factors including smoking, hypertension, obesity, and diabetes, not just lipid levels 2
• For extremely high-risk HeFH patients (symptomatic ASCVD or multivessel coronary atherosclerosis), consider combination therapy with high-potency statin, ezetimibe, and PCSK9 inhibitor as first-line treatment rather than sequential addition 1, 2, 6