What is the initial treatment for familial hyperlipidemia?

Initial Treatment for Familial Hypercholesterolemia

The initial treatment for familial hypercholesterolemia should be maximally tolerated high-potency statins with or without ezetimibe and/or bempedoic acid, combined with a fat-modified, heart-healthy diet to achieve LDL-cholesterol goals. 1

Treatment Algorithm

First-Line Therapy

• Start with maximally tolerated high-potency statins (such as atorvastatin, rosuvastatin, or pitavastatin) as the foundation of treatment 2
• Combine with dietary modifications and lifestyle changes (heart-healthy diet, regular physical exercise, stress reduction) 2
• For extremely high-risk patients (e.g., those with symptomatic ASCVD or multivessel coronary atherosclerosis), consider combination therapy with high-potency statin, ezetimibe, and PCSK9-targeted therapy as first-line treatment 2, 1

Second-Line Therapy (If LDL-C Goals Not Achieved)

• Add ezetimibe to statin therapy within 8 weeks of starting treatment 2, 1
• Consider adding bile acid sequestrants (such as colesevelam) if further LDL-C reduction is needed 2
• Plant sterols/stanols may be considered as adjunctive therapies 2

Third-Line Therapy

• Add PCSK9-targeted therapy (monoclonal antibodies or small interfering RNA) if LDL-C goals are not achieved with diet, maximally tolerated statins, ezetimibe, and other adjunctive therapies 2, 3
• For homozygous FH, consider lipoprotein apheresis if LDL-C goals are not achieved with maximally tolerated medication regimen 2, 1

LDL-C Treatment Goals

After achieving approximately 50% reduction in LDL-C concentration, target goals should be based on ASCVD risk level 2:

• LDL-C < 2.5 mmol/l (<100 mg/dl) in patients without ASCVD or other major ASCVD risk factors 2
• LDL-C < 1.8 mmol/l (<70 mg/dl) in patients with imaging evidence of ASCVD or other major ASCVD risk factors 2
• LDL-C < 1.4 mmol/l (<55 mg/dl) in patients with clinical ASCVD 2
• Consider LDL-C < 1.0 mmol/l (<40 mg/dl) in patients with recurrent ASCVD events within 2 years while on maximally tolerated statin treatment 2

Special Considerations

Heterozygous FH (HeFH)

• Begin with high-potency statins and lifestyle modifications 1
• Add ezetimibe if LDL-C goals are not achieved 1
• Consider PCSK9 inhibitors for patients not achieving goals with statins and ezetimibe 4, 3

Homozygous FH (HoFH)

• Treatment should begin at diagnosis, ideally by age 2 years 2
• Use sequential medication approach starting with high-potency statins rapidly up-titrated to maximally tolerated doses 2
• Add ezetimibe within 8 weeks, and possibly colesevelam if tolerated 2
• Consider lipoprotein apheresis when LDL-C goals are not achieved with medications 2, 5
• For patients with rapidly progressive ASCVD, consider lomitapide (microsomal triglyceride transfer protein inhibitor) or evinacumab (angiopoietin-related protein 3 inhibitor) 2

Monitoring and Follow-up

• Use non-fasting lipid profiles to monitor treatment in stable patients 2
• Use fasting LDL-C concentration when making decisions on changing treatment, especially in patients with hypertriglyceridemia 2
• Monitor plasma levels of liver enzymes, creatine kinase, glucose, and creatinine before starting drug therapy 2
• Continue to monitor liver and muscle enzymes, especially in patients with risk factors for hepatotoxicity 2

Common Pitfalls and Caveats

• FH is frequently underdiagnosed and undertreated, leading to premature cardiovascular disease 6
• Many FH patients do not achieve their target LDL-C levels with statin monotherapy alone 3
• Statin intolerance may require alternative approaches, including combination therapy or newer agents 5
• For patients with severe hypertriglyceridemia and FH, initial treatment should address both conditions, with fenofibrate potentially added to statin therapy 7
• Adolescent girls should receive counseling regarding contraception and the use of lipid-lowering medications during pregnancy 2