LDL-Lowering to Specific Targets May Offset Risk From High Lp(a)

Liam Davenport

May 30, 2022

MILAN — The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering low-density-lipoprotein (LDL) cholesterol to specific levels, suggests a novel study that also underscores the importance or early intervention.

The results, derived from an analysis of data on Lp(a) and LDL-cholesterol levels, and associated genetic risk scores in almost 500,000 individuals from the United Kingdom have been used to develop a series of age-related targets for lowering LDL-cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.

Measuring Lp(a) levels can "substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease," said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge, United Kingdom.

This can "directly inform treatment decisions about the intensity of LDL-lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a)."

Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people "who may benefit from potent Lp(a)-lowering therapies when they become available."

The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.

In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Ference is working with the EAS to develop an app to further deliver on that personalized prevention.

It will display an individual's lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.

"The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction," Ference told theheart.org | Medscape Cardiology.

"What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions."

In addition, Ference said that it will "show patients why it's important for them" to intensify LDL-lowering to overcome their particular level of Lp(a).

Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.

For Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.

"The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it," he said, noting that it could be with diet, lifestyle interventions, or medication.

Handy Tool

Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told theheart.org | Medscape Cardiology that the new app could be a "handy tool to counsel patients."

"We can say, look, you have high Lp(a)," he said. "This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient," said Kronenberg, who was not involved in the study.

He emphasized that it is crucial to get across the idea of an individual's global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.

Kronenberg also believes that the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.

During his presentation, Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.

"Unfortunately, unlike other proteins," he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.

"For that reason," he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Ference was a coauthor, "recommend that we intensify life risk-factor modification in persons with elevated risks."

However, he added, "this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians," with some concluding that they don't need to measure Lp(a) "because there's nothing they can do for it."

Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL-lowering needed to "overcome the increased risk caused by Lp(a)," he said.

They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL-cholesterol levels below 5 mmol/L at the time of enrolment to exclude people with presumed familial hypercholesterolemia.

The researchers used a Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.

The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.

When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.

For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.

Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol-lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.

For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.

This, Ference said, suggests that "diet and lifestyle modification is unlikely to be an effective strategy if started later."

No funding declared. Ference declares relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Phamaceuticals. Kronenberg declares relationships with Amgen, Novartis, and Kaneka.

European Atherosclerosis Society (EAS) 2022. Presented May 24, 2022.

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