The American Heart Association (AHA) has highlighted several strategies for managing elevated lipoprotein(a) [Lp(a)]
The American Heart Association (AHA) has highlighted several strategies for managing elevated lipoprotein(a) [Lp(a)], given its role as an independent risk factor for cardiovascular disease. While statins do not directly lower Lp(a)—and may even cause a slight increase—they remain essential for reducing LDL-C and overall cardiovascular risk.
Key Strategies Highlighted by AHA:
1. PCSK9 Inhibitors (Evolocumab, Alirocumab):
• Can reduce Lp(a) by 25-30%.
• Also effectively lower LDL-C and cardiovascular risk.
2. Lipoprotein Apheresis:
• Used in severe cases, especially for patients with very high Lp(a) and progressive cardiovascular disease.
• Can reduce Lp(a) levels by 50-75% per session.
3. Emerging RNA-based Therapies (Pelacarsen, Olpasiran):
• Target Lp(a) production at the genetic level.
• Clinical trials have shown reductions of 80% or more.
4. General Cardiovascular Risk Reduction:
• LDL-C lowering remains a priority, as high LDL-C combined with high Lp(a) further increases risk.
• Lifestyle modifications (healthy diet, exercise, smoking cessation) are still recommended, though they do not significantly reduce Lp(a) levels.
Key Findings from the AHA 2024 Presentations on Lp(a)-Lowering Therapies
Source: AHA 2024 Scientific Sessions; Published in JAMA
1. Overview of New Lp(a)-Lowering Therapies
• Two new drugs, zerlasiran (siRNA-based) and muvalaplin (oral agent), showed ~80% reduction in Lp(a) in Phase II trials.
• Both drugs target apolipoprotein(a) [apo(a)], preventing Lp(a) formation.
2. ALPACAR-360 Trial (Zerlasiran – siRNA Therapy)
• Led by Steven Nissen, MD (Cleveland Clinic, OH).
• Study Design:
• 178 patients with ASCVD and high Lp(a) randomized into different dosing regimens.
• Follow-up: 36 weeks.
• Key Results:
• 85.6% Lp(a) reduction at the highest dose (450 mg/24 weeks).
• Moderate LDL-C (-25% to -32%) and apoB (-10% to -15%) reductions.
• Well tolerated: Main side effects included injection-site reactions, headache, and nasopharyngitis.
3. KRAKEN Trial (Muvalaplin – Oral Therapy)
• Led by Stephen Nicholls, MBBS, PhD (Monash University, Australia).
• Study Design:
• 233 patients with ASCVD, diabetes, or familial hypercholesterolemia.
• Muvalaplin (10 mg, 60 mg, 240 mg) vs. placebo for 12 weeks.
• Key Results:
• 85.7% Lp(a) reduction (intact assay) at highest dose.
• No significant adverse events or safety concerns.
• First oral Lp(a)-lowering agent, addressing cost and patient preference issues with injectables.
4. Clinical Need & Future Directions
• Lp(a) is a strong genetic risk factor for ASCVD and aortic stenosis, affecting 1 in 5 people.
• Current lipid-lowering therapies (statins, ezetimibe) do not reduce Lp(a) and may increase it slightly.
• Major ongoing cardiovascular outcome trials:
• Lp(a)HORIZON (Pelacarsen – 2025)
• OCEAN(a)-Outcomes (Olpasiran – 2026)
• ACCLAIM-Lp(a) (Lepodisiran – 2029)
5. Future Challenges
• Defining the threshold for “too high” Lp(a) and when to intervene.
• Expanding access to Lp(a) testing worldwide, as it is not widely covered by payers.
Currently, no FDA-approved therapy specifically for lowering Lp(a) exists. While several drugs are in advanced clinical trials, including siRNA-based therapies (Pelacarsen, Olpasiran, Zerlasiran) and oral agents (Muvalaplin), they are not yet available for clinical use.
The most advanced candidate, Pelacarsen (Ionis/Novartis), is being evaluated in the Lp(a)HORIZON trial, with cardiovascular outcomes data expected in 2025. If successful, it could become the first FDA-approved treatment for Lp(a) reduction.
