Large US Study Links Elevated Lp(a) to Recurrent ASCVD Events

Elevated lipoprotein(a) [Lp(a)] levels were linked to a higher risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events, like myocardial infarction and stroke, but this threat may be attenuated by intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy.1

In the largest study to date of people living with CVD and a confirmed Lp(a) measurement, investigators analyzed data from more than 273,000 US individuals with ASCVD in the Family Heart Database, starting 30 days after diagnosis. The cohort’s size allowed investigators to assess the full Lp(a) spectrum, especially levels above 175–200 nmol/L.

“Among the many important findings in this study, we now know that in people living with CVD every nmol/L of Lp(a) confers increased risk of a subsequent cardiovascular event,” said Diane MacDougall, MS, vice president of science and research at the Family Heart Foundation, and first author of the study.2 “This is a meaningful advancement in our understanding of the impact of Lp(a) on one’s health.”

Elevated Lp(a) levels are a causal risk factor for the continuously elevated risk of incident ASCVD in healthy individuals, irrespective of sex and race or ethnicity, but it has not been determined whether recurrent ASCVD events are impacted by Lp(a) levels.3 Using medical claims data between 2012-2022 for 340 million individuals, 273,770 patients with diagnosed ASCVD and Lp(a) measured in nmol/L, including 43% women, 8% Black, 9% Hispanic, and 59% White individuals, were identified for analysis.1

This population was followed across a median of 5.4 years to determine whether they had another cardiovascular event, including myocardial infarction and ischemic stroke, or a cardiovascular procedure, including percutaneous coronary intervention or coronary artery bypass graft.

Lp(a) levels were higher in women than men and in Black participants, compared with Hispanic and White participants. About 33% of the overall population had low levels of Lp(a) (<15 nmol/L), 33% had moderate levels (15-79 nmol/L), 15% had moderate-to-high levels (80-179 nmol/L), 10% had high levels (180-299 nmol/L), and 5% had very high levels (≥300 nmol/L).

Across the follow-up, 41,687 individuals (15%) experienced recurrent ASCVD. Investigators confirmed an association between higher levels of Lp(a) and a continuously increasing risk of recurrent ASCVD. Compared with Lp(a) <15 nmol/L, adjusted hazard ratios (aHRs) for recurrent ASCVD events were 1.04 (95% CI, 1.01-1.07) for 15–79 nmol/L, 1.15 (95% CI, 1.12–1.19) for 80–179 nmol/L, 1.29 (95% CI, 1.25–1.33) for 180–299 nmol/L, and 1.45 (95% CI, 1.39–1.51) for ≥300 nmol/L.

Investigators found similar results across individual components of ASCVD, followed by sex, race and ethnicity, baseline ASCVD, and diabetes subgroups. At Lp(a) ≥300 nmol/L, the risk of recurrent ASCVD event was slightly higher in Hispanic and Black individuals than in White individuals.

Notably, MacDougall and colleagues found high-impact LDL-C-lowering therapy could potentially diminish the damaging effect of Lp(a) ≥180 nmol/L, particularly in those patients treated with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Within the full cohort, analyses showed the interactions of sex (P = .61), race/ethnicity (P = .06), baseline ASCVD (P = .33), and baseline diabetes (P = .91) with Lp(a) categories on risk of recurrent ASCVD event all had P > .05.

“The US has lagged behind many other countries in recommending that adults complete a simple blood test to measure Lp(a),” Katherine Wilemon, founder and chief executive officer of the Family Heart Foundation, said in a statement.2 “This study strongly confirms the importance of considering Lp(a) levels among other risk factors when determining an individual’s risk of future heart attacks and strokes.”

References

1. MacDougall DE, Tybjærg-Hansen A, Knowles JW, et al. Lipoprotein(a) and recurrent atherosclerotic cardiovascular events: the US Family Heart Database. Eur Heart J. Published online May 7, 2025. doi:10.1093/eurheartj/ehaf297

2. TheFHFoundation. Family Heart Foundation announces results of real-world study in 273,770 individuals with cardiovascular disease demonstrating that risk of subsequent cardiovascular event increases with rising lipoprotein(a) levels. EurekAlert! May 7, 2025. Accessed May 14, 2025. https://www.eurekalert.org/news-releases/1082940.

3. 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. 2024;18(3):e308-e319. doi:10.1016/j.jacl.2024.03.001