High Levels of Lp(a) Linked to Increased Ischemic Stroke Risk

High levels of lipoprotein(a), as well as genetic variants associated with elevated Lp(a) levels, are associated with an increased risk of ischemic stroke, lending further support to its use as a biomarker of atherosclerotic cardiovascular disease risk, according to a new analysis from Danish researchers.

For individuals with plasma Lp(a) concentrations in the 96th percentile or higher, which translated into Lp(a) levels greater than 93 mg/dL, the risk of stroke was 60% higher when compared with individuals with Lp(a) levels less than 10 mg/dL. The highest absolute risk of ischemic stroke was observed in people older than 70 years with hypertension and Lp(a) levels greater than 93 mg/dL, report investigators.

“Before our studies, I was not convinced that high Lp(a) was a cause of ischemic stroke,” Børge Nordestgaard, MD (Copenhagen University Hospital/Herlev and Gentofte Hospital, Denmark), one of the investigators, told TCTMD. “The results were unclear overall. So, I was surprised to see the clear results in our study of a causal association of high Lp(a) with high risk of ischemic stroke. It should be noted though that the risk estimate for ischemic stroke was roughly half of that of the risk of myocardial infarction and aortic valve stenosis.”

Given their findings, as well as evidence showing that high levels of Lp(a) are associated with other cardiovascular events, Nordestgaard said it is time for physicians to measure Lp(a) in patients at high risk for cardiovascular disease. “This is particularly needed in individuals with familial hypercholesterolemia and in those already with diagnoses of ischemic heart disease, stroke, claudication, or aortic valve stenosis,” he said. “As Lp(a) is a genetic risk factor, it only needs to be measured once. A number of clinicians argue that it should be measured once in anybody having a lipid panel, which, for me, also represents a valid approach.”

Before our studies, I was not convinced that high Lp(a) was a cause of ischemic stroke. Børge Nordestgaard

Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), who wrote an editorial accompanying the paper, points out there are no commercially available therapies for lowering Lp(a), although there are antisense technologies and small interfering RNAs in development showing “great promise.” Based on the epidemiology of plasma levels and genetic data, ischemic stroke may be reduced in high-risk individuals and this endpoint should be included in the large cardiovascular outcome trials, he says.  

Like Nordestgaard, Ballantyne believes there is sufficient evidence to “routinely perform one-time screening for Lp(a) and provide this valuable information so that individuals who have inherited high Lp(a) can try to avoid stroke and MI.” 

Plasma Lp(a) and Genetic Analysis

The new study, which was published July 1, 2019, in the Journal of American College of Cardiology, included 49,699 individuals from the Copenhagen General Population Study (CGPS) and 10,813 individuals from the Copenhagen City Heart Study (CCHS) who had measurements of plasma Lp(a) and genotyping of LPA, the gene primarily responsible for Lp(a) levels. The endpoint of ischemic stroke was ascertained from the Danish national health registry.

In the 48,022 subjects from CGPS without ischemic stroke at baseline, high levels of Lp(a) were associated with an increased risk of ischemic stroke. Compared with individuals with Lp(a) less than 10 mg/dL, the multivariable-adjusted risk of ischemic stroke was only borderline significant for those with levels of 43 to 93 mg/dL (HR 1.21; 95% CI 0.99-1.48) but was statistically significant for those with levels greater than 93 mg/dL (HR 1.60; 95% CI 1.24-2.05).

In the genetic analysis, individuals with a common variant of LPA (rs10455872), one that has been previously linked with an increased risk of coronary heart disease and aortic valve stenosis, were at an increased risk of ischemic stroke compared with noncarriers (HR 1.23; 95% CI 1.09-1.39). The researchers also looked at individuals with the LPA kringle-IV type 2 (KIV2) genotype. Lp(a) contains a covalently bound apolipoprotein(a) molecule and apo(a) has a variable number of looped segments known as kringles. The genetically determined number of KIV2 repeats determines the size of apo(a) protein and the number of KIV2 repeats are inversely associated with plasma Lp(a). In the present study, fewer KIV2 repeats was associated with an increased risk of ischemic stroke. 

Among the 10,438 individuals from the CCHS, the risk of ischemic stroke was not significantly increased with higher Lp(a) levels, although the risk estimates went in the same direction as those from the larger study, say investigators. Similar findings were observed in the genetic analysis.

To TCTMD, senior investigator Pia Kamstrup, MD, PhD (Copenhagen University Hospital/Herlev and Gentofte Hospital), said she agrees that Lp(a) measurements should be included as part of the standard lipid profile at least once for every individual to help with risk stratification. Repeat measurements aren’t necessary, at least not until the possible approval of future therapies targeting Lp(a).

“Lp(a) measurements can be performed on most automated standard laboratory platforms at little cost,” she said. In Denmark, the cost is approximately $10, which would decrease if the volume of tests ordered increased. “Measurements should be performed using well validated assays preferable with traceability to international standards to ensure compatibility of measurements performed at different labs. Further, assays should be designed to minimize measurement bias caused by the different Lp(a) isoforms. Assays fulfilling these requirements are commercially available.”

In the editorial, Ballantyne notes that even with current assays, which are problematic because they are not uniformly standardized, most people would only need to be tested once. Individuals with borderline Lp(a) levels may need to be reassessed because repeated measurements may vary in those with high Lp(a) levels. Lp(a) may also increase with age, particularly in women, writes Ballantyne.

Some Hurdles to Clear

Michelle O’Donoghue, MD (Brigham and Women’s Hospital, Boston, MA), who wasn’t involved in the study but has studied the relationship between Lp(a) and cardiovascular events in the FOURIER trial, noted that the relationship between Lp(a) and ischemic stroke has not been consistent across studies. A meta-analysis from the Emerging Risk Factors Collaboration a decade ago suggested there was a modest association between higher levels of Lp(a) and ischemic stroke, and mendelian randomization studies also support the concept of a causal link between Lp(a) and cardiovascular disease, she said.  

“However, there are two key challenges when it comes to the concept of measuring Lp(a) routinely at doctor visits,” O’Donoghue told TCTMD. “The first is that we don’t really know the optimal threshold to apply when it comes to telling a patient that they are at increased risk. The second is that we don’t currently have a large arsenal of drugs with demonstrated efficacy for Lp(a) reduction.” 

In this latest analysis, for example, the highest risk of ischemic stroke was observed only in individuals at the 96 to 100th percentile, or greater than 93 mg/dL. The European Society of Cardiology (ESC) recommendations suggest 50 mg/dL might be considered an appropriate threshold to designate risk but that number was arbitrarily set at the 80th percentile. “Until we have studies that demonstrate that Lp(a) lowering directly translates into clinical benefit, the jury will probably still be out regarding the optimal cut point,” said O’Donoghue.

In the American Heart Association/American College of Cardiology cholesterol guidelines, elevated Lp(a) levels (defined as 50 mg/dL or greater) are considered a “risk enhancer” for aiding in the decision about starting statin therapy for primary prevention. Similar to the ESC and US guidelines, a consensus statement from the European Atherosclerosis Society recommends physicians measure Lp(a) in patients at intermediate or high risk of cardiovascular disease and that a desirable level is less than 50 mg/dL. 

To TCTMD, Nordestgaard said physicians treating patients at high cardiovascular risk with elevated Lp(a) should be intensify treatment of all modifiable risk factors, particularly LDL cholesterol. This would include use of a high-intensity statin followed by ezetimibe or a PCSK9 inhibitor as needed.

The antisense oligonucleotide AKCEA-APO(a)-LRx (Akcea Therapeutics/Ionis Pharmaceuticals), which has been shown to lower Lp(a) levels by 80% in nearly all treated patients, is expected to enter into phase III study in 2020.