What are the guidelines for managing familial hypercholesterolemia (high levels of low-density lipoprotein cholesterol) in Canada?

Canadian Guidelines for Managing Familial Hypercholesterolemia

The management of familial hypercholesterolemia (FH) in Canada requires aggressive lipid-lowering therapy with maximally tolerated high-potency statins as first-line treatment, followed by ezetimibe and PCSK9 inhibitors if LDL-C targets are not achieved. 1

Diagnosis and Prevalence in Canada

• FH affects approximately 1 in 250 Canadians, with an estimated 145,000 individuals having FH, most of whom remain undiagnosed 2
• In Ontario, studies show approximately 1 in 378 older adults have FH, and 1 in 13 have severe hypercholesterolemia 3
• Diagnosis should be based on:
  • Elevated LDL-C levels (≥4.9 mmol/L or ≥190 mg/dL)
  • Family history of premature cardiovascular disease
  • Physical findings (tendon xanthomas, corneal arcus)
  • Genetic testing when available

Treatment Goals Based on Risk Stratification

LDL-C targets should be determined by ASCVD risk level 1:

1. Without ASCVD or major risk factors:

   • Target LDL-C <2.5 mmol/L (<100 mg/dL)

2. With imaging evidence of ASCVD or major risk factors:

   • Target LDL-C <1.8 mmol/L (<70 mg/dL)

3. With clinical ASCVD:

   • Target LDL-C <1.4 mmol/L (<55 mg/dL)

4. With recurrent ASCVD events within 2 years on statin therapy:

   • Consider lower target of <1.0 mmol/L (<40 mg/dL)

Treatment Algorithm

First-Line Therapy

• Maximally tolerated high-potency statins (atorvastatin, rosuvastatin, or pitavastatin) 1, 4, 5
  • Rosuvastatin has shown superior LDL-C reduction compared to atorvastatin in HeFH patients (57.9% vs. 50.4%) 6
  • Start with appropriate dose based on age and risk factors
  • For pediatric HeFH patients, statins are approved for use from age 8 years 1

Second-Line Therapy

• Add ezetimibe if LDL-C goals not achieved with statins alone 1
  • Provides additional 18-25% LDL-C reduction 1

Third-Line Therapy

• Add PCSK9 inhibitors (evolocumab or alirocumab) if LDL-C goals still not achieved 1, 7
  • Provides additional 40-65% LDL-C reduction 1
  • Recommended for patients who don't achieve targets despite maximum tolerated statin plus ezetimibe 2

Additional Options for Refractory Cases

• Plant sterols/stanols or bile acid sequestrants (such as colesevelam) may be considered as adjunctive therapies 1
• Bempedoic acid if available 1
• For extremely high-risk HeFH (post-MI or multivessel disease), consider combination of high-potency statin, ezetimibe, and PCSK9 inhibitor as first-line treatment 1

Special Populations

Homozygous FH (HoFH)

• Treatment should begin at diagnosis, ideally by age 2 years 1
• Use all available medications (high-potency statin, ezetimibe, colesevelam)
• Consider lipoprotein apheresis if LDL-C goals not achieved with medications 1
• For severe cases, consider lomitapide (microsomal triglyceride transfer protein inhibitor) or evinacumab (angiopoietin-related protein 3 inhibitor) 1, 7

Pediatric Patients with HeFH

• Consider statin therapy from age 8-10 years if LDL-C remains >4.9 mmol/L (>190 mg/dL) after lifestyle modifications 1
• Target LDL-C <3.5 mmol/L (<135 mg/dL) or approximately 50% reduction in those without additional risk factors 1
• Target LDL-C <2.5 mmol/L (<100 mg/dL) in those with additional risk factors 1

Pregnant Women

• Statins and systemically absorbed cholesterol-lowering drugs should be discontinued 3 months before planned conception and during pregnancy/lactation 1
• Consider bile acid sequestrants during pregnancy 1
• For women with HoFH and clinical ASCVD, continued statin use may be considered, especially after the first trimester 1

Monitoring and Follow-up

• Before starting therapy, measure baseline liver enzymes, creatine kinase, glucose, and creatinine 1
• Monitor liver enzymes in patients taking statins, especially those with risk factors for hepatotoxicity 1
• Measure creatine kinase if musculoskeletal symptoms are reported 1
• Monitor glucose or HbA1c in patients with risk factors for diabetes 1
• For stable patients, non-fasting lipid profiles can be used for monitoring, but fasting LDL-C should be used when making treatment changes 1

Implementation Challenges in Canada

• Despite high-risk status, many FH patients in Canada achieve suboptimal LDL-C control 3
• Treatment adherence decreases over time, with fewer patients remaining on statins at 5-year follow-up 3
• National FH registry has been established across 19 academic sites in Canada to improve identification and treatment of FH patients 8

Pitfalls to Avoid

• Underdiagnosis: Most FH patients in Canada remain undiagnosed; consider FH in all patients with LDL-C ≥4.9 mmol/L (≥190 mg/dL)
• Undertreatment: Don't hesitate to escalate therapy if LDL-C targets are not met
• Delayed treatment: Early diagnosis and treatment can normalize life expectancy in FH patients 2
• Inadequate family screening: Implement cascade screening of family members to identify additional cases 1
• Stopping medications during acute illness: Cholesterol-lowering therapies should be continued during acute illness unless specifically contraindicated 1