A nearly 30-year study shows a strong long-term association between very high lipoprotein(a) [Lp(a)] levels and cardiovascular disease (CVD) in women and raises questions about whether broader screenings may be warranted.

Investigators sought to determine whether elevated levels of Lp(a) predicted long-term cardiovascular risk in women. Because Lp(a) is largely determined by genetics — and only a small percentage of the population has levels high enough to meaningfully increase CVD risk — the researchers also examined whether screening the general population is clinically worthwhile.

The study cohort consisted of participants in the Women’s Health Study, an ongoing investigation of nearly 28,000 initially healthy women.

Participants were recruited between 1992 and 1995 and have been followed since 1993. At enrollment, none had known CVD, cancer, or other major chronic illnesses. Blood samples were collected at baseline to measure Lp(a), and participants provided detailed information on lifestyle factors, demographics, and self-reported race.

Major CVD Events

The primary outcome was the first occurrence of a major cardiovascular event, defined as myocardial infarction, coronary revascularization, ischemic stroke, or death from cardiovascular causes.

Researchers used spline models and hazard ratios (HRs) to examine long-term risk, adjusting for multiple cardiovascular risk factors including age, blood pressure, smoking status, alcohol intake, history of diabetes, low-density lipoprotein cholesterol, hormone therapy, and the inflammatory marker high-sensitivity C-reactive protein.

Most participants had low or normal Lp(a) levels at enrollment. About 75% had levels < 30 mg/dL. About one quarter had moderately elevated levels (≥ 30 mg/dL), while only roughly 1%-2% had extremely high levels, defined as ≥ 120 mg/dL.

Follow-Up Results

Over nearly 30 years of follow-up, cardiovascular risk did not increase evenly across all Lp(a) levels. Women with low to mildly elevated Lp(a) generally did not experience higher long-term cardiovascular risk. Risk began to rise once Lp(a) levels exceeded approximately 30 mg/dL.

The most striking increases in risk were observed among women with Lp(a) levels > 120 mg/dL. They experienced substantially higher rates of major cardiovascular events over time, with about 50%-100% higher relative risk than that of women with very low Lp(a) levels.

Mild or moderate elevations were not clearly associated with increased risks for ischemic stroke or death from cardiovascular causes.

Elevated risks for these outcomes were largely confined to women with the most extreme Lp(a) levels, suggesting that very high Lp(a) can drive risk across several different forms of CVD.

“I was surprised at the magnitude of risk among those with very high levels and the fact that elevated Lp(a) levels are strongly associated with high risk of ischemic stroke and cardiovascular death and not only coronary heart disease,” said Ask T. Nordestgaard, MD, PhD, lead author of the study and postdoctoral research fellow at Brigham and Women’s Hospital in Boston.

To Screen or Not to Screen?

The researchers concluded that routine Lp(a) testing may not meaningfully alter cardiovascular risk assessment for the population at large.

However, screening could be valuable for identifying a small subgroup of women at very high lifetime risk who might otherwise go undetected. For these women, monitoring, more aggressive prevention strategies, and future therapies could be particularly beneficial.

Steven E. Nissen, MD, MACC, chief academic officer of the Heart, Vascular, and Thoracic Institute at the Cleveland Clinic, Cleveland, agreed.

“These findings are consistent with prior studies showing a higher risk of cardiovascular outcomes with increasing levels of Lp(a) and longer follow-up,” said Nissen, who was not involved in the study.

“What is relatively unique here is the demonstration that Lp(a) is a strong risk factor even in relatively young women, emphasizing that no one is likely spared by this risk factor,” he said. “The advice to screen more widely is increasingly supported by data from many sources, including the current study.”

Nordestgaard reported receiving grants from the Independent Research Fund Denmark. Daniel I. Chasman reported holding a patent for LPA polymorphism and aspirin use for CVD prevention, with royalties paid from Quest Diagnostics. I-Min Lee and Julie E. Buring reported receiving grants from the US National Institutes of Health. Paul M. Ridker reported receiving institutional grants from Kowa, Novo Nordisk, Pfizer, the US National Cancer Institute, and the US National Heart, Lung, and Blood Institute and personal fees from Agepha, AstraZeneca, Cardio Therapeutics, CSL Behring, Eli Lilly and Company, New Amsterdam, NodThera, Novartis, Novo Nordisk, and Tourmaline Bio.

The Women’s Health Study was supported by grants from the US National Institutes of Health or National Heart, Lung, and Blood Institute and the US National Cancer Institute. The writing of the study was supported by the Independent Research Fund Denmark.

Lois Anzelowitz Levine is a medical writer living in Dallas.