Very high Lp(a) also correlated with higher risks of ischemic stroke and cardiovascular mortality in the Women’s Health Study.

Healthy women with elevated lipoprotein(a) levels are at greater risk of cardiovascular events over long-term follow-up, with the risk increasing in a stepwise fashion across Lp(a) thresholds and percentiles, according to an analysis of the Women’s Health Study.

At 30 years, the relative risk of major CV events was 16% higher in women with a baseline Lp(a) of 30 to less than 60 mg/dL compared with women with baseline levels below 10 mg/dL. It was nearly 55% higher in those with Lp(a) levels of 120 mg/dL or greater. The risk of coronary heart disease also increased in a stepwise manner with rising Lp(a) levels.   

Overall, the new findings aren’t surprising, said lead investigator Ask Tybjærg Nordestgaard, MD, PhD (Brigham and Women’s Hospital, Boston, MA), who noted that the Lp(a) thresholds associated with higher risk line up with prior studies. However, he said there were two novel, interesting findings that emerged from the analysis.

“One was that the relative risk across 30 years is the same as you’d see in a cohort with shorter follow-up, with 10 years’ follow-up,” he told TCTMD. “Across 30 years’ follow-up, this amounts to a very big difference in absolute risk. We saw an almost 10% increase in absolute risk between those with low and high Lp(a) levels. The second important finding was that those with very high Lp(a) also have very high relative and absolute risks of cardiovascular death and ischemic stroke.”

Over the years, there have been numerous studies showing that Lp(a) is a significant risk factor for cardiovascular disease, aortic valve stenosis, and cardiovascular mortality. In the US guidelines for the treatment of high cholesterol, it’s considered a risk-enhancing factor to help physicians and patients make an informed decision about LDL cholesterol-lowering treatment. In Europe, clinical guidelines recommend checking Lp(a) for the purpose of CVD risk stratification at least once during the patient’s lifetime, although the recommendation is relatively weak.

High Lp(a) has historically been a untreatable abnormality, but there are now several drugs in development to lower Lp(a), including lepodisiran (Eli Lilly), zerlasiran (Silence Therapeutics), and pelacarsen (Novartis/Ionis Pharmaceuticals). The cardiology community is eagerly anticipating results from the large-scale, cardiovascular outcomes trials, including Lp(a)HORIZON with pelacarsen and OCEAN(a) with olpasiran (Amgen), both of which are expected this year.   

Diving Into Lp(a)

The new study, which was published in JAMA Cardiology this week, is a follow-up to another analysis from the Women’s Health Study, said Tybjærg Nordestgaard. Last year, Paul M. Ridker, MD (Brigham and Women’s Hospital), the senior author of the current paper, presented and published data showing that three biomarkers—LDL cholesterol, high-sensitivity C-reactive protein (CRP), and Lp(a)—at middle age were strongly linked to cardiovascular events over 30 years.

“In that study, we didn’t look at clinical thresholds of Lp(a), which is probably the most meaningful measure when you’re looking at Lp(a),” said Tybjærg Nordestgaard.

The study included 27,748 women with baseline Lp(a) measurements and median follow-up duration of 27.8 years. Women with elevated Lp(a), beginning at a clinical threshold of 30 mg/dL, had an increased risk of major CV events and coronary heart disease when compared with those with the lowest levels. When Lp(a) levels were stratified as a percentile, similar results were observed, with the 30-risks of major CV events and coronary heart disease increased in those above the 75th percentile (corresponding to approximately 33 mg/dL).

Major CV Event Risk Across Lp(a) Thresholds

 

Adjusted HR (95% CI)

< 10 mg/dL

1 (reference)

10 to < 30 mg/dL

0.99 (0.92-1.08)

30 to < 60 mg/dL

1.16 (1.05-1.28)

60 to < 90 mg/dL

1.28 (1.15-1.43)

90 to < 120 mg/dL

1.41 (1.17-1.71)

In women with Lp(a) levels greater than the 99th percentile, which worked out to 131 mg/dL or above, the 30-year risk of ischemic stroke was 85% higher than in those with lower levels (≤ 50th percentile). Similarly, for women with the highest Lp(a) levels, the risk of cardiovascular death was 86% higher when compared with those at lower levels (> 99th versus ≤ 50th percentile).

“We can say that across 30 years of follow-up, very high Lp(a) levels are associated with high risk of all cardiovascular endpoints and not just coronary heart disease,” said Tybjærg Nordestgaard.

It’s relatively easy and cheap to measure, and I do think we should consider screening for this and doing it at a young age. Ask Tybjærg Nordestgaard

The results, he suggested, also make an important case for screening healthy individuals for elevated Lp(a).

“Obviously, the one thing we still need to see is whether Lp(a)-lowering actually reduces cardiovascular risk,” he said. “We don’t know that yet and that’s why we’re waiting for the results from the HORIZON and OCEAN trials this year, and from other trials. Nevertheless, perhaps catching the people who have very extremely high Lp(a) levels would help us prioritize general preventive measures among these people. Even though we cannot lower Lp(a), we can lower their overall cardiovascular risk by addressing LDL cholesterol, hypertension, and other traditional cardiovascular risk factors.”  

Moreover, Lp(a) is largely genetically determined, meaning it doesn’t need to be measured multiple times, said Tybjærg Nordestgaard. “You just have to measure it once in a lifetime in every person,” he said. “That’s more or less it. It’s relatively easy and cheap to measure, and I do think we should consider screening for this and doing it at a young age.”