Elevated lipoprotein(a): a risk enhancer in peripheral artery disease

October 2025

Findings from the Mass General Brigham (MGB) Lp(a) registry show that elevated lipoprotein(a) was strongly associated with both cardiovascular and adverse lower limb events.

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

STUDY SUMMARY

Objective

To investigate the association between lipoprotein(a) [Lp(a)] and major adverse cardiovascular events (MACE) and major acute lower limb events (MALE) among patients with peripheral artery disease (PAD) at baseline.  

 

 

Study design

Registry: The Mass General Brigham Lp(a) registry included individuals with Lp(a) measured at two U.S. tertiary care centres from 2000 to 2019.

 

 

Study population

The registry included 21,410 patients of whom 3757 had PAD (39% female, median age 68 years). In total, 81% of patients with PAD had dyslipidaemia and were treated with a statin.

 

 

Main study variables

 

·         MACE, a composite of cardiovascular  death, nonfatal myocardial infarction (MI), or coronary revascularization

·         MALE, a composite of endovascular or surgical peripheral revascularization, acute limb ischaemia, or major lower extremity amputation.

 

 

Methods

Patients were grouped in quartiles based on Lp(a) percentile: Quartile 1, 1st–25th, Lp(a) ≤14 nmol/L; Quartile 2, 26th – 50th, Lp(a) 14–<42 nmol/L;  Quartile 3, 51st – 75th, Lp(a) 42–<132 nmol/L; and Quartile 4, 76th – 100th, Lp(a) 132–855 nmol/L. Cox proportional hazard modelling was used to assess the association between Lp(a) and risk for MACE and MALE after adjustment for traditional risk factors.

 

Results

Over a median follow-up of 15.1 years (interquartile range [IQR] 13.9–16.1), 12% (n=447) of patients experienced a non-fatal MI, 14% (n=516) underwent coronary revascularization, and 24% (n=904) died of cardiovascular causes. When compared with patients in the first Lp(a) quartile (reference), patients in the highest Lp(a) quartile had a 36% higher hazard of MACE (p<0.001, unadjusted hazard). These findings remained robust after adjustment, with a 30% higher risk of MACE (adjusted hazard ratio 1.30, 95% CI 1.12–1.50, p=0.001). Even among patients in quartile 3 (42–<132 nmol/L), there was an increase in risk of incident MACE of 24% (adjusted hazard ratio 1.30, 95% CI 1.07-1.45, p=0.005). For individual endpoints, patients in the highest Lp(a) quartile had a 45% higher adjusted hazard of MI (p = 0.004) and an 68% higher hazard of coronary revascularization (p < 0.001) when compared with those in quartile 1.

Over the same follow-up, 9% (n=355) of patients experienced acute limb ischaemia, 24% (n=919) underwent peripheral revascularization, and 2.4% (n=90) underwent a major lower extremity amputation. Patients in the fourth quartile had a 19% higher risk of MALE (adjusted hazard ratio 1.19, 95% CI 1.01–1.40, p=0.043), including a 20% higher hazard of peripheral revascularization (p=0.045) compared with those in the first quartile.

 

Author conclusions

Elevated Lp(a) in patients with PAD was associated with an increased risk of both MACE and MALE. Accordingly, measurement of Lp(a) may convey important prognostic value and allow for further risk stratification within this high-risk population.

Comment

Elevated Lp(a) is recognized as a risk factor for atherosclerotic cardiovascular disease including PAD (1). Current guidelines identify elevated Lp(a) as a risk enhancer, and thus a residual risk factor in high-risk patients (2,3). Although evidence supports Lp(a) and PAD as risk factors for MACE, the relationship between elevated Lp(a) and subsequent cardiovascular and limb outcomes in patients with PAD is less clear.

 

This study has addressed this question, providing evidence that elevated Lp(a) concentration is strongly associated with incident cardiovascular events and adverse lower limb events in patients with PAD. For patients with PAD and Lp(a) levels between 132–855 nmol/L (as in quartile 4), the risk of incident MACE was 30% higher and incident MALE 19% higher compared with those patients with Lp(a) levels ≤14 nmol/L. Even among patients in quartile 3 (42–<132 nmol/L), which is considered within the ‘grey’ or interim Lp(a) concentration (i.e. 30–50 mg/dL; 75–125 nmol/L) for clinical decision making (1), there was an increase in risk of incident MACE of 24% (p=0.005), although no significant increase in risk of incident MALE, possibly relating to lower absolute numbers of MALE relative to MACE outcomes, and/or more frequent diagnosis of MACE relative to MALE. However, these findings are consistent with a previous study which reported an increased risk of MALE only at Lp(a) concentrations > 75th percentile (4).

 

Despite the retrospective nature of this real-world registry, the size of the study population and the extended duration of follow-up add to the robustness of the study and provide a rationale for measuring Lp(a) to identify patients with PAD at highest risk and to intensify treatment accordingly. Beyond clinical considerations, adoption of this strategy could have important socioeconomic benefits, given that PAD is prevalent (5,6), and the clinical sequelae are associated with substantial mortality, morbidity and impaired quality of life (7).

 

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. Mach F, Koskinas KC, Roeters van Lennep JE, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Developed by the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Eur Heart J 2025; https://doi.org/10.1093/eurheartj/ehaf190
  3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2020;41:111–88.
  4. Bellomo TR, Liu Y, Gilliland TC, et al. Associations between lipoprotein(a), oxidized phospholipids, and extracoronary vascular disease. J Lipid Res 2024;65:100585.
  5. 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.
  6. 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.
  7. Kou T, Qian X, Liu Y, et al. Global, regional, and national burden of peripheral artery disease: a systematic analysis of prevalence, incidence, deaths, and DALYs with projections for the next 15 years. Nutr Metab Cardiovasc Dis 2025 Jul 11:104226.

Key words: peripheral artery disease; lipoprotein(a); registry; MACE; MALE