Familial Hypercholesterolemia

Use the untreated or pretreatment LDL-C phenotype, premature ASCVD history, and family pattern to identify patients with clinical FH; formal clinical criteria such as the Dutch Lipid Clinic Network score can support classification. A score above 5 has been used to define possible or definite clinical FH, but a substantial proportion of such patients are mutation-negative by conventional testing, often because of polygenic LDL-C elevation. Wolters Kluwer+1Wolters KluwerImproving the cost-effectiveness equation of... : Current Opinion in LipidologyScienceDirectClinical Genetic Testing for Familial Hypercholesterolemia

Escalate immediately to a lipid specialist or experienced FH center when the phenotype suggests HoFH: LDL-C approximately 4 to 10 times normal, severe hypercholesterolemia in childhood, or childhood-onset cardiovascular disease. By comparison, HeFH typically produces LDL-C 2 to 3 times normal and may cause ASCVD from young adulthood. Wolters KluwerWolters KluwerGenotype–phenotype correlation in a large cohort... : Current Opinion in Lipidology

Do not defer intensive LDL-C lowering while pursuing molecular confirmation. Current FH guidance places maximally tolerated statins and ezetimibe at the base of therapy, with more rapid intensification for established ASCVD, inadequate LDL-C reduction, or a severe phenotype. ScienceDirect+1ScienceDirectUpdate on familial hypercholesterolemia: An expert clinical ...PubMedManagement of Familial Hypercholesterolemia with Special Emphasis on Evinacumab - PMC

Offer FH genetic testing to patients with definite or probable FH and to at-risk relatives. The recommended core panel includes LDLR, APOB, and PCSK9, with phenotype-directed expansion when appropriate. A pathogenic variant facilitates definitive diagnosis, identifies a group at higher cardiovascular risk, and can improve treatment initiation and adherence. ScienceDirect+1ScienceDirectClinical Genetic Testing for Familial HypercholesterolemiaScienceDirectIntegrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

A negative conventional genetic result does not exclude a clinically actionable FH phenotype. Among patients with a Dutch Lipid Clinic score above 5, approximately 60% may be mutation-negative by conventional testing; evidence indicates that many mutation-negative cases reflect accumulation of common LDL-C-raising alleles rather than an undiscovered monogenic cause. Continue phenotype-based LDL-C management rather than withdrawing therapy because testing is negative. Wolters KluwerWolters KluwerImproving the cost-effectiveness equation of... : Current Opinion in Lipidology

When an index patient has a pathogenic variant, test first-degree relatives for that familial variant and include children. FH cascade testing is classified as a CDC Tier 1 application, and DNA-based cascade testing avoids misclassification caused by overlap in LDL-C distributions between mutation carriers and noncarriers within the same family. jacc+2jaccClinical Genetic Testing for Familial Hypercholesterolemia - JACCjaccChildhood Screening for Familial Hypercholesterolemia: JACC Review Topic of the WeekScienceDirectClinical Genetic Testing for Familial Hypercholesterolemia

Start a high-intensity statin unless contraindicated or not tolerated, then titrate to the maximum tolerated dose. Statin monotherapy can reduce LDL-C by as much as 55% to 60%, but this is often insufficient for patients with FH and clinically manifest coronary disease. The minimum practical response target is a 50% LDL-C reduction from pretreatment LDL-C. jacc+1jaccThe Severe Hypercholesterolemia Phenotype: Clinical Diagnosis, Management, and Emerging TherapiesPubMedManagement of Familial Hypercholesterolemia with Special Emphasis on Evinacumab - PMC

Add ezetimibe when maximal tolerated statin therapy does not produce at least a 50% LDL-C reduction or when residual LDL-C remains unacceptable for the patient's ASCVD risk. Ezetimibe is the usual second-line agent; contemporary FH guidance then incorporates PCSK9 inhibitors and bempedoic acid as additional treatment options when statin-ezetimibe therapy remains inadequate or cannot be fully tolerated. ScienceDirect+1ScienceDirectUpdate on familial hypercholesterolemia: An expert clinical ...PubMedManagement of Familial Hypercholesterolemia with Special Emphasis on Evinacumab - PMC

Use clinical risk to determine how quickly to intensify. Prior cardiovascular disease, diabetes, hypertension, smoking, elevated lipoprotein(a), and other risk factors identify patients more likely to need multidrug therapy. Earlier consensus targets cited LDL-C below 100 mg/dL for adults and below 70 mg/dL for adults with known coronary heart disease or diabetes, while emphasizing a percentage reduction of at least 50%. jaccjaccThe Severe Hypercholesterolemia Phenotype: Clinical Diagnosis, Management, and Emerging Therapies

Consider lipoprotein apheresis for selected patients with severe clinical FH when drug therapy does not achieve adequate LDL-C lowering; contemporary guidance includes apheresis for both heterozygous and homozygous FH. This is a procedure-based escalation with access and treatment-burden tradeoffs, not a substitute for establishing maximally tolerated drug therapy. ScienceDirect+1ScienceDirectUpdate on familial hypercholesterolemia: An expert clinical ...PubMedAdvances in targeting LDL cholesterol: PCSK9 inhibitors and beyond

Initiate maximally tolerated statin plus ezetimibe in HoFH, but anticipate inadequate LDL-C lowering because both therapies depend substantially on residual LDL receptor activity. Advanced treatment should begin with or shortly after statin-ezetimibe therapy, rather than being delayed until symptoms or clinical ASCVD develop. PubMed+1PubMedNew algorithms for treating homozygous familial hypercholesterolemiaPubMedCholesterol Lowering Drugs - Endotext - NCBI Bookshelf

A PCSK9 monoclonal antibody is commonly an initial add-on in HoFH and produces an average LDL-C reduction of about 25% in reported studies; response is variable and depends on residual LDLR expression. In LDLR null/null disease, PCSK9 inhibitors are generally completely ineffective. Measure the LDL-C response after addition and discontinue the agent if it does not significantly lower LDL-C. PubMed+1PubMedNew algorithms for treating homozygous familial hypercholesterolemiaPubMedCholesterol Lowering Drugs - Endotext - NCBI Bookshelf

For receptor-independent LDL-C lowering, use therapies reserved for HoFH. Lomitapide and evinacumab are FDA-approved for HoFH; lomitapide is an oral microsomal triglyceride transfer protein inhibitor, whereas evinacumab inhibits angiopoietin-like protein 3. Lomitapide carries a boxed warning for hepatotoxicity, including aminotransferase elevations and hepatic steatosis that may progress to cirrhosis. PubMed+1PubMedAdvances in targeting LDL cholesterol: PCSK9 inhibitors and beyondPubMedLipid-Lowering Drug Therapy - StatPearls - NCBI Bookshelf

Evinacumab is administered intravenously at 15 mg/kg every 4 weeks. In a placebo-controlled HoFH trial with mean baseline LDL-C approximately 250 to 260 mg/dL despite extensive background therapy, evinacumab produced a 47% LDL-C reduction at 24 weeks versus a 1.9% LDL-C increase with placebo; lowering appeared after 2 weeks and was observed regardless of concomitant therapy, apheresis use, or LDLR genotype. PubMedPubMedCholesterol Lowering Drugs - Endotext - NCBI Bookshelf

Use lipoprotein apheresis as an effective advanced option in HoFH, particularly when pharmacologic response is inadequate or access to receptor-independent drugs is limited. If apheresis is the only available add-on after poor first-line response, do not delay initiation until cardiovascular symptoms occur. PubMed+1PubMedNew algorithms for treating homozygous familial hypercholesterolemiaPubMedAdvances in targeting LDL cholesterol: PCSK9 inhibitors and beyond

Test first-degree relatives of an index case, including children, through cascade screening. Pediatric FH screening remains controversial in the United States because long-term trials linking childhood statin treatment to events decades later are limited, but the American Academy of Pediatrics has endorsed multisociety pediatric cholesterol-screening guidance and FH is a Tier 1 cascade-testing condition. jaccjaccChildhood Screening for Familial Hypercholesterolemia: JACC Review Topic of the Week

Available pediatric approvals include pravastatin and rosuvastatin from age 8 years, simvastatin from age 10 years, ezetimibe for patients older than 10 years, evolocumab from age 10 years for FH, evinacumab from age 5 years for HoFH, and lomitapide from age 18 years for HoFH. Use age-approved therapy in consultation with a pediatric lipid specialist for severe phenotypes. PubMedPubMedLipid-Lowering Drug Therapy - StatPearls - NCBI Bookshelf

Address pregnancy planning before conception in every patient receiving systemic LDL-lowering therapy. Statins should be discontinued before conception and are contraindicated during pregnancy in the cited clinical literature. For severe FH, particularly HoFH or established ASCVD, bile acid sequestrants are the pharmacologic option generally regarded as safest because they are not systemically absorbed, although they can reduce absorption of fat-soluble vitamins; consider LDL apheresis when cardiovascular risk is very high. Wiley+1WileyPregnancy in homozygous familial hypercholesterolemia—A case ...PubMedFamilial Hypercholesterolaemia and the Risk of Cardiovascular Events

Avoid ezetimibe, PCSK9 inhibitors, lomitapide, and bempedoic acid during pregnancy because sufficient pregnancy safety data are lacking. Reassess LDL-C therapy after pregnancy and breastfeeding decisions with an FH specialist, especially in patients with HoFH or prior ASCVD. PubMedPubMedFamilial Hypercholesterolaemia and the Risk of Cardiovascular Events