Lp(a) Linked to ASCVD and Aortic Stenosis Regardless of CRP Level

MILAN, Italy—Elevations in lipoprotein(a) are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis in patients with and without evidence of systemic inflammation as measured by high-sensitivity C-reactive protein (hs-CRP), according to a new analysis.

The findings, which were presented this week at the European Atherosclerosis Society Congress 2022, are unique in that they challenge previously published studies suggesting the risk associated with Lp(a) was mediated by the extent of systemic inflammation.

In a post hoc analysis of ACCELERATE, for example, Lp(a) was associated with a higher risk of ASCVD events only in patients with elevated hs-CRP. An analysis from the MESA study also showed similar findings, with investigators reporting that Lp(a)-associated ASCVD was only seen in patients who had evidence of systemic inflammation. 

“If that was true, then it could have a potentially huge impact on the potential treatment for lipoprotein(a),” Peter Thomas, MD (Herlev and Gentofte Hospital, Copenhagen), who led the new analysis, told TCTMD. “If you’re trying show that pharmaceuticals lower lipoprotein(a) and reduce cardiovascular risk, which phase III trials are attempting to show, but lipoprotein(a) only causes cardiovascular disease when there is systemic inflammation, then you need to measure systemic inflammation when you’re deciding which patients should be treated.”

In the new analysis, which includes nearly 70,000 patients and dwarfs the previous studies, researchers saw no evidence that the ill effects of Lp(a) were mediated through hs-CRP, said Thomas.

Awaiting Long-term Outcomes

Lp(a), which is an atherogenic, proinflammatory, and prothrombotic lipoprotein particle, is a promising therapeutic target to reduce the residual risk of ASCVD. Epidemiologic, experimental, and genetic studies have described a causal relationship between elevated Lp(a) and the risk of MI, stroke, and calcific aortic valve stenosis. High levels of Lp(a) arise from variants in the LPA gene, but so far there are limited treatments because Lp(a) is not modifiable with diet, exercise, or other LDL-lowering drugs.

Researchers are hopeful that may one day change.

The Lp(a)HORIZONS investigators are furthest along, testing pelacarsen (Novartis Pharmaceuticals), an antisense oligonucleotide (ASO) therapy, in more than 8,000 patients with established ASCVD. Amgen has olpasiran, a small interfering RNA (siRNA) agent that is a little further behind in clinical testing but has demonstrated impressive reductions in Lp(a) across a range of doses. Silence Therapeutics also is developing siRNA technology for lowering Lp(a).  

Given what’s at stake with these ongoing studies, Thomas, along with senior investigator Børge Nordestgaard, MD, DMSc (Copenhagen University Hospital/Herlev and Gentofte Hospital), wanted to determine if the risks associated with Lp(a) were indeed mediated by hs-CRP levels. To do so, they analyzed data from the Copenhagen General Population Study, which is a primary-prevention cohort.  

For the analysis, investigators first assessed the risks of ASCVD in patients with low levels of hs-CRP (< 2 mg/L). Compared with those who had the lowest Lp(a), those with levels in the 90th percentile and above (≥ 70 mg/dL or ≥ 147 nmol/L) had a significantly increased risk of ASCVD (HR 1.61; 95% CI 1.43-1.81). When focusing only on patients with elevated hs-CRP (≥ 2 mg/L), those with highest Lp(a) levels also had a significantly higher risk of ASCVD (HR 1.59; 95 CI 1.37-1.84).

The researchers performed a similar analysis to examine the risks of aortic valve stenosis. For those with low hs-CRP levels, individuals with Lp(a) levels in the 90th percentile and above had a twofold higher risk of aortic valve stenosis compared with those with low Lp(a) levels (HR 2.00; 95% CI 1.58-2.53). Among those with systemic inflammation, the same relationship held—those with highest Lp(a) levels also had a higher risk of aortic valve stenosis (HR 1.76; 95% CI 1.34-2.32).

The researchers observed no evidence of interaction between Lp(a) and hs-CRP on the risk of ASCVD or aortic valve stenosis (P = 0.58 and 0.56 for interaction, respectively).

The group also examined the 10-year risk of ASCVD and aortic valve stenosis based on Lp(a) and hs-CRP levels in men and women across different age categories. The data showed that the adverse effects of elevated Lp(a) and hs-CRP were additive, with the highest 10-year risk of ASCVD and aortic stenosis seen in people with elevations of both Lp(a) and hs-CRP. For example, a male aged 70-79 years with hs-CRP ≥ 2 mg/L and Lp(a) ≥ 70 mg/dL, the estimated 10-year risks of ASCVD and aortic valve stenosis are 36% and 14%, respectively.

Interaction Between Lp(a) and hs-CRP

To TCTMD, Thomas noted that some researchers have questioned whether Lp(a) is associated with low-grade systemic inflammation in aortic valve stenosis and MI. It’s plausible, he said, that there is an interaction between inflammation and Lp(a), noting that Lp(a) is the main carrier of oxidized phospholipids in the blood and these oxidized phospholipids are known to be proinflammatory. However, a 2015 study showed that while hs-CRP increased as Lp(a) increased, a genetic analysis demonstrated that elevated Lp(a) levels were not causally associated with inflammation as measured by hs-CRP.

As to why their results differed from earlier studies, Thomas noted that their study was significantly larger than the two previous analyses. He also pointed out that the ACCELERATE findings emerged from a post hoc analysis of a randomized trial in patients with established ASCVD who were well treated on background therapy.

“It’s not representative of the general population,” he said. MESA did include a primary-prevention population, but the racial/ethnic makeup differed significantly from the Copenhagen General Population Study, which included a fairly homogenous patient mix. “It’s a limitation of our study, especially when applying our results to other ethnicities, but at the same time we reduce the risk of population stratification bias given that Lp(a) levels are 80% to 90% predicted by genetics,” said Thomas.

Antonio Gotto, MD, DPhil (Weill Cornell Medicine, New York, NY), who wasn’t involved in the current study, said that physicians are aware there is some degree of residual risk in patients with optimized LDL-cholesterol levels. The field has seen a plethora of new treatments emerge, as well as others with potential to come.

“We currently have different approaches to reduce LDL cholesterol where we can dial it down to almost as low a level as we wish,” Gotto told TCTMD. “Still, there is significant occurrence of events in patients treated in this way. We’re looking at different things that could be affecting that residual risk, over and above LDL cholesterol.”

For that reason, there is excitement around the potential to modify that risk with Lp(a)-lowering therapy, as well as therapies to modify systemic inflammation, non-HDL-cholesterol levels, and apolipoprotein C-III (apoC-III), he said. “Pursuing Lp(a) as a therapeutic target is certainly reasonable and plausible,” said Gotto.

The only currently available treatment for patients with elevated Lp(a) is lipoprotein apheresis. In 2020, the US Food and Drug Administration revised approval criteria for lipoprotein apheresis to include patients with high levels of Lp(a) but without abnormal lipid levels.  

As for reducing Lp(a) to prevent aortic stenosis, Thomas noted that this area of research will be more challenging than in patients with ASCVD. While Lp(a) has been implicated in the calcification of the aortic valve, the development of aortic stenosis takes many, many years. Conducting clinical trials to prevent aortic stenosis, or delay the progression of aortic stenosis, would be more time consuming and expensive as opposed to those in ASCVD where the maximum follow-up is usually 5 years or less before a benefit is observed, he noted.