Lipoprotein (a) as a Biomarker for Cardiovascular Diseases and Potential New Therapies to Mitigate Risk

Background: Lipoprotein (a) [Lp(a)] is a molecule that induces inflammation of the blood vessels, atherogenesis, valvular calcification, and thrombosis. Methods: We review the available evidence that suggests that high Lp(a) levels are associated with a persisting risk for atherosclerotic cardiovascular diseases despite optimization of established risk factors, including low-density lipoprotein cholesterol (LDL-C) levels. Observations: Approximately a quarter of the world population have Lp(a) levels of >50 mg/dL (125 nmol/L), a level associated with elevated cardiovascular risk. Lifestyle modification, statins, and ezetimibe do not effectively lower Lp(a) levels, while proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors and niacin only lower Lp(a) levels modestly. We describe clinical studies suggesting that gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting Lp(a), offer a targeted approach with the potential for safe and robust Lp(a)- lowering with only a few doses (3-4) per year. Prospective randomized phase 3 studies are ongoing to validate safety, effectiveness in improving hard clinical outcomes, and tolerability to assess these therapies. Conclusion: Several emerging treatments with robust Lp(a)-lowering effects may significantly lower atherosclerotic cardiovascular risk.