Less Is More: Lp(a) Much More Atherogenic Than LDL

Lipoprotein(a), the low-density lipoprotein (LDL)-like particle that is currently the focus of so much enthusiastic research, is significantly more atherogenic than LDL cholesterol, according to a genetic analysis and a second corroboratory study.

While LDL cholesterol particles are much more abundant than Lp(a), and as such remain the biggest contributor to atherosclerotic cardiovascular disease (ASCVD) risk, Lp(a) is more than six times more atherogenic than LDL on a per-particle basis, report Elias Björnson, PhD (University of Gothenburg, Sweden), and colleagues in a study published online ahead of the January 23, 2024, issue of the Journal of the American College of Cardiology.

“Our data, what it really shows us and what we're trying to emphasize, is that LDL cholesterol is still the most important risk factor, but there are several risk factors in addition to LDL cholesterol,” senior investigator Jan Borén, MD, PhD (University of Gothenburg), told TCTMD. “And Lp(a) is a very important risk factor.”

The search for a drug that lowers Lp(a) and reduces the risk of ASCVD has been likened to the Holy Grail in contemporary prevention circles. It’s an attractive target for physicians, researchers, and drug manufacturers because it’s highly genetically determined and large observational studies, including genetic analyses, have shown that higher levels are linked with ASCVD and calcific aortic valve disease.

There are several small-interfering RNA (siRNA) therapies in development that target LPA, the gene that encodes for apolipoprotein(a), which is an essential component needed by the liver to make Lp(a). These include the injectables lepodisiran (Eli Lilly), olpasiran (Amgen), and zerlasiran (Silence Therapeutics), as well as an oral small molecule inhibitor, muvalaplin (Eli Lilly), in early testing. Pelacarsen (Novartis/Ionis Pharmaceuticals), an antisense oligonucleotide (ASO) is furthest along in development, with data from the Lp(a)HORIZON cardiovascular outcomes study expected in 2025.  

“A lot of focus has been on LDL cholesterol for many, many years,” said Borén. “We know that lowering our total plasma cholesterol has been very successful in lowering the risk of myocardial infarction. However, even though we have [patients] at optimal LDL cholesterol values, we still have a highly significant residual risk of cardiovascular disease. Many people have been working trying to explain what lipoproteins account for the residual risk.”

That research has focused on the role of triglyceride-rich lipoproteins, their remnants, and Lp(a), he added.

LDL cholesterol is still the most important risk factor, but there are several risk factors in addition to LDL cholesterol. Jan Borén

According to Borén, it’s vital to understand the atherogenicity of the different lipoproteins relative to LDL cholesterol when developing new interventions, but Lp(a) remains a challenge for several reasons. For one, it’s difficult to accurately gauge its plasma concentration because of calibration issues with different assays. The field has been hampered by these technical difficulties, as well as by the fact that there are different Lp(a) isoforms, which makes it hard to calculate the genetic variant effect sizes on Lp(a).

Comparing Apples to Apples

To overcome these issues, researchers took a different approach and focused on apolipoprotein B (apoB) instead. Lp(a) is formed by the addition of apo(a) to apoB on LDL particles. LDL cholesterol, Lp(a), and other remnant particles each contain one molecule of apoB: this allowed investigators to relate the change in apoB to the respective change in coronary heart disease risk.

“We would then compare apoB in LDL versus apoB in Lp(a), comparing apples to apples instead of apples to something else,” said Borén.

The study population included 502,413 people enrolled in the UK Biobank study. In a genome-wide association study, researchers identified two clusters of genetic variants associated with Lp(a) and LDL cholesterol concentrations. These included 107 single nucleotide polymorphisms (SNPs) associated with Lp(a) concentrations and 143 SNPs linked to LDL cholesterol concentrations. In these two clusters, they assessed the relationship of genetically predicted variations of apoB in the Lp(a) and LDL particles with coronary heart disease (MI and coronary revascularization).

They found that the odds of a coronary event were 28% higher for every 50-nmol/L increase in apoB levels in Lp(a). In contrast, each 50-nmol/L increase in apoB in LDL cholesterol was associated with a 4% higher risk. A replication analysis from a case-control study confirmed the finding, showing a higher risk for coronary heart disease with each 50-nmol/L increase for apoB in Lp(a). Similarly, a polygenic risk that ranked individuals according to differences in apoB in Lp(a) versus apoB in LDL cholesterol showed that the hazard of coronary heart disease was significantly higher with every 50-nmol/L increase in apoB in Lp(a).

The researchers also assessed the relative per-particle atherogenicity for Lp(a) compared with LDL cholesterol. The relative atherogenicity—assessed as the coronary heart disease risk quotient—was 6.6 times higher per unit of apoB in Lp(a) compared with apoB in LDL cholesterol. In the case-control replication cohort, Lp(a) appeared to be nearly four times more atherogenic. 

A second study published in JACC and led by Nicholas Marston, MD, MPH (Brigham and Women’s Hospital, Boston, MA), tackled a nearly identical question, with researchers estimating the cardiovascular risks associated with Lp(a) versus the non-Lp(a) apoB-containing particle.

Here, Marston and colleagues turned to patients without preexisting ASCVD in the UK Biobank who were not taking lipid-lowering therapy and who had apoB and Lp(a) measurements. In 355,912 participants (mean age 56 years; 57.0% women), each 100-nmol/L increase in non-Lp(a) apoB was associated with a 5% higher risk of major cardiovascular events. In contrast, each 100-nmol/L increase in Lp(a) was associated with a 24% higher risk.

Potency of Lp(a)

To TCTMD, Borén stressed that LDL cholesterol is the more abundant particle and is responsible for the largest extent of patient risk, but the present study helps understand the contribution of Lp(a) on a per-particle basis.

Right now, there aren’t a lot of strong data to explain why Lp(a) is such a potent particle when it comes to ASCVD. He noted that apo(a) in the Lp(a) particle carries oxidized phospholipids, which are not present on the LDL particle. Basic science and animal models have suggested that oxidized phospholipids are an important driver of atherosclerotic plaque formation.  

In an editorial, Sotirios Tsimikas, MD (University of California San Diego, La Jolla, and Ionis Pharmaceuticals), and Vera Bittner, MD, MSPH (University of Alabama at Birmingham), said the study by Borén and colleagues overcomes some of the complexities associated with measuring Lp(a), but these results will need to be confirmed in other databases, particularly those with a more diverse patient population with and without ASCVD. Another limitation is that plasma Lp(a) concentrations can be influenced not just by variants at the LPA locus, which the researchers studied, but also at APOE, LDLR, CETP, and APOH, which weren’t studied.

Still, Tsimikas and Bittner, based on the relative atherogenicity of the two particles, estimate that an Lp(a) concentration of 250 nmol/L would be akin to an LDL cholesterol level of 100 mg/dL. Moreover, they calculate, if the Lp(a)-lowering therapies are to achieve a 20% relative reduction in ASCVD risk, they’d need to cut Lp(a) levels by 32 to 101.5 mg/dL (or 80 to 254 nmol/L).

“This level of reduction is feasible with all RNA-based Lp(a) drugs in development,” they write.