How bad is Lipoprotein(a)?

It is well known that lipoprotein(a) is associated with increased risk of cardiovascular disease, including calcific aortic valve disease. New treatment modalities are being investigated in clincal trials like Lp(a)HORIZON and OCEAN(a) which are expected to be completed within a year or two. A recent retrospective cohort study evaluated the incidence of major adverse cardiovascular events (MACE) among patients with and without baseline atherosclerotic cardiovascular disease and their association with lipoprotein(a) levels. MACE includes nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and cardiovascular mortality [1].

Nearly sixteen thousand and five hundred individuals were analyzed and had a median follow up of nearly 12 years. There were over six thousand and two hundred individuals without established atherosclerotic cardiovascular disease at baseline. A continuously higher hazard of MACE with increasing Lp(a) levels was noted in the study.

Lp(a) was considered as an unmodifiable cardiovascular risk factor. The clinical trials mentioned intially are investigating the effects of antisense oligonucleotides and small interfering RNAs in reducing the risk due to Lp(a). PCSK9 inhibitors have been shown to decrease Lp(a) levels by about 20%. FOURIER [2] and ODYSSEY [3] trials had shown that those with baseline elevated Lp(a) levels in addition to elevated LDL had the greatest cardiovascular benefit from PCSK9 inhibitors.

Reference

1. Adam N. Berman, David W. Biery, Stephanie A. Besser, Avinainder Singh, Arthur Shiyovich, Brittany N. Weber, Daniel M. Huck, Sanjay Divakaran, Jon Hainer, Gurleen Kaur, Michael J. Blaha, Christopher P. Cannon, Jorge Plutzky, James L. Januzzi, John N. Booth, J. Antonio G. López, Shia T. Kent, Khurram Nasir, Marcelo F. Di Carli, Deepak L. Bhatt, and Ron Blankstein. Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease. J Am Coll Cardiol. 2024 Mar, 83 (9) 873–886.
2. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Češka R, Ezhov MV, Jukema JW, Jensen HK, Tokgözoğlu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019 Mar 19;139(12):1483-1492. doi: 10.1161/CIRCULATIONAHA.118.037184. PMID: 30586750.
3. Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, Fras Z, Goodman SG, Halvorsen S, Hanotin C, Harrington RA, Jukema JW, Loizeau V, Moriarty PM, Moryusef A, Pordy R, Roe MT, Sinnaeve P, Tsimikas S, Vogel R, White HD, Zahger D, Zeiher AM, Steg PG, Schwartz GG; ODYSSEY OUTCOMES Committees and Investigators. Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome. J Am Coll Cardiol. 2020 Jan 21;75(2):133-144. doi: 10.1016/j.jacc.2019.10.057. PMID: 31948641.