R3i Editorials

R3i editorials, created by members of the R3i board, focus on addressing the persistent challenges of residual cardiovascular risk. These editorials serve to educate healthcare professionals about emerging insights and therapeutic strategies related to lipid-related risk factors, such as triglyceride-rich lipoproteins and lipoprotein(a).

October 2025
Lipoprotein(a) is a residual cardiovascular risk factor: identify and manage
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco, Prof. Lale Tokgözoglu 

Recognition of lipoprotein(a) [Lp(a)] as a residual cardiovascular risk factor is gaining momentum. Already clear evidence supports the causality of high Lp(a) levels in increased risk for atherosclerotic cardiovascular disease (ASCVD) (1). These findings provided the foundation for guidelines to advocate for screening for Lp(a) at least once in adults, recognise elevated Lp(a) concentration as a risk enhancer, and (in the absence of licensed specific treatment to date) to recommend aggressive control of modifiable cardiovascular risk factors (2-5). While there is no universal consensus regarding cutoffs to define what is meant by a high Lp(a), levels exceeding the 80th population percentile, i.e., levels >50 mg/dL or > 100 to 125 nmol/L, have been proposed as thresholds to define an elevated Lp(a) contributing to cardiovascular risk (1,2).

Identifying elevated Lp(a) also offers important prognostic information to tailor treatment strategies in high-risk patients. Among patients with acute coronary syndrome (ACS), evidence from the ODYSSEY OUTCOMES trial showed that participants with elevated Lp(a) appeared to derive enhanced benefit from treatment with the PCSK9 inhibitor alirocumab, with greater reduction in cardiovascular events and adverse lower limb events among patients with elevated Lp(a) than in those with lower levels (6,7). Recent time-to-event analysis, discussed in this month’s Landmark report, showed that this benefit was evident early, from 15 months, for cardiovascular events but even before 3 months for adverse limb events after the initiation of alirocumab treatment (8).

Furthermore, this month’s Focus report shows that elevated Lp(a) offers important prognostic information in the setting of peripheral artery disease (PAD). Real-world data from the Mass General Brigham Lp(a) registry including nearly 4,000 patients with PAD showed that elevated Lp(a) was associated with increased risk for both cardiovascular and lower limb events. For PAD patients with Lp(a) levels in the range of 42–<132 nmol/L, the higher level equating approximately to 50 mg/dL signifying increased risk (1), there was 24% increase in the risk for incident MACE (p=0.005), and this was even higher (30%) for patients in the highest Lp(a) quartile. Increased risk for lower limb events was also demonstrated for patients with highest Lp(a) levels. The lack of statistical significance for the quartile 3 range may relate to limited numbers of lower limb events.

While there are caveats to each study, the take home message is that high-risk patients with elevated Lp(a) have increased risk for both cardiovascular and adverse lower limb events. For PAD, prevalent but usually underdiagnosed and undertreated (10,11) the implications are especially important. Lower extremity PAD is already the third leading cause of ASCVD morbidity, but as populations age, will pose even more of a global healthcare burden (12,13), due to the cost of managing complications of both cardiovascular disease and critical limb ischaemia (14).

There is strong evidence that elevated Lp(a) associates with progression of PAD in large arteries (12) and predisposes to an increased risk for cardiovascular and lower limb adverse events. Findings from these studies reinforce the critical importance of measuring Lp(a) (3), to enable clinicians to identify and tailor best treatment to those patients at the highest risk. Overcoming clinical inertia on measurement of Lp(a) is key to implementing this strategy. Reducing the residual vascular risk of high-risk patients with elevated Lp(a) will translate to improved quality of life and morbidity, and benefit healthcare systems with increasingly finite resources. Measurement of Lp(a) in our patients can also trigger discussions regarding cascade screening in families, as elevated Lp(a) is strongly heritable.

References

  1. 1. 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 2022;43:3925–46.
    2. Wilson DP, Jacobson TA, Jones PH, et al. Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374–92.
    3. Pearson GJ, Thanassoulis G, Anderson TJ, et al. 2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol 2021;37:1129–50.
    4. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis 2019;290:140–205.
    5. Mach F, Koskinas KC, Roeters van Lennep JE, et al. Focused update of the 2019 ESC/EAS guidelines for the management of dyslipidaemias. Atherosclerosis 2025. https://doi.org/10.1016/j.atherosclerosis.2025.120479.
    6. 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 2020;41:4245-55.
    7. Schwartz GG, Steg PG, Szarek M et al. Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial. Circulation 2020;141:1608-17.
    8. Ray KK, Szarek M, Bhatt DL, et al. Lipoprotein(a) identifies patients with acute coronary syndromes who derive cardiovascular benefit from alirocumab, particularly for limb events. J Am Coll Cardiol 2025; https://doi.org/10.1016/j.jacc.2025.08.043
    9. McClintick DJ, Biery DW, Berman AN, et al. Association between lipoprotein(a) and cardiovascular events in patients with peripheral artery disease: the Mass General Brigham Lp(a) registry. Eur J Prevent Cardiol 2025; https://doi.org/10.1093/eurjpc/zwaf475
    10. Varvel S, McConnell JP, Tsimikas S. Prevalence of elevated Lp(a) mass levels and patient
    thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol 2016;36:2239–45.
    11. Criqui MH, Matsushita K, Aboyans V, et al. Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the American Heart Association. Circulation 2021;144:e171–e191.
    12. Global Burden of Disease study. Global burden of peripheral artery disease and its risk factors. 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet Global Health 2023;11:e1553–e1565.
    13. Prince MJ, Wu F, Guo Y, et al. The burden of disease in older people and implications for health policy and practice. Lancet 2015; 385:549–62.
    14. Aboyans V, Criqui MH, Denenberg JO, et al. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation 2006;113:2623–9.

Key words: Lipoprotein(a); peripheral artery disease; ODYSSEY OUTCOMES; residual vascular risk