A Drug Slashed Lp(a) by 78%. Why Didn’t It Prevent Heart Attacks?

Cardiovascular disease impacts 626 million people and is the leading cause of death globally.¹ The Lp(a) HORIZON study, a large phase III clinical trial, tested whether a drug called pelacarsen could prevent heart attacks, strokes, and other cardiovascular events.

Full results, presented on Saturday, November 7, at the American Heart Association’s Scientific Sessions and published in The New England Journal of Medicine, show that it didn’t.²

Dr. Steven Nissen, the chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, led the trial. Nissen told NBC News, “Everybody, me included, believed that lowering levels of lipoprotein(a) substantially would reduce the risk of major cardiovascular events. There is simply no evidence here that people that got more reduction did better.”³

What the drug did do

The drug did exactly what it was designed to do: lower Lp(a).² That matched what earlier, smaller trials had shown.^4,5

Lipoprotein(a), Lp(a) for short, is a cholesterol-carrying protein in your blood. About 1 in 5 people have high Lp(a).⁶ When your Lp(a) levels are high, you’re at a higher risk of heart attack or stroke. Lp(a) levels are mostly determined by your genes and stay fairly stable throughout life, which is why diet and exercise barely move them.

The logic was simple: lower Lp(a), and you should prevent heart attacks and strokes. Pelacarsen, developed by Ionis and licensed to Novartis, is a monthly injection that blocks the liver from making a key building block of Lp(a).⁵

HORIZON enrolled more than 8,300 people with high Lp(a) who had already had a heart attack, stroke, or other cardiovascular disease. They received monthly injections of pelacarsen or a placebo for a median of nearly five years. After one year, Lp(a) in the pelacarsen group had dropped by 78%.²

But heart attacks, strokes, cardiovascular deaths, and emergency procedures to reopen blocked arteries were just as common in both groups: about 12% of patients had one of these events, whether they got the drug or the placebo.²

Why a lower number didn’t mean fewer heart attacks

One lesson here is that moving a number in the blood doesn’t always change what happens to patients.

Researchers have offered several possible explanations. One possibility is that Lp(a) damages arteries over decades, but the patients in this trial already had cardiovascular disease. Therefore, lowering Lp(a) later in life may not undo the damage already done, especially when LDL cholesterol and blood pressure are well controlled.

But there’s a troubling finding: even patients whose Lp(a) fell the most showed no measurable benefit. We still don’t know whether the problem was the drug, the timing, or whether lowering Lp(a) alone is simply not enough to prevent heart attacks in people with established disease. Genetic studies suggest that a very large absolute reduction may be needed to see a benefit.

Also, patients in the trial were already on strong cholesterol and blood pressure medicines, potentially leaving little room for improvement. And about one in five people on pelacarsen stopped because of side effects, compared with fewer than one in ten on placebo.^2,7

What these results mean

Several other Lp(a)-lowering drugs are still in large trials, including olpasiran (Amgen) and lepodisiran (Eli Lilly).^8,9 Those results will help show whether the problem is with pelacarsen specifically or with targeting Lp(a) at all.

Trials like this are also enormously expensive. Novartis, which sponsored HORIZON, has not disclosed the trial’s cost. A comparable Novartis cardiovascular outcomes trial of about 8,400 patients was estimated at roughly $347 million in a 2018 JAMA Internal Medicine analysis, so HORIZON likely cost in the hundreds of millions.¹⁰

For patients and the pharmaceutical industry writ large, this is a disappointment.

Even though it looks like Lp(a) lowering on its own doesn’t lower the risk of new heart attacks or strokes, new ACC/AHA guidelines recommend getting Lp(a) measured at least once. People with high levels can lower their overall risk by managing LDL cholesterol and blood pressure, exercising, and talking with their doctor about other options, which may include aspirin for some people.

These results are a stark reminder that a disease risk biomarker can move dramatically without affecting the disease itself. This trial’s failure is no stain on the pharmaceutical industry. Companies still take on enormous risk to develop new medicines, in what remains one of the most difficult, expensive, and uncertain human pursuits.

References

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Last Updated: Nov 9, 2026 · 4 minute read