Lipoprotein(a) as an Unmodifiable Risk Marker in a Modifiable Risk World: Testing, Interpretation and Communication
DOI:
https://doi.org/10.5281/zenodo.22305492Keywords:
Lipoprotein(a), Cardiovascular risk, Aortic stenosis, Mendelian randomization, Antisense oligonucleotide, Small interfering RNAAbstract
Lipoprotein(a) has long been taught as the archetypal unmodifiable cardiovascular risk marker: concentration is set
overwhelmingly by the LPA locus, is largely fixed by early adulthood, and is essentially unmoved by diet, exercise or statin
therapy. Genetic evidence, particularly Mendelian-randomization studies of the LPA variant rs10455872, supports a causal
rather than merely associative relationship with calcific aortic-valve disease, and guideline bodies now recommend testing
every adult at least once in a lifetime. But two things have changed the picture this decade. First, testing itself is not as simple
as a single number: mass (mg/dL) and molar (nmol/L) results are not related by one fixed factor, because apolipoprotein(a)
isoform size varies between patients, and population median levels vary several-fold by ancestry. Second, lipoprotein(a) is no
longer pharmacologically unmodifiable: antisense and small-interfering-RNA therapies now lower it by 80% to over 100%,
far beyond the roughly 25-27% achieved incidentally by PCSK9 inhibitors. What has not yet followed is proof that lowering it
changes outcomes. Topline results from the Lp(a)HORIZON trial of pelacarsen, released in September 2026 in 8,323 patients
with elevated lipoprotein(a) and established cardiovascular disease, showed substantial lipoprotein(a) reduction but did not
meet its primary composite cardiovascular endpoint. This review sets out the genetic case for causality, the practical difficulty
of testing and communicating a single risk number, and the widening gap between a marker that is now pharmacologically
modifiable and one that has been shown to improve outcomes when modified.
References
Kronenberg F, Mora S, Stroes ESG, et al. "Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement". Eur Heart J 43(2022):3925-3946.
Kronenberg F, Mora S, Stroes ESG, et al. "Frequent questions and responses on the 2022 lipoprotein(a) consensus statement of the European Atherosclerosis Society". Atherosclerosis 374(2023):107-120.
Mach F, Baigent C, Catapano AL, et al. "2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk". Eur Heart J 41(2020):111-188.
Al-Dalakta A, Cho LS, Sarraju A. "Lipoprotein(a) in clinical practice: What clinicians need to know". Cleve Clin J Med 92(2025):679-685.
Thanassoulis G, Campbell CY, Owens DS, et al. "Genetic Associations with Valvular Calcification and Aortic Stenosis". N Engl J Med 368(2013):503-512.
O'Donoghue ML, Fazio S, Giugliano RP, et al. "Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk". Circulation 139(2019):1483-1492.
Szarek M, Bittner VA, Aylward P, et al. "Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial". Eur Heart J 41(2020):4245-4255.
O'Donoghue ML, Rosenson RS, Gencer B, et al. "Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease". N Engl J Med 387(2022):1855-1864.
Cho L, Nicholls SJ, Nordestgaard BG, et al. "Design and Rationale of Lp(a)HORIZON Trial: Assessing the Effect of Lipoprotein(a) Lowering With Pelacarsen on Major Cardiovascular Events in Patients With CVD and Elevated Lp(a)". Am Heart J 287(2025):1-9.
Novartis. "Novartis announces Lp(a)HORIZON Phase III topline results for pelacarsen in patients with elevated Lp(a) and established cardiovascular disease (CVD)". Media release, 4 September 2026.
Kronenberg F, Utermann G. "Lipoprotein(a): resurrected by genetics". J Intern Med 273(2013):6-30.
Tsimikas S. "A Test in Context: Lipoprotein(a)". J Am Coll Cardiol 69(2017):692-711.
Wilson DP, Jacobson TA, Jones PH, Koschinsky ML, McNeal CJ, Nordestgaard BG, Orringer CE. "Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association". J Clin Lipidol 13(2019):374-392.
Koschinsky ML, Bajaj A, Boffa MB, et al. "A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice". J Clin Lipidol 18(2024):e308-e319.
Schmidt K, Noureen A, Kronenberg F, Utermann G. "Structure, function, and genetics of lipoprotein(a)". J Lipid Res 57(2016):1339-1359.
Danesh J, Collins R, Peto R. "Lipoprotein(a) and Coronary Heart Disease: Meta-Analysis of Prospective Studies". Circulation 102(2000):1082-1085.
AIM-HIGH Investigators. "Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy". N Engl J Med 365(2011):2255-2267.
HPS2-THRIVE Collaborative Group. "Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients". N Engl J Med 371(2014):203-212.
Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, Mora S. "Lipoprotein(a) Concentrations, Rosuvastatin Therapy, and Residual Vascular Risk: An Analysis from the JUPITER Trial". Circulation 129(2014):635-642.
de Boer LM, Oorthuys AOJ, Wiegman A, Langendam MW, Kroon J, Spijker R, Zwinderman AH, Hutten BA. "Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis". Eur J Prev Cardiol 29(2022):779-792.
Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. "Statin therapy increases lipoprotein(a) levels". Eur Heart J 41(2020):2275-2284.
ClinicalTrials.gov. "Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a)) - Outcomes Trial". NCT05581303. Accessed September 2026.
