• Lp(a) is a highly atherogenic particle with no available targeted therapeutics.
• Endocrinologists can play a role in getting patients screened for elevated Lp(a) and managing those shown to be at high risk.

A single lipoprotein(a) screening in a person’s lifetime could significantly reduce their risk for heart disease-related morbidity and mortality, yet this opportunity is often missed.

Screening for elevated lipoprotein(a), or Lp(a), and targeting modifiable risk factors and lifestyle, whether done by an endocrinologist, cardiologist or primary care professional, could meaningfully lower risk for atherosclerotic cardiovascular disease (ASCVD) and potentially thrombosis, even in people with very high levels.

Image: Caitlin Rice.

No targeted therapies are currently approved to lower Lp(a) levels, but that does not mean nothing can be done to mitigate its impact on cardiometabolic health.

“My hope is that endocrinologists embrace Lp(a) as part of routine cardiometabolic care rather than viewing it as a niche lipid marker,” Vishnu Priya Pulipati, MD, FACE, FNLA, endocrinologist at Warren Clinic Endocrinology in Tulsa, Oklahoma, who gave a talk on Lp(a) at the American Association of Clinical Endocrinology Annual Scientific and Clinical Conference in April, told Healio | Endocrine Today. “The future of endocrinology is increasingly centered on preventing cardiovascular disease, and Lp(a) fits perfectly within that mission.”

Lp(a) is an atherogenic, prothrombotic particle distinct from LDL in that it carries a single apolipoprotein A-I strand bound to its apolipoprotein B-100 component, according to the American Heart Association/American College of Cardiology (ACC) Guideline on the Management of Dyslipidemia, which was updated in March.

“Lp(a) is important because it is more strongly associated with cardiovascular morbidity and mortality than many traditional lipids such as LDL cholesterol,” Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said in an interview. “For a long time, it didn’t receive much attention. Elevated Lp(a) is common. Depending on what cut point you use, about one in every five individuals has an Lp(a) level in a range where there is increased risk. That’s more than 1 billion people on our planet, and it has taken a while for the guidelines to recognize it.”

What makes Lp(a) different from other lipid particles is that levels are mostly determined by genetics, with more than 90% of measurable circulating levels linked to a single gene, making it a potent, inheritable ASCVD risk factor, according to Harpreet S. Bhatia, MD, MAS, FACC, FAHA, FASPC, assistant professor of medicine in the division of cardiovascular medicine, associate program director of cardiovascular diseases fellowship and director of exploration and innovation at the University of California, San Diego School of Medicine.

Nissen said if a patient has elevated Lp(a), the concordance among first-degree relatives is approximately 47% that they also have high Lp(a).

“Earlier studies failed to show an association between Lp(a) and CVD. One of the reasons for that is that Lp(a) is hard to measure. It’s a complex particle, and prior studies used ways of measuring Lp(a) that were less accurate,” Bhatia told Healio | Endocrine Today. “The field was revived when genome sequencing-type studies became easier and cheaper, and it was clear that the LPA gene was strongly associated with CVD.”

The updated guideline made one-time Lp(a) screening for all adults a class I recommendation to identify individuals at increased risk for ASCVD.

“We have definitely seen an increase in testing as awareness has spread about Lp(a) being a significant cardiovascular risk-enhancing factor. However, testing in the general population is still less than 1%, so we still have work to do,” Allison Bigeh, DO, noninvasive cardiologist at Ohio State University Wexner Medical Center, told Healio | Endocrine Today. “Currently the recommendation is to test once in everyone. The reason being Lp(a) is genetically determined, so it is not influenced by things like lifestyle changes or diet. There are certain conditions like pregnancy that can affect the levels, but for the most part Lp(a) levels are established very early in life before adolescence.”

Discussion of risk stratification continues.

In 2024, the National Lipid Association (NLA) issued a focused update, published in the Journal of Clinical Lipidology, on Lp(a) in clinical practice with recommendations for risk-stratification based on Lp(a) levels. According to the NLA statement, high risk was defined as Lp(a) of 125 nmol/L (50 mg/dL) or more, intermediate risk was defined Lp(a) of 75 nmol/L to 125 nmol/L (30 mg/dL to 50 mg/dL) and low risk was defined as Lp(a) levels less than 75 nmol/L (30 mg/dL).

In the American Heart Association/ACC guideline, Lp(a) was established as a significant ASCVD risk factor at levels exceeding 125 nmol/L (50 mg/dL).

What is most important is that action is taken once a patient’s Lp(a) categorizes them as high risk, Pulipati said.

“The biggest misconception is that if we can’t lower Lp(a), there’s nothing we can do. I would challenge that notion,” Pulipati told Healio | Endocrine Today. “While Lp(a)-lowering therapies are on the horizon, the most important thing we can do today is aggressively reduce overall cardiovascular risk. Rather than treating the Lp(a) number in isolation, we should treat the patient comprehensively. Although lifestyle changes do not meaningfully lower Lp(a), they remain one of the most powerful tools for reducing cardiovascular risk. We should encourage patients to follow the American Heart Association’s Life’s Essential 8 — healthy eating, regular physical activity, healthy sleep, weight management, avoiding nicotine and optimizing blood pressure, cholesterol and glucose. Observational studies, including the EPIC-Norfolk study, suggest that even among individuals with elevated Lp(a), maintaining ideal cardiovascular health is associated with substantially lower cardiovascular risk.”

An Lp(a) level of 125 nmol/L or more is associated with an approximately 1.4-fold increased risk for ASCVD, and Lp(a) of 250 nmol/L or more is associated with more than twofold higher risk, according to the American Heart Association/ACC guideline.

The guideline authors stated that levels of 125 nmol/L or more warrant intensified lipid-lowering therapy and management of all possible modifiable risk factors to prevent ASCVD events.

“Intensively treat every other risk factor. Get LDL and blood pressure down. Treat diabetes and obesity. We can mitigate at least some of the risk by taking care of all the other risk factors,” Nissen said. “We can’t treat the Lp(a), but we can treat everything else, and that’s an important component of why we think it ought to be measured in everybody.”

Aspirin 81 mg daily may reduce CV events in patients with elevated Lp(a), but no prospective trials have been done to date, Bigeh told Healio | Endocrine Today.

Bhatia said aspirin may play a direct role in reducing the “theorized prothrombotic and particularly proplatelet effects of Lp(a).”

For patients with established ASCVD and elevated Lp(a) who are not at target LDL and non-HDL goals despite maximally tolerated statin therapy, the addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is recommended in the American Heart Association/ACC and NLA guidelines. However, statins may slightly increase Lp(a), according to both documents.

“The prior attitude was if Lp(a) is genetically determined, and people can’t do anything about it, what is the point of screening?” Michael C. Honigberg, MD, MPP, cardiologist and researcher at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, told Healio | Endocrine Today. “Lp(a) is not destiny, but it makes comprehensive risk factor management a lot more important.”

Many patients seen by endocrinologists have high Lp(a), underscoring the important role endocrinologists play in its management, Pulipati told Healio | Endocrine Today.

“[Endocrinologists] probably see patients with elevated Lp(a) far more often than many people realize,” Pulipati said. “About one in five adults has elevated Lp(a), and endocrinologists routinely care for high-risk individuals with hypercholesterolemia and premature cardiovascular disease — populations in which elevated Lp(a) is common.”

Pulipati said the role of endocrinologists “extends well beyond ordering the test. Our responsibility is to recognize elevated Lp(a) as a risk-enhancing factor, incorporate it into cardiovascular risk assessment and shared decision-making, and identify patients who may benefit from more intensive preventive strategies. We also play an important role in family screening, since Lp(a) is inherited and identifying one affected patient can lead to testing relatives before cardiovascular disease develops. Finally, education is critical. Patients often worry when they hear they have a genetic risk factor. We need to reassure them that genetics may set the baseline risk, but aggressively controlling other cardiovascular risk factors can meaningfully reduce overall risk.”

Eventually, clinicians may have options beyond risk factor management for patients with elevated Lp(a). A number of drugs specifically targeting Lp(a) are in development, and the first phase 3 trial results are anticipated by the end of 2026.

Pelacarsen (Ionis/Novartis) is a monthly, self-injected antisense oligonucleotide therapy designed to lower Lp(a). It is being evaluated for secondary prevention in the ongoing phase 3 Lp(a)HORIZON trial, which enrolled about 8,300 patients with a prior ASCVD event and Lp(a) level of at least 70 mg/dL. (Editor’s Note: On Aug. 28, Ionis and Novartis announced that the Lp(a)HORIZON trial did not meet its primary endpoint.)

Several injectable small interfering RNA therapies are currently in development for Lp(a) lowering, including lepodisiran (Eli Lilly), olpasiran (Amgen) and zerlasiran (Silence Therapeutics).

Oral therapies for Lp(a) lowering are also being explored, including muvalaplin (Eli Lilly), HRS-5346 (Merck/Jiangsu Hengrui) and YS2302018 (AstraZeneca/CSPC Pharmaceutical Group). These therapies are in earlier phases compared with pelacarsen and the injectable small interfering RNA therapies.

Recent data published in The New England Journal of Medicine demonstrated the potential for gene-editing therapy (CTX310, CRISPR Therapeutics) to lower atherogenic lipids in patients with uncontrolled hypercholesterolemia, hypertriglyceridemia or mixed dyslipidemia despite maximally tolerated lipid-lowering therapy. CTX310 is designed to induce permanent ANGPTL3 gene loss of function and is intended to be a one-time treatment for high LDL and triglycerides.

Another research-stage gene-editing therapy (VERVE-301, Verve/Eli Lilly) is currently being developed to permanently deactivate the LPA gene. This therapy incorporates a novel in vivo gene-editing mechanism that lowers Lp(a) by permanently deactivating the LPA gene in the liver, according to a company press release.

Once therapies specifically targeting Lp(a) become available, endocrinologists will have a role to play in prescribing them, Pulipati told Healio | Endocrine Today.

“I think endocrinologists will be among the key prescribers of Lp(a)-targeted therapies. We already prescribe complex injectable therapies, practice precision medicine in diabetes and obesity, and navigate care for patients longitudinally. Those skills translate naturally to Lp(a)-targeted treatments,” Pulipati said. “Our expertise would shine in identifying the right patient, placing that therapy in the context of the patient’s overall cardiometabolic risk and following them over the long term. More importantly, endocrinologists often identify high-risk patients before they experience a cardiovascular event. As routine Lp(a) testing becomes more common, we will have an opportunity to recognize elevated inherited risk earlier and intervene sooner.”

One treatment will not “win out” over the others, Bhatia said, since some of the current therapeutics being evaluated will initially have more evidence for the secondary prevention population while ongoing trials of other therapies will provide evidence for the primary prevention population.

“Even though these therapies are not yet available, they are close. In the meantime, there are still things that we do every day to help manage individuals with high Lp(a),” Bhatia said. “Now is a great time to get tested.”

That is especially true for patients at high CV risk who are seen by endocrinologists, Pulipati told Healio | Endocrine Today.

“Lp(a) isn’t new or uncommon. What’s changing is our ability to measure it, interpret it, and soon, directly treat it,” Pulipati said. “I think we’re entering a new era where Lp(a) will become a routine part of cardiovascular risk assessment. The question is no longer whether Lp(a) matters. The question is whether we identify patients early enough to change their cardiovascular trajectory.”

• For more information:
• Harpreet S. Bhatia, MD, MAS, FACC, FAHA, FASPC, can be reached at hsbhatia@health.ucsd.edu.
• Allison Bigeh, DO, can be reached at endocrinology@healio.com.
• Michael Honigberg, MD, MPP, can be reached at mhonigberg@mgh.harvard.edu or X @mchonig.
• Steven E. Nissen, MD, MACC, can be reached at nissens@ccf.org.
• Vishnu Priya Pulipati, MD, FACE, FNLA, can be reached at vppulipati@saintfrancis.com or LinkedIn www.linkedin.com/in/vppulipati.