Summary of the review “Lipoprotein(a) and Cardiovascular Disease”

Summary of the review “Lipoprotein(a) and Cardiovascular Disease“

By Prof Børge G Nordestgaard and Anne Langsted

Key Takeaways for Practicing Physicians:

1. Significance of Lipoprotein(a) [Lp(a)]:
   • Causal Risk Factor: Elevated Lp(a) is a genetically determined causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis.
   • Prevalence: Approximately 1 in 5 individuals globally have high Lp(a) levels, increasing their cardiovascular risk.
2. Genetic Determinants and Ethnic Variations:
   • Genetic Influence: Over 90% genetically determined with minimal lifestyle impact.
   • Ethnic Differences:
     • Lowest levels: East Asians, Europeans, Southeast Asians.
     • Intermediate levels: South Asians, Middle Easterners, Latin Americans.
     • Highest levels: Individuals of African descent.
   • Sex Differences: Postmenopausal women have about 17% higher Lp(a) levels than men.
3. Clinical Measurement and Interpretation:
   • When to Measure:
     • Once in a Lifetime: Recommended for all individuals to measure Lp(a) at least once.
     • High-Risk Patients: Especially important in those with premature ASCVD, familial hypercholesterolaemia (FH), family history of elevated Lp(a) or early ASCVD.
   • Stability of Levels: Lp(a) levels are stable after age two and are unaffected by most lifestyle factors.
   • Interpreting Levels:
     • Elevated Risk Thresholds:
       • >30 mg/dL (≥62 nmol/L): Increased risk begins.
       • >50 mg/dL (≥105 nmol/L): Clinically significant high risk.
       • >90 mg/dL (≥190 nmol/L): Severe risk, comparable to FH.
   • Laboratory Considerations:
     • Assay Selection: Use isoform-independent assays with standardized calibration.
     • Reporting Units: Preferably in nmol/L; however, mg/dL is acceptable with appropriate conversion.
4. Impact on Patient Care:
   • Risk Stratification:
     • Independent Risk Factor: High Lp(a) increases ASCVD risk independent of other lipids.
     • Reclassification: Can reclassify patients into higher risk categories, influencing management decisions.
   • Management Strategies:
     • Current Limitations: No approved therapies specifically targeting Lp(a) reduction.
     • Aggressive Risk Factor Control:
       • LDL Cholesterol: Intensive lowering with high-intensity statins, ezetimibe, and PCSK9 inhibitors.
         • PCSK9 Inhibitors: Lower Lp(a) by ~25% and reduce cardiovascular events.
       • Lifestyle Modifications: Emphasize smoking cessation, healthy diet, physical activity, and weight management.
       • Blood Pressure and Diabetes Management: Optimize control per guidelines.
     • Avoid Unproven Therapies: Niacin is not recommended due to side effects and lack of cardiovascular benefit.
5. Familial Hypercholesterolaemia (FH):
   • Dual Risk: Elevated Lp(a) often coexists with FH, compounding cardiovascular risk.
   • Screening: Measure Lp(a) in all patients with FH and consider cascade screening in families.
6. Emerging Therapies:
   • Gene-Silencing Drugs:
     • Pelacarsen, Olpasiran, Lepodisiran: Lower Lp(a) levels by 80–98%.
     • Administration: Subcutaneous injections, varying from monthly to quarterly.
   • Small Molecule Inhibitors:
     • Muvalaplin: Oral agent reducing Lp(a) by ~65%.
   • Clinical Trials:
     • Phase 3 Trials Ongoing: Evaluating cardiovascular outcomes with significant Lp(a) reduction.
     • Potential Change in Practice: These therapies may soon provide effective options for patients with high Lp(a).
7. Practical Recommendations:
   • Include Lp(a) in Lipid Panels: Encourage laboratories to add Lp(a) measurements to standard profiles.
   • Patient Communication:
     • Educate on Risks: Explain the significance of high Lp(a) and its genetic nature.
     • Lifestyle Advice: Reinforce the importance of modifiable risk factor control.
   • Family Screening: Consider evaluating first-degree relatives due to genetic inheritance patterns.
8. Monitoring and Follow-Up:
   • Re-measurement: Generally, one measurement suffices unless a significant event (e.g., menopause) occurs.
   • Acute Phase Reactant Consideration: Be cautious interpreting levels during acute illness; recheck once stabilized.

Conclusion:

Elevated Lp(a) is a significant and prevalent cardiovascular risk factor that is largely genetic and stable throughout life. While direct treatments are on the horizon, current management focuses on aggressive modification of other cardiovascular risk factors. Measurement of Lp(a) should become a routine part of cardiovascular risk assessment, guiding more personalized and effective patient care.

Reference: Nordestgaard, B. G., & Langsted, A. (2024). Lipoprotein(a) and cardiovascular disease. The Lancet, 404(10153), 295-306. https://doi.org/10.1016/S0140-6736(24)01308-4