What treatment options are available to reduce cardiovascular risk in individuals with elevated lipoprotein(a) (Lp(a)) levels?

Treatment Options for Reducing Cardiovascular Risk in Individuals with Elevated Lipoprotein(a)

For individuals with elevated lipoprotein(a) [Lp(a)] levels, aggressive management of traditional cardiovascular risk factors, particularly intensive LDL-C reduction, is the cornerstone of treatment to reduce cardiovascular risk, while novel targeted therapies are emerging that may provide more specific Lp(a) reduction in the future. 1

Understanding Lipoprotein(a) Risk Stratification

Lp(a) is an independent and causal risk factor for cardiovascular disease (CVD) and aortic stenosis. Risk levels are typically categorized as:

• Low risk: <30 mg/dL or <75 nmol/L
• Intermediate risk: 30-50 mg/dL or 75-125 nmol/L
• High risk: ≥50 mg/dL or ≥125 nmol/L 1

Approximately 20-25% of the global population has Lp(a) levels ≥50 mg/dL, making this a prevalent condition that contributes to residual cardiovascular risk even in patients receiving standard lipid-lowering therapy 2.

Current Treatment Approaches

1. Intensive LDL-C Reduction

• High-intensity statin therapy is recommended as first-line treatment for patients with elevated Lp(a), aiming for ≥50% LDL-C reduction from baseline 1

  • Important caveat: Statins may have neutral or slightly elevating effects on Lp(a) levels themselves 2

• PCSK9 inhibitors should be considered for patients not reaching LDL-C goals or with progressive CVD despite statin therapy, particularly in those with familial hypercholesterolemia and elevated Lp(a) 1

  • These agents reduce Lp(a) by 20-30%, though the clinical impact of this reduction on Lp(a)-mediated risk remains uncertain 2

2. Lipoprotein Apheresis

• Lipoprotein apheresis is currently the most effective available treatment for very high Lp(a) levels 1
• It efficiently lowers Lp(a) and has been associated with reduction of cardiovascular events by ~80% in patients with ongoing CVD and Lp(a) >60 mg/dL 3
• In patients with refractory angina and elevated Lp(a) >60 mg/dL, apheresis therapy has been shown to improve coronary blood flow and reduce angina frequency 3
• However, apheresis is time-intensive, only modestly effective long-term, and in the United States, very few patients (<50) with isolated increased Lp(a) receive this therapy 3, 2

3. Niacin (Nicotinic Acid)

• Niacin can reduce Lp(a) by 20-30% 1
• FDA-approved indications include reducing elevated total cholesterol, LDL-C, apolipoprotein B, and triglycerides, and increasing HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia 4
• However, niacin has significant side effects and unclear cardiovascular benefit specifically related to its Lp(a)-lowering effect 1, 2
• The AIM-HIGH trial showed that addition of niacin to statin therapy did not reduce cardiovascular morbidity or mortality 4

Emerging Targeted Therapies

The most promising emerging therapies specifically targeting Lp(a) include:

• Antisense oligonucleotides (e.g., pelacarsen) can reduce Lp(a) by >80% 1, 5
• Small interfering RNA agents (e.g., olpasiran, SLN360) also show substantial Lp(a) reduction 1, 2
• These compounds work by blocking the translation of messenger RNA into apolipoprotein(a), thereby reducing Lp(a) synthesis in the liver 2
• The ongoing Lp(a)HORIZON cardiovascular outcomes study will provide evidence on whether selective Lp(a) lowering with antisense oligonucleotides reduces major cardiovascular events 5

Clinical Approach to Management

1. Identify patients who should have Lp(a) measured:

   • Those with premature CVD
   • Family history of premature CVD
   • Familial hypercholesterolemia
   • Recurrent CVD despite optimal lipid-lowering therapy 1, 6

2. Risk stratification based on Lp(a) levels:

   • Incorporate Lp(a) levels into existing risk assessment tools
   • Consider Lp(a) ≥50 mg/dL as a significant risk enhancer 1

3. Treatment algorithm:

   • For all patients with elevated Lp(a): Aggressive management of traditional cardiovascular risk factors
   • Initiate high-intensity statin therapy aiming for ≥50% LDL-C reduction 1
   • If LDL-C goals not achieved or progressive CVD despite statin therapy: Add PCSK9 inhibitor 1
   • For patients with very high Lp(a) (>60 mg/dL) and recurrent CVD events, progressive CAD, or refractory angina despite optimal therapy: Consider lipoprotein apheresis 3
   • Consider aspirin for primary prevention and prolonged dual antiplatelet therapy for secondary prevention in patients with elevated Lp(a) 6

4. Monitoring:

   • Reassess lipid profile 4-12 weeks after initiating therapy and then every 3-12 months 1
   • Monitor for medication side effects

Special Considerations

• Patients with familial hypercholesterolemia (FH) and elevated Lp(a) have significantly increased lifetime risk of CVD and require more intensive LDL-C reduction 1
• Children with elevated Lp(a) have a fourfold increased risk of acute ischemic stroke, and the risk of recurrent ischemic strokes is increased by more than 10 times in those with Lp(a) >90th percentile 3
• Patients with calcific aortic valve disease and elevated Lp(a) may benefit from targeted therapy, as it's estimated that 1 in 7 cases of aortic stenosis could be prevented by marked Lp(a) lowering 3

While we await the results of clinical trials with novel targeted therapies, aggressive management of traditional risk factors remains the cornerstone of treatment for patients with elevated Lp(a) levels.