Highlight
– In a large US claims cohort of 273,770 individuals with prior ASCVD and measured lipoprotein(a) (Lp[a]) in nmol/L, higher Lp(a) was associated with continuously increasing risk of recurrent atherosclerotic cardiovascular disease (ASCVD) over a median 5.4 years.
– Adjusted hazard ratios for recurrent ASCVD rose across Lp(a) categories versus <15 nmol/L: 1.04 (15–79), 1.15 (80–179), 1.29 (180–299), and 1.45 (≥300).
– The association was consistent across sex, race/ethnicity, baseline ASCVD type, and diabetes status; high-impact LDL‑C lowering—particularly PCSK9 inhibitor use—appeared to partially mitigate risk from very high Lp(a).
– Findings support routine Lp(a) assessment in secondary prevention and strengthen the rationale for aggressive LDL lowering and emerging Lp(a)-lowering therapies in high-risk patients.
Background
Lipoprotein(a) is a genetically determined lipoprotein particle characterized by an LDL-like moiety covalently bound to apolipoprotein(a). Lp(a) carries oxidized phospholipids and exerts both proatherogenic and prothrombotic effects. Lifetime exposure to elevated Lp(a) increases the risk of incident coronary heart disease and ischemic stroke. Lp(a) levels vary markedly between individuals and across racial/ethnic groups; concentrations are generally higher in people of African ancestry. Clinical guidelines increasingly recognize Lp(a) as an important risk modifier: measurement is recommended at least once in adult life in many guideline statements to help refine cardiovascular risk and guide management decisions.
Study design
The study by MacDougall et al. used the US Family Heart Database, a medical claims dataset covering approximately 340 million individuals between 2012 and 2022, to identify adults with diagnosed ASCVD who had an Lp(a) measurement expressed in nmol/L. The analytic cohort comprised 273,770 individuals (117,269 women [43%], 156,501 men [57%]) including self-identified Black (n = 22,451; 8%), Hispanic (n = 24,606; 9%), and White (n = 161,165; 59%) patients. Median follow-up was 5.4 years.
Key exposures and outcomes
– Exposure: Lp(a) categorized as <15, 15–79, 80–179, 180–299, and ≥300 nmol/L.
– Primary outcome: recurrent ASCVD events (composite of coronary, cerebrovascular, and peripheral atherosclerotic events) identified in claims.
– Covariates: demographic variables, baseline ASCVD subtype, diabetes, and medication use, including LDL‑C‑lowering therapies (statins, ezetimibe, PCSK9 inhibitors).
Statistical approach
– Time-to-event analyses with adjusted Cox proportional hazards models estimated hazard ratios (HRs) for recurrent ASCVD across Lp(a) categories compared to <15 nmol/L.
– Interaction testing evaluated whether associations varied by sex, race/ethnicity, baseline ASCVD type, diabetes status, and intensity/class of LDL‑C–lowering therapy.
Key findings
Cohort characteristics and Lp(a) distribution
– Overall, women had higher Lp(a) levels than men; Black individuals had higher levels than Hispanic and White individuals.
– During median 5.4 years follow‑up, 41,687 participants (15%) experienced a recurrent ASCVD event.
Primary associations
– There was a graded, continuous relationship between Lp(a) concentration and risk of recurrent ASCVD. Compared with Lp(a) < 15 nmol/L, adjusted HRs were:
– 15–79 nmol/L: 1.04 (95% CI 1.01–1.07)
– 80–179 nmol/L: 1.15 (95% CI 1.12–1.19)
– 180–299 nmol/L: 1.29 (95% CI 1.25–1.33)
– ≥300 nmol/L: 1.45 (95% CI 1.39–1.51)
– Associations were present for individual ASCVD components (coronary, cerebrovascular, peripheral) as well as for the composite.
Subgroup analyses
– The Lp(a)-recurrent ASCVD relationship was broadly consistent by sex and race/ethnicity. Interaction P-values were nonsignificant for sex (P = .61) and for diabetes (P = .91). The race/ethnicity interaction approached significance (P = .06) but did not meet conventional thresholds.
Impact of LDL‑C lowering therapy
– A key observation was attenuation of Lp(a)-related excess risk among patients receiving high‑impact LDL‑C lowering therapy, most pronounced in those on PCSK9 inhibitors. The interaction between Lp(a) category and intensity/class of LDL‑C therapy was highly significant (P = 2 × 10−8), suggesting treatment effect modification.
– The protective signal was strongest for participants with Lp(a) ≥180 nmol/L who were treated with PCSK9 inhibitors; however, the study design cannot demonstrate causality and residual confounding by indication is possible.
Robustness and statistical considerations
– The analyses adjusted for multiple clinical covariates; the graded effect across categories and consistent component findings strengthen causal inference but do not eliminate limitations inherent to observational claims data.
Expert commentary and interpretation
Clinical implications
– This large real‑world analysis extends prior observations about Lp(a) as a lifelong risk factor to the important domain of secondary prevention: higher Lp(a) predicts recurrent ASCVD events in patients with established disease.
– The magnitude of effect is clinically meaningful, particularly at Lp(a) ≥180 nmol/L where the adjusted HR nears 1.3–1.5 depending on the stratum. For a patient with prior ASCVD, such incremental risk meaningfully affects absolute event rates and decision thresholds for intensified therapy.
– The apparent mitigation of Lp(a)-related risk by high‑impact LDL‑C lowering—especially PCSK9 inhibitors—is biologically plausible. PCSK9 monoclonal antibodies reduce LDL‑C substantially and have been shown to lower Lp(a) modestly (≈20–30% in some trials); moreover, reducing LDL exposure lowers atherogenic burden independent of Lp(a) changes. Observations from major randomized trials (e.g., FOURIER) have suggested that Lp(a) reduction with PCSK9 inhibitors contributes to the observed clinical benefit, though mediation is partial.
Biological plausibility and mechanism
– Lp(a) is proatherogenic through cholesterol delivery to the arterial wall and by carrying oxidized phospholipids that promote inflammation. Its structure—apolipoprotein(a) attached to apolipoprotein B—also confers antifibrinolytic properties, augmenting thrombotic risk. Thus, Lp(a) plausibly increases both plaque formation/progression and event precipitating thrombosis, leading to recurrent events in those with established atherosclerosis.
Study strengths
– Very large sample size and diversity (sex and major race/ethnicity groups) increase precision and generalizability within the US insured population.
– Use of nmol/L units for Lp(a) reduces inter-assay comparability issues relative to mass (mg/dL) units, as nmol/L better reflects particle concentration.
– Detailed medication data allowed exploratory evaluation of treatment interaction, which has important clinical relevance.
Limitations and cautionary notes
– Observational claims data lack the rigor of randomized assignment. Residual confounding is likely: patients receiving PCSK9 inhibitors differ systematically (e.g., in care access, baseline risk, adherence) from those who do not.
– Lp(a) testing is not universally performed; selection bias may occur if clinicians preferentially test higher-risk patients.
– Claims-based event ascertainment lacks adjudication; misclassification of exposures or outcomes is possible.
– The database does not report Lp(a) isoform size (kringle IV repeat number), which influences measured concentration and risk, nor does it necessarily capture LDL‑C values obtained contemporaneously with Lp(a) or precise adherence data for lipid therapies.
– The study reports associations but cannot determine whether the Lp(a) effect is mediated by Lp(a) particle number, oxidized phospholipids, or correlated genetic factors.
Clinical and policy implications
For practicing clinicians
– Consider Lp(a) measurement in patients with established ASCVD if not previously measured; a single lifetime measurement is often sufficient given its strong genetic determination.
– Recognize that markedly elevated Lp(a) (e.g., ≥180–300 nmol/L) identifies patients at substantially higher residual risk who may benefit from intensified secondary prevention strategies.
– Intensify LDL‑C lowering in patients with high Lp(a). Where available and guideline‑appropriate, high‑efficacy therapies (maximally tolerated statin ± ezetimibe and, when indicated, PCSK9 inhibitors) should be used to lower overall atherogenic lipoprotein burden.
– In selected patients with very high Lp(a) and recurrent events despite optimal LDL‑C lowering, consider referral to lipid specialists and trial enrollment as targeted Lp(a)-lowering agents (antisense oligonucleotides and siRNA agents) advance through clinical development.
For guideline developers and payers
– These data support incorporation of Lp(a) into secondary prevention algorithms as a risk stratifier and potential treatment consideration. Policy should facilitate access to Lp(a) testing and to high‑impact LDL‑C therapies for patients with elevated Lp(a) and recurrent events.
Conclusion
In a very large US claims cohort of 273,770 individuals with established ASCVD and measured Lp(a), higher Lp(a) levels were associated with a continuously increasing risk of recurrent ASCVD across sexes and racial/ethnic groups. Importantly, intensified LDL‑C lowering—particularly with PCSK9 inhibitors—was associated with attenuation of the Lp(a)‑related risk, although causality cannot be inferred from observational data. These results reinforce the prognostic value of Lp(a) in secondary prevention, support routine Lp(a) assessment in people with ASCVD, and underscore the need to apply aggressive LDL‑C lowering and, when available, targeted Lp(a) therapies to address residual risk.
Funding and clinicaltrials.gov
Funding: As reported in the original publication (MacDougall et al., Eur Heart J. 2025), details of study funding are provided in the cited article. This analysis used commercial claims data and was observational in design.
ClinicalTrials.gov: This is an observational analysis of claims data and is not a registered interventional trial; no clinicaltrials.gov identifier applies.
References
1. MacDougall DE, Tybjærg-Hansen A, Knowles JW, Stern TP, Hartsuff BK, McGowan MP, Baum SJ, Wilemon KA, Nordestgaard BG. Lipoprotein(a) and recurrent atherosclerotic cardiovascular events: the US Family Heart Database. Eur Heart J. 2025 Nov 21;46(44):4762-4775. doi: 10.1093/eurheartj/ehaf297 IF: 35.6 Q1 . PMID: 40331569 IF: 35.6 Q1 ; PMCID: PMC12634116 IF: 35.6 Q1 .
2. Sabatine MS, Giugliano RP, Keech AC, et al.; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–1722.
3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC Guideline on the Management of Blood Cholesterol: Executive Summary. Circulation. 2019;139(25):e1046–e1081.
4. Catapano AL, Graham I, De Backer G, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111–188.
(Readers should consult the cited original article for full methodological and funding details.)
