In 1963, a Norwegian physician and geneticist named Kåre Berg discovered a new structure that transports molecules of cholesterol to the body. He dubbed this genetically inherited particle lipoprotein(a), or Lp(a) (pronounced “LP-little-A”). A little more than a decade later, Berg found that Lp(a) increased the risk of cardiovascular disease.

Many years of research that followed revealed more about the dangers of Lp(a). People with high levels of the particle are at greater risk of developing atherosclerotic cardiovascular disease, which is caused by sticky plaque that stiffens, narrows and inflames arteries.

In addition, Lp(a) plaque deposits increase the risk of aortic stenosis, or thickening of the aortic valve, the two-way door through which oxygen-rich blood flows to the rest of the body. These individuals are also more prone to blood clots, another contributor to heart attack and stroke.

Yet until relatively recently, the work of Berg and his successors hit a wall. As an inherited trait, Lp(a) proved immune from therapies that reduce high levels of other types of cholesterol-carrying particles that enter artery walls and produce plaque. For example, the most familiar of these, low-density lipoproteins (LDLs), often called “bad cholesterol,” can be treated with medications and changes to exercise and diet.

One result: even though Lp(a) levels can be measured with a simple blood test, a relatively small number of people have done so.

“Lp(a) has been known for some time as a risk for cardiovascular disease as well as aortic stenosis. It hasn’t been checked much in the past because there really wasn’t much we could do about it,” said Dr. Steven Simon, a heart specialist at UCHealth and assistant professor of Medicine in the Division of Cardiology at the University of Colorado Anschutz School of Medicine.

Clinical trials at UCHealth target Lp(a)

That may change, thanks to clinical trials of targeted drugs that aim to lower levels of Lp(a). The hoped-for outcome: decrease the risk of heart attack, stroke, medical procedures to restore blood flow to the heart, and death from cardiovascular disease, compared to a placebo. Two of these trials are nearing completion at UCHealth University of Colorado Hospital.

The phase 3, multinational HORIZON trial of the injectable drug pelacarsen began in 2021 and should conclude early this summer, said Dr. David Saxon, principal site investigator for the study, which is being run out of the University of Colorado Anschutz Health and Wellness Center.

Saxon is an endocrinologist and associate professor of Medicine in the Division of Endocrinology, Metabolism, and Diabetes at the University of Colorado Anschutz School of Medicine.

Simon and Saxon are at the forefront of work that helps people manage their cholesterol and reduce their risk of heart disease. They co-direct the prevention-focused Cardiometabolic and Advanced Lipid Clinic at the University of Colorado Anschutz, where they treat patients with the often-interlinked problems of cardiovascular disease, diabetes, obesity and cholesterol disorders, Simon said.

News of Lp(a)-lowering drug trials have spurred referrals to the clinic, Simon said.

“A lot of primary care providers have started checking Lp(a), along with more cardiologists and endocrinologists, so we are getting referrals from all of them,” he said.

Promising data from multiple studies

Saxon said a previous study showed that pelacarsen lowered Lp(a) levels by as much as 80%. Another investigational drug, lepodisiran, reduced Lp(a) levels by about 94%. Lepodisiran is the subject of the phase 3, multinational ACCLAIM trial, led at the University of Colorado Anschutz campus by Dr. Neda Rasouli, a UCHealth endocrinologist. Rasouli is professor of Medicine in the Division of Endocrinology, Metabolism, and Diabetes and director of the Diabetes and Endocrinology Clinical Trial Program at the University of Colorado Anschutz School of Medicine.

The ACCLAIM-Lp(a) trial, also closed to enrollment, is following roughly 12,500 patients worldwide for four or five years. Some of the study patients already have atherosclerotic cardiovascular disease and include those who have had heart attacks, strokes and artery blockages, Rasouli said. Other study patients are at high risk of suffering one of these events for the first time because they have multiple cardiovascular disease risk factors, she added. The study will determine whether lowering Lp(a) results in fewer serious cardiovascular events.

Rasouli said her study team will soon begin enrolling participants in a new clinical trial, called MOVE-Lp(a), of muvalaplin, an oral Lp(a)-lowering therapy. The drug “offers another promising strategy to address genetically driven cardiovascular risk,” Rasouli said.

A cause for both optimism and caution

The statistics are promising, but expectations should be tempered, pending the final results of the trials, Saxon said. Regardless of how much the new drugs might lower Lp(a) levels, the real test is whether those lower levels translate to lower cardiovascular disease risk and fewer deaths.

“I think of HORIZON as a landmark trial, whether it is positive or negative,” Saxon said. “It’s not only testing this specific drug and the ability of it to reduce cardiovascular events, but it’s really testing the Lp(a) hypothesis. We’ve shown that Lp(a) is a risk factor, but a trial like this could really prove if reducing it matters for people’s cardiovascular health. We’ve never had that before.”

If nothing else, the trials of pelacarsen, lepodisiran and other drugs still in the pipeline give patients with this inherited risk a possible path to help, Simon said.

“Now we can at least enroll people in these clinical trials of agents that directly target lipoprotein(a),” he said.

A path to defy genetics

How do they work? The key lies in understanding how Lp(a) is different from LDL and other lipoproteins.

Lipoprotein particles that ferry cholesterol to the arteries all contain a protein called apolipoprotein b (apoB). It’s the key that allows these particles to penetrate the walls of arteries once they reach them. In addition to apoB, the Lp(a) particle has a separate protein structure, apolipoprotein(a), or apoA, that Saxon said “gives it very different properties” from LDL, notably the power to drive dangerous blood clotting in addition to forming plaque and thickening the aortic valve.

In very simple terms, both pelacarsen and lepodisiran target the liver cells that produce apoA proteins, the defining feature of Lp(a). The two drugs work in different ways to prevent liver cells from producing apoA. That, in turn, thwarts the body from making the Lp(a) particles that carry potentially damaging cholesterol to the arteries.

Slow progress toward possible approval

At present, pelacarsen requires a once-monthly injection, while lepodisiran and other drugs in development could need injections only once or twice a year.

For now, the number of people who could be helped if the new drugs prove successful will be a fraction of those with high Lp(a) levels. Saxon noted that the HORIZON trial limited enrollment to patients who had suffered a previous heart attack or stroke. That means that if pelacarsen is approved, it likely will be only for patients who have already had those issues, he said.

“It’s unlikely to be approved for primary prevention, at least not yet,” Saxon said.

Greater incentive to test for Lp(a)

Nonetheless, the National Lipid Association recommended in 2024 that all adults should have their Lp(a) levels measured at least once in their lifetime, adding that “high Lp(a) levels warrant early and more-intensive risk factor management.”

Simon said a “high-risk threshold” for Lp(a) levels is 50 milligrams per deciliter or higher.

For people concerned with their Lp(a) levels today, Simon said, “We’re really moving toward everyone should have it checked once.” He noted that people who should consider it most seriously are those who have had early cardiovascular disease, including aortic stenosis and buildup of plaque in the arteries, or family members who had these problems, especially at an early age.

Why recommend tighter risk management if Lp(a) levels are genetically determined? Saxon stressed that people in this group can still manage their LDL levels, together with their doctor, with more intensive statin treatments and perhaps baby aspirin. In addition, a different class of drugs called PCSK-9 inhibitors, which reduce LDL levels, can help in some cases to lower Lp(a) levels by 20% to 30%, he said.

Saxon added that Lp(a) is not the only cholesterol-transporting particle that contributes to cardiovascular disease. He estimated that others, including LDLs, very‑low‑density lipoproteins (VLDLs) and intermediate density lipoproteins (IDLs), typically account for 80% of the cholesterol-containing particles that cause heart disease. All of them can be treated with medications and lifestyle changes.

“That’s why it makes sense to say, ‘I know I have Lp(a), and I don’t have a drug for that, but I can impact the other 80% of the bad particles by driving them down with medications,’” Saxon said.

For now, the question of whether pelacarsen, lepodisiran, muvalaplin and other drugs can actually decrease the risk of cardiovascular disease remains unanswered, Saxon said. But the work represents progress toward understanding the roots of the nation’s number-one killer.

“Even if questions remain, we’ve advanced our knowledge base, no matter what,” he said.