RNA therapeutics
Review explains why statins raise Lp(a) by 10-20% while PCSK9 inhibitors and inclisiran lower it, ahead of dedicated Lp(a) drugs (Rev Cardiovasc Med 2024)
Original title: Lipoprotein (a): Underrecognized Risk with a Promising Future
This review summarises the pathophysiology and clinical implications of elevated Lp(a), noting that no therapy is currently approved to directly target it. Routine lipid-lowering drugs often have no effect on Lp(a); niacin and estrogens can lower it substantially but are not recommended given their adverse safety profiles, and statins actually raise Lp(a) by 10-20%, complicating their benefit calculus in patients with elevated Lp(a). FDA-endorsed agents for dyslipidaemia, PCSK9 inhibitors and inclisiran (a small interfering RNA), also significantly reduce Lp(a), though more clinical data are needed before this effect is leveraged in practice. The review surveys ongoing trials of dedicated antisense oligonucleotides and small interfering RNAs targeting hepatic Lp(a) production, as well as small molecules inhibiting Lp(a) particle assembly, framing the current therapeutic landscape as transitional ahead of purpose-built Lp(a)-lowering agents.
Original abstract
Lipoprotein a (Lp(a)) is a lipid biomarker that binds cholesterol and bears independent cardiovascular risk. Strategies to lower the level of Lp(a) and mitigate such risk are important both for primary and secondary prevention. Currently there are no approved therapies targeting Lp(a) directly. Lipid lowering therapies prescribed routinely may have no effect on Lp(a) levels. Some agents such as niacin and estrogens can significantly decrease Lp(a), but their use is not recommended due to their adverse safety profile. Statins increase Lp(a) levels by 10-20%, questioning the benefit of such therapy when this biomarker is elevated. The Food and Drug Administration (FDA) endorses new agents to address dyslipidemia such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) and Inclisiran, a small interfering RNA. These approaches have been shown to also significantly reduce Lp(a), but more clinical data is needed before implementing their use in clinical practice. Clinical trials are currently ongoing to test the efficacy of newly developed antisense oligonucleotides and small interfering RNAs targeting the gene encoding for Lp(a) in hepatocytes, while other investigations assess small molecules that inhibit Lp(a) assembly. This review summarizes the pathophysiology and clinical implications of Lp(a) elevation, and focuses on proposed Lp(a) therapies and the current state of the clinical trials of such novel agents.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.