Traditional Lp(a) drugs barely reach 50% reduction while new RNA-interfering agents may exceed 95%, a review of emerging pharmacotherapies (Int J Mol Sci 2023)

Original title: Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a)

Int J Mol Sci · 3 September 2023 · 6

Kosmas CE, Bousvarou MD, Papakonstantinou EJ, Tsamoulis D, Koulopoulos A, Echavarria Uceta R, Guzman E, Rallidis LS

This review summarises pharmacological approaches to hyperlipoproteinemia(a), defined as Lp(a) above 30 mg/dL in the US or 50 mg/dL in Europe, and recommends testing at least once in a lifetime. Traditional agents, niacin, statins, ezetimibe, aspirin, PCSK9 inhibitors, mipomersen, estrogens and CETP inhibitors, achieve at most about 50% Lp(a) reduction, with statins actually increasing Lp(a), while an estimated 80-90% reduction is thought necessary for a meaningful cut in major cardiovascular events. Novel hepatocyte-targeted RNA-interfering agents, the antisense oligonucleotide pelacarsen and the siRNAs olpasiran, LY3819469 and SLN360, all conjugated to N-acetylgalactosamine, silence LPA gene expression and can achieve Lp(a) reductions exceeding 95% with monthly subcutaneous dosing. The authors anticipate that results from ongoing trials of these agents could soon support guidelines for tailored management of elevated Lp(a).

Original abstract

Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.