Increased Lp(a) Ups CV Risk Regardless of hs-CRP Level

Lipoprotein(a) appears tied to the risk of major adverse cardiac events, MI, and peripheral artery disease in both primary and secondary prevention populations independent of baseline high-sensitivity C-reactive protein (hs-CRP), according to registry data.

The mechanism by which elevated Lp(a) affects cardiovascular risk has been thought to be at least partially related to inflammation, with prior research suggesting that hs-CRP levels might be linked as well.

However, “these results suggest that these are likely capturing two separate and independent risk pathways,” senior author Pradeep Natarajan, MD, MMSc (Massachusetts General Hospital, Boston, MA), told TCTMD in an email. “While we cannot rule out the possibility of lipoprotein(a) also influencing inflammatory pathways that subsequently influence atherosclerotic cardiovascular disease risk, these results indicate that hs-CRP measures are not capturing this feature.”

The scope of the study makes it fairly certain that the Lp(a) and hs-CRP pathways are independent, according to Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), who was not involved in the research. “There are a lot of events, there is a lot of power, and I think [the authors] pretty clearly show that it's not an issue,” he told TCTMD.

Lp(a) Not Dependent on hs-CRP

For the study, published online this week in JAMA Cardiology with Aeron Small, MD (Brigham and Women’s Hospital, Boston), as lead author, the investigators included data from 357,220 individuals without prevalent atherosclerotic cardiovascular disease (ASCVD) from the UK Biobank and 34,020 participants from the FOURIER and SAVOR-TIMI 53 trials who had baseline Lp(a) and hs-CRP measured.

About one-third of the UK Biobank cohort had high hs-CRP values, defined as ≥ 2 mg/L. Analyses adjusted for ASCVD risk factors showed that higher Lp(a) was associated with increased MACE risk for baseline hs-CRP values that were both high (HR per 50-nmol/L higher Lp[a] 1.05; 95% CI 1.04-1.07) and low (HR 1.05; 95% CI 1.04-1.07; P = 0.80 for interaction). Similar patterns were observed for MI, ischemic stroke, and PAD individually.

There is now a lot of evidence that high levels of Lp(a) . . . increase risk if you have an elevated CRP or if you have a normal CRP. Christie Ballantyne

Similarly, in the FOURIER and SAVOR cohorts—where just under half of all patients had high baseline hs-CRP—higher baseline Lp(a) was associated with increased risk for MACE again whether patients had high (HR per 50-nmol/L higher Lp[a] 1.02; 95% CI 1.00-1.05) or low hs-CRP (HR 1.05; 95% CI 1.02-1.08; P = 0.16 for interaction). The findings were maintained for MI and PAD individually here as well.

The findings are important because “lipoprotein(a) is increasingly being checked, and understanding if its risk is context-important is helpful in understanding clinical utility,” Natarajan said.

On caveat, he commented, relates to patient race. “The studies to date, including the present study, are largely comprised of European ancestry populations,” Natarajan said. “As lipoprotein(a) distributions are distinct in some non-European populations, analyses in similarly large diverse populations are needed.”

Ballantyne agreed, noting specifically that Black patients or those with African ancestry were not sufficiently included in past studies to be able to statistically test how Lp(a) levels affect their risk. That’s important given prior findings indicating that race might play a role. “So, [this study] does not answer all the questions about could there be something that wasn't seen here with these very robust numbers,” he said.

“But overall, there is now a lot of evidence that high levels of Lp(a) . . . increase risk if you have an elevated CRP or if you have a normal CRP,” Ballantyne added. Both Lp(a) and hs-CRP could be “useful as risk enhancers to identify people are who are the highest risk.”

This has important implications for future studies of Lp(a)-lowering drugs, he continued. “With all these trials that we are doing, if you are enrolling somebody into a trial, they wouldn't have to have a high level of CRP to get benefit necessarily,” Ballantyne said. “That would be the same thing in clinical practice if the therapies that we are testing work.”