Highlight
This large-scale UK Biobank analysis identifies high lipoprotein(a) (Lp(a)) concentrations as a significant risk marker for incident extracoronary atherosclerotic vascular diseases, including peripheral artery disease (PAD) and carotid artery stenosis, and their subsequent complications. Elevated Lp(a) associates with increased risk of major adverse limb events and suggests potential for guiding risk stratification beyond traditional lipid measurements.
Study Background and Disease Burden
Atherosclerotic vascular disease remains a leading cause of morbidity and mortality worldwide despite widespread implementation of cholesterol-lowering therapies and lifestyle interventions. While coronary artery disease has been the primary focus, extracoronary vascular beds such as peripheral arteries and carotid arteries also contribute substantially to adverse cardiovascular and limb events. Peripheral artery disease (PAD) affects millions globally and is associated with risks of limb ischemia and amputation, while carotid artery stenosis heightens the risk of ischemic stroke.
Despite aggressive management, a significant residual risk of these complications persists, motivating research into novel biomarkers that might more precisely predict atherosclerotic disease progression. Lipoprotein(a) is a genetically determined lipoprotein variant structurally similar to LDL but containing apolipoprotein(a). Elevated Lp(a) is implicated in proatherogenic, prothrombotic, and proinflammatory pathways that may accelerate arterial disease beyond LDL cholesterol alone.
Study Design
This study utilized data from 460,544 participants in the UK Biobank, a large prospective cohort predominantly of European ancestry. Baseline plasma concentrations of Lp(a) were measured prospectively. Participants were followed over a median 13.6 years to assess incident extracoronary atherosclerotic disease and progression to major complications.
The investigators employed Cox proportional hazards regression models to evaluate associations between Lp(a) levels (modeled per 75 nmol/L increase) and first incidence of peripheral artery disease (PAD) and carotid artery stenosis. For participants with prevalent disease at baseline, the risks of progression to major adverse limb events (for PAD) and ischemic stroke (for carotid stenosis) were examined.
Covariates including age, sex, smoking status, diabetes, and baseline demographics were controlled for in multivariable models. The large sample size and extended follow-up afforded high statistical power and precision.
Key Findings
The cohort had a median age of 58 years, slightly over half were male, and most participants were of European descent. Prevalence of diabetes was 5.5%, and about 10.5% were current smokers at enrollment.
During follow-up, 1.4% (6,347) developed incident PAD and 0.43% (1,972) developed carotid stenosis. Among those with preexisting PAD and carotid stenosis, 2.7% and 1.9% progressed to major adverse limb events and stroke, respectively.
Median Lp(a) concentrations were distinctly higher across the disease progression spectrum: 19.5 nmol/L in participants without vascular disease; 25.3 nmol/L in those with incident PAD; 33.3 nmol/L in PAD patients progressing to limb events; 29.5 nmol/L for incident carotid stenosis; and 37.8 nmol/L corresponding to carotid stenosis progressing to ischemic stroke.
Risk estimates showed that each 75 nmol/L increase in Lp(a) raised incident PAD risk by 18% (HR 1.18, 95% CI 1.15–1.20, P<0.0001) and incident carotid stenosis by 17% (HR 1.17, 95% CI 1.13–1.20, P<0.0001). In those with PAD, high Lp(a) levels conferred a 57% increased risk of major adverse limb events (HR 1.57, 95% CI 1.14–2.16, P=0.006). For carotid stenosis patients, a 40% higher risk of ischemic stroke was observed but did not reach statistical significance (HR 1.40, 95% CI 0.81–2.40, P=0.228).
These consistent associations across extracoronary sites emphasize Lp(a) as a potential independent prognostic biomarker for vascular disease beyond traditional risk factors, particularly for PAD and its debilitating complications.
Expert Commentary
These findings align with emerging data positioning elevated Lp(a) as a genetically driven, causal factor in atherosclerosis and thrombosis. The strength of this study lies in its scale, prospective design, and ability to link Lp(a) with both incident disease and clinically meaningful endpoints such as major limb events.
However, the predominance of European ancestry participants may limit direct generalizability to more diverse populations where Lp(a) concentrations and cardiovascular risk profiles differ. Furthermore, while the association with ischemic stroke progression in carotid stenosis was directionally consistent, it was not statistically significant, suggesting the need for studies focused on cerebrovascular outcomes.
Mechanistically, Lp(a) mediates atherogenesis through lipid accumulation and promotes proinflammatory and prothrombotic states via its apolipoprotein(a) component’s homology with plasminogen, potentially impairing fibrinolysis. These combined effects could plausibly drive both the development and progression of extracoronary atherosclerosis.
Clinical guidelines have increasingly recognized Lp(a) testing, particularly for individuals with premature or unexplained atherosclerotic disease. Yet, evidence for interventions specifically targeting Lp(a) remains limited, with novel agents under investigation. The ability of Lp(a) levels to stratify risk in PAD and carotid disease could inform patient selection for these emerging therapies.
Conclusion
This extensive study provides robust evidence that elevated lipoprotein(a) concentrations are independently associated with increased risk of incident extracoronary atherosclerotic vascular diseases and their progression to major complications such as limb events and stroke. Lp(a) measurement may improve risk stratification for PAD and carotid stenosis beyond conventional lipid panels, identifying high-risk patients who might benefit from more aggressive surveillance or emerging targeted treatments.
Future research should evaluate Lp(a)-lowering interventions in randomized trials and explore diverse populations to enhance the generalizability and clinical implementation of these findings. Integrating Lp(a) into routine clinical risk assessment could mark a pivotal advance in personalized prevention of extracoronary atherosclerotic disease and its devastating sequelae.
References
Bellomo TR, Bramel EE, Lee J, Urbut S, Flores A, Yu Z, Koyama S, Truong B, Haidermota S, Eagleton MJ, Natarajan P, Patel AP. Evaluation of Lipoprotein(a) as a Prognostic Marker of Extracoronary Atherosclerotic Vascular Disease Progression. Circulation. 2025 Sep 2;152(9):585-598. doi: 10.1161/CIRCULATIONAHA.124.073579. Epub 2025 Jul 28. PMID: 40718930; PMCID: PMC12313207.
