Lp(a) Linked to Higher ASCVD Risks in Diverse Patient Groups

Lipoprotein(a) appears to be an egalitarian risk factor, with high levels tied to an increased risk of atherosclerotic cardiovascular disease (ASCVD) in a wide range of primary-prevention patients, including those from different racial and ethnic backgrounds, new observational research shows.

The heightened risk with Lp(a) was seen in men and women, in Black and non-Black participants, and in those at low-intermediate and high risk for cardiovascular disease over more than 20 years of follow-up, report investigators. Among patients with diabetes mellitus, elevations in Lp(a) were linked to an even greater risk of cardiovascular events.

“The novelty of our study is the long follow-up in five well-characterized US prospective studies of cardiovascular disease,” lead investigator Nathan D. Wong, PhD (University of California-Irvine), told TCTMD. “Up until now, we haven't had a large US-specific cohort that has followed people as long as we did. We also had a multiethnic group, and particularly good power to look at the relationship [between Lp(a) and ASCVD risk] in Black participants.”

Right now, Lp(a) is one of the hottest targets in cardiovascular medicine. Several companies are developing Lp(a)-lowering agents, with pelacarsen (Novartis/Ionis Pharmaceuticals), an antisense oligonucleotide, being tested in the phase III Lp(a)HORIZON study of patients with ASCVD. Those results are expected next year. Olpasiran (Amgen), a small-interfering RNA that targets LPA, the gene that encodes for apolipoprotein(a), is also in phase III testing but results of the OCEAN(a)-Outcomes study won’t arrive until 2026.

Other therapies, including lepodisiran (Eli Lilly) and zerlasiran (Silence Therapeutics), which are both siRNAs targeting LPA, have shown they are capable of cutting Lp(a) levels by as much as 100% in early-phase testing.

Five Multiethnic US Cohorts

The present study, which was published this week in the Journal of the American College of Cardiology, included 27,756 people (mean age 51.2 years; 55.0% female) without previous ASCVD who were enrolled in MESA, CARDIA, ARIC, FHS-Offspring, and Jackson Heart Study. Roughly one-third of participants were Black, 4.7% were Hispanic, and 2.5% were Asian. More than 82% of people were at low-intermediate risk of ASCVD and 7.6% had a diagnosis of diabetes at baseline. 

The median Lp(a) levels were 3.6, 13.5, 25.9, and 52.6 mg/dL in the < 50th, 50 to < 75th, 75th to < 90th, and ≥ 90th percentile groupings, respectively. Those with higher Lp(a) were more likely to be female, Black, and have lower education. Systolic blood pressure, body mass index, LDL cholesterol, a diagnosis of diabetes, use of any cholesterol medication, and family history of ASCVD were all higher in those with higher Lp(a) levels. 

Compared with those with the lowest Lp(a) levels, those with Lp(a) in the 75th to < 90th percentile and ≥ 90th percentile had 18% and 46% significantly higher risks of ASCVD, respectively. The heightened risk among those with Lp(a) levels in the 75th and higher percentile was seen in those at low-intermediate risk, at high risk, and without diabetes at baseline. However, for those with diabetes, elevated Lp(a) levels conferred even higher risks, where Lp(a) in the 50th to < 75th, 75th to < 90th, and ≥ 90th percentile groups had ASCVD risks that were 47%, 54% and 92% higher compared with those with the lowest Lp(a) levels.

“It really points towards the new recommendations for all adults to get Lp(a) screened, and it really points towards the need for all patients, including those with diabetes, to ask their doctor about getting this test done,” said Wong.

The risks associated with elevated Lp(a) were seen in male and female patients and across the different ethnic groups. It was also seen across the spectrum of LDL-cholesterol levels, especially when ≥ 70 mg/dL. Higher levels of Lp(a) were also associated with increased risks of the individual endpoints, including a higher risk of MI, stroke, revascularization, and coronary heart disease mortality.

Even though there’s no treatment available yet, Wong said that identifying patients with high Lp(a) levels will help find patients at a higher overall risk of ASCVD. “These individuals need to do everything they can to reduce their overall ASCVD risk,” he advised, “such as intensifying lifestyle management and optimizing their blood pressure, diabetes control, and LDL-cholesterol if these can be improved.”

Like others, Wong is cautiously optimistic that the cardiovascular outcomes trials testing the investigational agents will be positive. “Of course, you never know for sure until the results are out,” he said.

These individuals need to do everything they can to reduce their overall ASCVD risk. Nathan D. Wong

Ron Blankstein, MD (Brigham and Women’s Hospital, Boston), who has studied the relationship between Lp(a) and ASCVD risk, said the new analysis has several strengths, especially its diverse patient population. His group published similar data from the Mass General Brigham Lp(a) Registry, but they reported higher hazards associated with Lp(a). The attenuated risks seen in this new analysis may be related to the unselected population studied, he said.

Regarding the heightened risk in patients with diabetes, Blankstein noted that prior analyses have also shown that Lp(a)-associated risk is higher in patients with coronary heart disease and those with higher calcium score.

“I think that suggests that Lp(a) in and of itself has to be interpreted in the context of other risk factors, as well as the overall profile of the patient,” he said. “Whether that higher risk is due to diabetes per se or the fact that individuals with diabetes are more likely to have underlying coronary disease or faster progression of coronary disease, I think is something that needs to be teased out a little bit more.”

Still, it suggests that Lp(a) is an important part of the picture in some patients with diabetes, said Blankstein.

Should Lp(a) Screening Start Now?

To TCTMD, Wong said the European and Canadian guidelines recommend measuring Lp(a) at least once in the patient’s lifetime, while US guidelines consider elevated Lp(a) to be a “risk-enhancing” feature that can help inform treatment decisions in select patients. He also noted that just 2 weeks ago the National Lipid Association (NLA) updated an earlier 2019 statement on Lp(a) and is now recommending its measurement at least once in all adults, with earlier and more-intensive risk factor management in those with high Lp(a) levels.

“I think our results support the recently updated recommendations from the NLA,” said Wong. 

Blankstein also thinks the US prevention guidelines should change to recommend screening for Lp(a) at least once during a person’s lifetime.

“It doesn't change a whole lot throughout the lifecycle,” he told TCTMD. “All you need for most individuals is just a one-time value. In the past, some have suggested we shouldn't check it because we don't have a treatment, but even without a treatment—of course, there are treatments that will hopefully be shown to be effective soon—there's a lot we could do today if we know that an individual has a higher risk of cardiovascular disease.”

There's a lot we could do today if we know that an individual has a higher risk of cardiovascular disease. Ron Blankstein

Roughly 20% of the population has elevated Lp(a) levels shown to be associated with a higher risk of ASCVD in a wide range of observational and genetic studies. Niacin can reduce Lp(a) by 30%, while inclisiran (Leqvio, Novartis) can lower levels by approximately 15% to 25%. Additionally, PCSK9 inhibitors can lower Lp(a) by anywhere from 20% to 30%.

However, none of these therapies are approved by the US Food and Drug Administration to lower Lp(a), and contemporary niacin trials have failed to show benefit in reducing cardiovascular events. Lipoprotein apheresis is FDA approved for certain high-risk persons with elevations in both Lp(a) and LDL cholesterol, but this is time-consuming and not widely available, said Wong.

‘Equal-Opportunity’ Risk Factor

Gregory G. Schwartz, MD, PhD (University of Colorado School of Medicine, Aurora), who wrote an accompanying editorial, says there had been some uncertainty about whether elevated Lp(a) conveyed the same risk in men and women (particularly after menopause), and in those from different racial/ethnic backgrounds. Prior observational studies, he writes, were largely made up of predominantly white populations. 

These new data indicate that Lp(a) is an “equal opportunity risk factor across several demographic and clinical categories,” writes Schwartz.

Regarding the guidelines, Schwartz also believes the US approach of measuring Lp(a) only in select patients might be too restrictive, including the recommendation only to screen in women with hypercholesterolemia. “Current European and Canadian guidelines that recommend testing in most adults would appear to be supported by the current findings,” he states.