High Lp(a) Levels Harmful in Patients With and Without ASCVD

Elevated lipoprotein(a) increases the risk of major adverse cardiovascular events in patients with and without preexisting atherosclerotic cardiovascular disease (ASCVD), a new study shows.

The analysis, however, suggests there may be different thresholds for risk with heightened Lp(a) in these diverse patient populations, investigators say.

“When we use Lp(a) as a risk marker, it behaves quite differently between patients with ASCVD and patients without ASCVD,” senior investigator Ron Blankstein, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. For those without ASCVD, for example, “the threshold of risk is only for those who have a very high Lp(a), above the 90th percentile, which in our study corresponded to roughly 216 nmol/L.”

Blankstein said patients referred to specialty clinics because of elevated Lp(a) are often concerned about their risk of cardiovascular events, but that these new data can be reassuring.

“Not everybody who has a high Lp(a) is going to have an event,” he said, noting that the event rates in patients without ASCVD are still quite low. In the primary-prevention patient, “unless they have a really high Lp(a), I think we can reassure some of those patients that their Lp(a) level is not that high,” said Blankstein.

For patients with ASCVD, the risk of major adverse cardiovascular events plateaued at Lp(a) levels around 112 nmol/L, or more than 53 mg/dL, in the present study, “suggesting Lp(a) may be a marker of increased risk at an even lower level in secondary prevention,” said Blankstein.

Right now, there’s a lot of excitement in cardiovascular medicine about Lp(a), not just as a marker but also as a potential target for therapies that can lower it, said Blankstein. Lp(a) levels are highly determined by genetics, and it’s been estimated that approximately 20% of the population have Lp(a) levels 50 mg/dL or higher (125 nmol/L), which is considered elevated. A number of studies, including genetic analyses, have shown that higher Lp(a) levels are linked with ASCVD and calcific aortic valve disease.

Not everybody who has a high Lp(a) is going to have an event. Ron Blankstein

There are two ongoing phase III clinical trials testing whether lowering Lp(a) reduces the risk of cardiovascular events. The Lp(a)HORIZON study is testing pelacarsen (Novartis/Ionis Pharmaceuticals), an antisense oligonucleotide, in patients with ASCVD and is furthest along, with results expected next year. The OCEAN(a)-Outcomes trial is testing olpasiran (Amgen), a small-interfering RNA that targets LPA, the gene that encodes for apolipoprotein(a), in patients with ASCVD but results aren’t expected until late 2026 or beyond. 

“Just knowing that there are therapies on the horizon, we wanted to take a look at a large US cohort, to see what the association is between Lp(a) and outcomes,” said Blankstein. “I think that’s important because a lot of the [observational] outcome studies have been done outside the US and there may be some variability, perhaps, based on genetics and ancestry.”

Anurag Mehta, MD (Virginia Commonwealth University, Richmond), who wasn’t involved in the study, said these new findings are largely confirmatory, but that unlike other analyses this one includes real-world patients from two large academic medical centers.   

Looking to the primary-prevention patient, Mehta noted that while the risk of major adverse cardiovascular events wasn’t statistically significant until Lp(a) reached very high levels, the risk increased in a linear manner beyond 50 mg/dL. He suggested that in such patients with moderately elevated Lp(a), coronary artery calcium screening can help fine-tune risk stratification further, something they showed in a previous study.

“What we found was that once your Lp(a) crosses a certain threshold, and if you have coronary artery calcium score [and it’s] a high coronary artery calcium score, then both of them kind of combine together to give you the information about the highest-risk patients,” said Mehta.

Mass General Brigham Lp(a) Registry

The new retrospective study, which was published yesterday in the Journal of the American College of Cardiology, included 16,419 individuals (median age 60 years; 41% women) with Lp(a) levels measured at the Brigham and Women’s Hospital and Massachusetts General Hospital between 2000 and 2019. Of these, 62% of patients had a history of ASCVD, which was defined as a prior MI, coronary revascularization, or ischemic stroke. Those with a history of ASCVD had a higher median Lp(a) level than those without ASCVD (37.8 vs 31.1 nmol/L; P < 0.001), and the median follow-up time was 12 years.

For those with ASCVD, 53.3% had Lp(a) levels in the 1st to 50th percentile (0-41 nmol/L), 20.5% had levels in the 51st to 70th percentile (42-111 nmol/L), 18.0% in the 71st to 90th percentile (112-215 nmol/L), and 8.3% had levels in the 91st percentile and beyond (≥ 216 nmol/L). For those without ASCVD, the corresponding values were 58.0%, 17.9%, 17.1%, and 7.0%, respectively.  

The annual event rates for the primary composite endpoint of MI, coronary revascularization, ischemic stroke, or cardiovascular death across the four Lp(a) percentile groups (lowest to highest) were 4.1%, 4.9%, 5.3%, and 5.3% in patients with ASCVD at baseline. In those without ASCVD, the rates were 1.1%, 1.2%, 1.3%, and 2.2%, respectively.

In a fully adjusted model, the risk of the primary composite outcome in patients with ASCVD increased with higher Lp(a) levels but plateaued at approximately 70 nmol/L. In contrast, the risk of major adverse cardiovascular events increased linearly with rising Lp(a) levels in those without preexisting ASCVD, but the difference in risk was not statistically significant until the highest levels.

MACE Risk by Percentile of Lp(a): Adjusted HR (95% CI)

 

While there is no treatment available yet, European guidelines recommend measuring Lp(a) at least once in the patient’s lifetime and US guidelines consider elevated Lp(a) to be a “risk-enhancing” feature.

“Right now, it's not widely adopted by everyone in the US,” said Blankstein. “It's now used at least for risk assessment and our paper very much supports that, whether someone's already had a prior ASCVD event, in which case they fall into that secondary-prevention population, or if they've never had an event, in which case they fall under the primary-prevention umbrella.”

Cascade Screening in Family Members

In an editorial, Nathan Wong, (University of California, Irvine), PhD, like others before him, asks whether Lp(a) is ready for “prime time.” Guidelines in the US still relegate screening to patients at high risk for ASCVD, such as those with a family history of premature disease. Wong, however, endorses universal Lp(a) screening, even before the outcomes trials are complete.

“But assuming positive results from ongoing cardiovascular outcomes trials for Lp(a), in order for treatment of elevated Lp(a) to have adequate population impact, we must do better to identify those at risk,” he writes, noting that less than 1% are screened for elevated Lp(a) in the US. He adds that there can be as much a 10-year lag between guideline recommendations and widespread adoption.

“The failure to screen and identify those with Lp(a)-associated risks represents a missed opportunity to address this risk, not only with our existing repertoire of treatments but hopefully in the future with the development of promising therapies targeting Lp(a),” writes Wong.

To TCTMD, Mehta said that while he already measures Lp(a) in his own clinical practice, that’s not the norm for others, even within his own healthcare system. The lack of approved therapies to lower Lp(a), not to mention the absence of studies showing that doing so reduces the risk of cardiovascular events, is likely the reason many clinicians aren’t measuring Lp(a) at this point, he said.

If he identifies a patient with high Lp(a), Mehta said he sees his role as helping patients understand Lp(a) is causal genetic risk factor that may have contributed to their MI, stroke, or peripheral artery disease.

“The second thing that I discuss with them is that this is a genetic risk marker, which is more than 95% genetically determined, [so] it’s very important to consider cascade screening in family members, [such as] parents, siblings, and children. From a therapeutic standpoint, I discuss with them aggressive cardiovascular risk-reduction strategies, such as high-intensity statin therapy or other lipid-lowering therapies to bring their LDL cholesterol down to low levels and manage other cardiovascular risk factors.”

Lastly, Mehta said he encourages patients with high Lp(a) to enroll in ongoing trials testing various Lp(a)-lowering strategies.   

Benefit Beyond Phase III Trials?

To TCTMD, Blankstein noted that both Lp(a)HORIZON and OCEANS(a)-Outcomes are secondary-prevention studies. In the former, patients were randomized to treatment if they had ASCVD and Lp(a) levels 70 mg/dL or higher (approximately 175 nmol/L), while OCEANS(a)-Outcomes randomized ASCVD patients with Lp(a) levels 200 nmol/L or higher during initial screening.

The results of this new analysis, however, suggest that benefit of Lp(a) reduction might extend to ASCVD patients with lower baseline Lp(a) levels than included in those two phase III trials, said Blankstein.

“Somebody asked me last week about this,” said Blankstein. “They asked, ‘Does this mean that those studies were conducted wrong?’ Absolutely not. I think these are the first ever studies to try to prove the Lp(a) hypothesis—that lowering Lp(a) lowers risk—and I think it was appropriate to select the really high-risk patients. If those studies show that there is efficacy of these agents, then we’ll need to think about whether those agents could be extended to people who have lower Lp(a).”