What is the key clinical approach to each distinctive type of Familial Hypercholesterolemia (FH)?

Clinical Approach to Familial Hypercholesterolemia by Type

The clinical approach to FH must be stratified by genotype and severity: heterozygous FH (HeFH) requires aggressive statin-based combination therapy targeting LDL-C <70-100 mg/dL depending on ASCVD risk, while homozygous FH (HoFH) demands immediate maximal medical therapy plus lipoprotein apheresis, with both requiring lifelong treatment initiated as early as possible to prevent premature cardiovascular death. 1, 2, 3

Heterozygous FH (HeFH) - The Most Common Form

Initial Management Strategy

• Start high-intensity statin therapy immediately upon diagnosis as the foundation of treatment, combined with a fat-modified, heart-healthy diet 2, 3
• Add ezetimibe within 8 weeks if LDL-C goals are not achieved with statin monotherapy 2
• For extremely high-risk HeFH patients (those with clinical ASCVD or imaging evidence of atherosclerosis), consider triple combination therapy with high-potency statin, ezetimibe, and PCSK9 inhibitor as first-line treatment 2

Risk-Stratified LDL-C Targets

The treatment intensity must be guided by cardiovascular risk stratification, not a one-size-fits-all approach 2, 3:

• LDL-C <100 mg/dL (<2.5 mmol/L) in patients without ASCVD or other major risk factors, with minimum 50% reduction from baseline 2, 3
• LDL-C <70 mg/dL (<1.8 mmol/L) in patients with imaging evidence of subclinical ASCVD or major risk factors (elevated Lp(a), tendon xanthomas, strong family history of premature CAD) 2, 3
• LDL-C <55 mg/dL (<1.4 mmol/L) in patients with established clinical ASCVD 2

Cardiovascular Imaging for Risk Stratification

• Perform coronary artery calcium scoring, CT coronary angiography, or carotid ultrasonography in asymptomatic adults with HeFH to document subclinical atherosclerosis, which guides treatment intensity 1, 3
• Imaging is integral to management protocols for escalating LDL-cholesterol-lowering therapies and considering cardiac interventions 1

Sequential Treatment Escalation Algorithm

When LDL-C goals are not met 2, 4:

1. Maximize statin dose to highest tolerated intensity
2. Add ezetimibe (typically reduces LDL-C an additional 15-20%)
3. Consider adding bempedoic acid if still not at goal
4. Add PCSK9 inhibitor for severe or treatment-resistant cases 2, 4
5. Consider lipoprotein apheresis only for severe heterozygous FH resistant to maximal drug therapy 1, 4

Critical Pitfall to Avoid

Do not delay pharmacotherapy in favor of lifestyle modifications alone - HeFH patients have lifetime exposure to elevated LDL-C from birth, making early aggressive treatment essential to prevent cumulative atherosclerotic burden 3. General population risk calculators significantly underestimate cardiovascular risk in FH and should never be used 3.

Homozygous FH (HoFH) - The Severe Form

Immediate Aggressive Approach

• HoFH requires more aggressive treatment starting at diagnosis, with sequential medication use beginning with high-potency statins rapidly up-titrated to maximally tolerated doses 2
• Add ezetimibe within 8 weeks of statin initiation 2
• Consider adding colesevelam (bile acid sequestrant) if tolerated, though adherence is often challenging 2

Early Apheresis Consideration

• Initiate lipoprotein apheresis early if LDL-C goals are not achieved with maximal medical therapy - apheresis is safe and effective for lifelong treatment of HoFH, especially when combined with statins and ezetimibe 1
• Weekly apheresis treating 1.5-2.0 times the blood or plasma volumes plus optimal drug therapy reduces interval mean LDL-C by 64-77% 1
• Lower LDL-C concentrations achieved with apheresis combined with drug treatment correlate with greater reduction in mortality 1

Novel Therapies for HoFH

• Consider PCSK9 inhibitors, though response varies depending on residual LDL receptor function 4
• Consider MTP inhibitors (lomitapide) for severe cases 1, 4
• Consider ANGPTL3 inhibitor (evinacumab) - particularly valuable as it works independently of LDL receptor function 1

Intensive Monitoring Protocol

• Perform Doppler echocardiographic evaluation of the heart and aorta annually to assess for supravalvular aortic stenosis and aortic root disease 3
• Conduct CT coronary angiography every 5 years or more frequently if clinically indicated 3
• Clinical ASCVD and aortic stenosis are common in HoFH, making imaging integral to management protocols for escalating treatment and considering cardiac interventions such as aortic valve replacement or coronary artery bypass surgery 1

Multidisciplinary Care Requirement

• Children and adolescents with HoFH should ideally be managed by a multidisciplinary team in centers with pediatric expertise in lipidology, cardiology, and apheresis 1
• Higher-complexity patients with HoFH should be managed in specialist centers, with option of shared care with general practice 1

Pediatric FH Management (Both HeFH and HoFH)

Age-Specific Treatment Initiation

• Test children with suspected HoFH (physical stigmata or both parents with FH) as early as possible - at newborn stage or by age 2 years 5
• Screen children at risk of HeFH at or after age 5 years, or as early as age 2 in those with strong family history of premature cardiovascular disease 5
• Offer pharmacological treatment at age 8-10 years if LDL-C >190 mg/dL on two fasting occasions 3
• For children with additional risk factors, consider treatment at age 8-10 years if LDL-C >160 mg/dL 3

Pediatric Treatment Approach

• Initiate treatment earlier and improve adherence to maximize health outcomes - the atherosclerotic burden begins at birth and accumulates over time 1
• Management should focus on the nuclear or immediate family, with at minimum annual reviews to assess well-being, mental health, medication safety, and adherence 1
• Transition of care to adult services should be planned well in advance, with support to facilitate self-management into adulthood 1

Severe FH Phenotype - A Distinct Clinical Entity

Defining Severe FH

• Severe FH represents a phenotype requiring particular attention: individuals with markedly elevated LDL-C who are poorly responsive to conventional lipid-lowering treatment, regardless of genetic confirmation 6
• These patients benefit particularly from early and more aggressive cholesterol-lowering treatment, including PCSK9 inhibitors 6
• The phenotypes of HeFH and HoFH overlap considerably, and response to treatment is heterogeneous - making phenotypic severity classification clinically valuable even without complete genetic characterization 6

Universal Management Principles Across All FH Types

Shared Decision-Making Framework

• Develop a personalized treatment plan for all patients using shared decision-making, considering age, additional ASCVD risk factors, psychological and sociocultural factors, economic status, barriers to adherence, and personal and family values 1
• Provide clear information in written, diagrammatic, and electronic formats that addresses age-related, sociocultural, psychological, language, and health literacy barriers 1

Comprehensive Risk Factor Management

• Address all cardiovascular risk factors beyond LDL-C: smoking cessation, hypertension control, obesity management, metabolic syndrome, and diabetes mellitus 2
• Encourage lifestyle modifications including regular physical exercise, reduction in psychological stress, moderation in alcohol intake, and sleep hygiene 2
• Consider low-dose aspirin as primary prevention in asymptomatic patients at higher ASCVD risk 2

Monitoring Strategy

• Assess lipid panel 4-6 weeks after initiating or adjusting therapy, then every 6-12 weeks until goals are achieved, followed by every 3-12 months once stable 3
• Use non-fasting lipid profiles to monitor treatment in stable patients 2
• Use fasting LDL-C when making treatment change decisions, especially in patients with hypertriglyceridemia 2
• Monitor liver enzymes periodically in patients at increased risk of hepatotoxicity on statin therapy 3

Cascade Testing Imperative

• After identifying a pathogenic variant in the proband, offer cascade genetic testing for that specific variant to all first-degree relatives, then extend sequentially to second-degree and third-degree relatives until all at-risk family members have been offered testing 5, 3
• This family-based approach is essential as FH affects up to 35 million people worldwide, but only 10% are currently diagnosed 1

Pregnancy Considerations

• Provide pre-conception counseling about pregnancy risks, including cardiovascular assessment if clinically indicated 3
• Discontinue statins, ezetimibe, and PCSK9 inhibitors during pregnancy and lactation due to lack of safety data 3
• Women with FH planning pregnancy should be referred to a specialist center providing dedicated multidisciplinary service 1

Key Implementation Barrier to Overcome

The persistent reality is that >80% of treated FH patients do not achieve recommended LDL-C goals 1. This failure stems from delayed diagnosis, inadequate treatment intensification, poor medication adherence, and limited access to novel therapies. Systematic identification of multifactorial barriers (patient-related, clinician-related, drug-related, health system-related, and sociocultural/psychological/financial) must be addressed using appropriate resources by all healthcare providers 1.