In the largest study of its kind, researchers have found that elevated lipoprotein(a) [Lp(a)] levels are directly linked to an increased risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events, with risk rising continuously across all Lp(a) levels. The groundbreaking research, simultaneously presented at the European Atherosclerosis Society Congress in Glasgow and published in the European Heart Journal, analyzed data from more than 273,000 individuals with ASCVD in the United States.
The study, conducted by researchers from the Family Heart Foundation, represents a significant advancement in understanding cardiovascular risk factors, particularly for patients who have already experienced a cardiovascular event.
Continuous Risk Increase Across All Lp(a) Levels
The research team analyzed medical claims data between 2012-2022 from the Family Heart Database, which contains information on 340 million individuals. They identified 273,770 patients with diagnosed ASCVD and measured Lp(a) levels, following them for a median of 5.4 years to track subsequent cardiovascular events.
"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.
During the follow-up period, 41,687 individuals (15%) experienced recurrent ASCVD events, including myocardial infarction, ischemic stroke, percutaneous coronary intervention, or coronary artery bypass graft. The researchers found a clear dose-response relationship between Lp(a) levels and recurrent events.
Compared with patients having Lp(a) levels below 15 nmol/L, the adjusted hazard ratios 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
- 1.45 (95% CI, 1.39–1.51) for ≥300 nmol/L
This pattern demonstrates that the risk increases continuously with rising Lp(a) levels, with no evidence of a plateau effect.
Demographic Variations in Lp(a) Risk
The study revealed important demographic differences in both Lp(a) levels and associated risks. Women had higher Lp(a) levels than men, and Black participants showed higher levels compared to Hispanic and White participants.
Within the study population, approximately one-third had low levels of Lp(a) (<15 nmol/L), one-third 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).
At Lp(a) levels of 300 nmol/L or higher, the magnitude of risk for recurrent ASCVD events was slightly higher in Hispanic and Black individuals than in White individuals, highlighting potential racial and ethnic disparities in cardiovascular risk.
Potential Risk Mitigation with LDL-C-Lowering Therapy
One of the most promising findings was that high-impact LDL cholesterol-lowering therapy appeared to diminish the harmful effects of elevated Lp(a), particularly in patients with levels ≥180 nmol/L. This effect was especially notable in patients treated with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
"This finding suggests that aggressive lipid management may help mitigate some of the cardiovascular risk associated with high Lp(a) levels, even though these therapies don't directly target Lp(a)," MacDougall explained.
While no FDA-approved medications currently target Lp(a) reduction specifically, several investigational therapies demonstrating 80-98% reductions in Lp(a) are currently being evaluated in clinical trials for ASCVD patients with elevated levels.
Implications for Clinical Practice
Katherine Wilemon, founder and chief executive officer of the Family Heart Foundation, emphasized the clinical implications of these findings: "The US has lagged behind many other countries in recommending that adults complete a simple blood test to measure Lp(a). 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."
The study underscores the need for routine Lp(a) testing in cardiovascular risk assessment, particularly for patients who have already experienced a cardiovascular event. Current guidelines vary regarding Lp(a) testing recommendations, but this research provides compelling evidence for its inclusion in standard cardiovascular risk assessment.
Future Directions
The findings highlight an unmet medical need for Lp(a)-lowering treatments across diverse ASCVD populations. Several pharmaceutical companies are currently developing therapies specifically targeting Lp(a), with phase 3 clinical trials underway.
"Should the ongoing trials of lipoprotein(a)-lowering agents prove safe and effective, these agents should be added to the armamentarium of effective lipid-altering medications," the researchers concluded.
This landmark study not only confirms Lp(a) as an independent risk factor for recurrent cardiovascular events but also suggests potential strategies for risk mitigation through existing therapies while awaiting the development of Lp(a)-specific treatments.
