Pelacarsen Failure: Heart Drug Lowers Lp(a) but NOT Heart Attacks

Have you ever heard the expression: “The operation was successful, but the patient died.” It’s not a perfect analogy to the Lp(a) drug story…but it does convey the disappointment drug companies, doctors and patients are experiencing after this week’s Novartis announcement about the pelacarsen failure.

 We have been writing about lipoprotein a, also known as Lp(a), for decades. In our book, Best Choices from The People’s Pharmacy (2006) we shared this story from a reader:

“I’m a 44-year-old male and as an active masters swimmer I have always eaten a low-fat diet and have a total cholesterol of 160. For all intents and purposes, I’m the picture of health.

“However, I recently survived a heart attack caused by plaque and a blood clot blocking one coronary artery. Further testing showed that my HDL level is low (25) and my level of Lp(a) is very high (80). I’ve been told that these risk factors could help explain the recent heart attack.”

What is Lp(a) and Why Is It a Bad Actor?

Cardiologists call Lp(a) “Lp little a.” We call it the best kept secret in cardiology. That’s because for decades physicians never mentioned it to patients and never requested a blood test to measure it.

First, what is it? This bad actor combines protein, cholesterol and fat into a particle that can wreak havoc inside the heart. Imagine “bad” cholesterol (LDL-cholesterol) stuck to apoliprotein(a). Together, this hot mess leads to something cardiologists call “high-risk plaque” in coronary arteries (European Journal of Preventive Cardiology, April 23, 2026). That is plaque that is “non-calcified.” This atherosclerotic plaque is “unstable,” suggesting that it is more likely to fracture and spill inflammatory nastiness into a coronary artery leading to a heart attack.

There is another complication from high levels of Lp(a). They can increase the risk for aortic valve stenosis (AVS). This stiffening of heart valves is responsible for significant heart damage and death. The bottom line is that elevated Lp(a) levels are bad for the heart! It has been estimated that one fifth of the population has inherited this serious risk factor.

Please note that word inherited. This problem appears to be genetic. If grandpa, dad and cousin Charlie all died of heart disease at a relatively early age, it is conceivable that they all had this risk factor. It runs in families!

Why Haven’t Doctors Measured Lp(a) Frequently?

Although cardiologists have been aware of the Lp(a) problem for decades, they rarely requested a blood test for their heart patients. That’s because they believed that they had no drug to lower it.

They also were taught that lifestyle interventions were ineffective. That’s to say, diet and exercise did not seem to make much of a difference. So, it was a case of see no evil, hear no evil, and speak no evil. Most patients were left in the dark if they had high Lp(a) levels. Ignorance is not bliss.

All that changed as major pharmaceutical companies began to develop drugs to lower Lp(a) levels.

How High Is Too High for Lp(a)?

As mentioned above, most physicians paid relatively little attention to lipoprotein(a). That is changing fast. The newest American College of Cardiology/American Heart Association guidelines recommend that adults have Lp(a) measured at least once during their lifetime.

An Lp(a) level of 50 mg/dL or greater, or 125 nmol/L or greater, is now considered a cardiovascular risk-enhancing factor. Lp(a) results may be reported in two different units, depending on the laboratory and assay. Some measure Lp(a) in milligrams (mg) per deciliter (dL) while others measure in nanomoles (nmol) per liter (L).

Those two ways of reporting Lp(a), however, are not directly interchangeable. Milligrams per deciliter measure the mass of Lp(a), while nanomoles per liter reflect the concentration of Lp(a) particles. Because the size of those particles varies from person to person, experts caution against using a simple conversion formula.

Lp(a) is unusual in another important way. Your level is determined primarily by your genes. Losing weight, jogging five miles a day or eating a Mediterranean diet may improve many other cardiovascular risk factors, but they generally do very little to lower Lp(a).

That may help explain the gentleman we described at the beginning of this article, whose story we first told in Best Choices From The People’s Pharmacy two decades ago. Some people seem to do virtually everything “right” and nevertheless develop cardiovascular disease. An inherited Lp(a) elevation can be an important part of that puzzle. And statins do not lower Lp(a). If anything, they actually raise Lp(a) levels, which one cardiologist described as an “inconvenient truth.”

Why the Pelacarsen Failure Is Such a Big Deal

Pelacarsen was designed specifically to attack Lp(a) at its source. It is an antisense oligonucleotide, a short strand of genetic material engineered to interfere with the messenger RNA the liver uses to manufacture apolipoprotein(a). Less apo(a) should mean less Lp(a) circulating in the bloodstream.

The preliminary results were spectacular.

In a randomized Phase II study published in the New England Journal of Medicine (Jan. 16, 2020), Dr. Sotirios Tsimikas and his colleagues studied 286 people with established cardiovascular disease and elevated Lp(a). The experimental drug was then called AKCEA-APO(a)-LRx, or APO(a)-LRx. It was developed by Ionis Pharmaceuticals and its affiliate Akcea Therapeutics and was subsequently licensed to Novartis. The compound was later renamed pelacarsen and was also known during development as TQJ230.

Depending on the dose, the drug lowered Lp(a) by 35 percent to as much as 80 percent. That was enough to get cardiologists very excited. It also thrilled pharmaceutical companies. Here was a new medication that could conceivably reduce cardiovascular disease in one out of five people with elevated Lp(a) levels. That could mean a huge advance against heart attacks and strokes, if it worked.

But there was one enormous unanswered question:

Would lowering Lp(a) prevent heart attacks, strokes and cardiovascular deaths?

That is very different from asking whether a drug can make a laboratory number look better.

The Pelacarsen Failure Emerges From Lp(a)HORIZON

Novartis launched the huge Phase III Lp(a)HORIZON trial to find out whether lowering Lp(a) would actually protect patients.

The trial was sponsored by Novartis, but the company assembled an impressive international group of cardiovascular researchers. The published design paper (American Heart Journal, Sept. 2025) includes Dr. Leslie Cho, Dr. Stephen Nicholls, Dr. Børge Nordestgaard, Dr. Ulf Landmesser, Dr. Sotirios Tsimikas, Dr. Michael Blaha, Dr. A. Michael Lincoff and Dr. Steven Nissen, among others.

The investigators enrolled 8,323 people with established cardiovascular disease and elevated Lp(a). Participants were randomly assigned to receive an 80-mg injection of pelacarsen once a month or placebo. One other important detail that almost everyone has ignored. All “high-risk” patients enrolled in the study had elevated Lp(a) levels equal to or greater than 70 mg/dL (approximately 149 nmol/L). Participants received either pelacarsen or placebo on top of optimized cardiovascular treatment, including the highest tolerated doses of statins and/or other LDL-lowering therapy. Over 75% received high-intensity statin treatment.

But here’s the rub. Dr. Sotirios Tsimikas and his colleagues wrote an intriguing article in the European Heart Journal (Jan. 1, 2020) titled:

“Statins and increases in Lp(a): an inconvenient truth that needs attention“

We have suggested that driving with your foot on the gas and the brake simultaneously might be counterproductive. That point may become extremely important as cardiologists analyze what went wrong.

A brief disclosure: three of the prominent researchers involved in the evolving Lp(a) story — Dr. Steven Nissen, Dr. Sotirios Tsimikas and Dr. Michael Blaha — have been guests on The People’s Pharmacy radio show and podcast. We have interviewed them over the years about cardiovascular risk, cholesterol and Lp(a).

That gives us no special insight into the unpublished details of the Lp(a)HORIZON results, but it does mean we have followed this field — and the expectations surrounding Lp(a)-lowering therapy — especially closely.

The Lp(a)HORIZON Study Revealed the Pelacarsen Failure

The trial was designed to answer the question that really matters to patients: Would pelacarsen reduce cardiovascular death, nonfatal heart attacks, nonfatal strokes or urgent coronary procedures requiring hospitalization?

On September 4, 2026, Novartis supplied its topline answer.

No.

Pelacarsen lowered Lp(a), just as everyone expected. But according to Novartis, the drug did not meet its primary endpoint of reducing cardiovascular events compared with placebo.

Novartis announcement, Sept. 4, 2026

That is the essence of the Pelacarsen Failure.

The medicine succeeded at changing the risk marker. It failed, at least in the overall study population, to demonstrate that changing that marker improved the clinical outcomes patients actually care about.

Pelacarsen Failure: Cardiologists Were Stunned

The reaction from prominent cardiologists was extraordinary. Dr. David Maron, president of the American Society for Preventive Cardiology, reacted to the news by saying:

“This is a huge blow.”

Yale cardiologist Dr. Harlan Krumholz called the news “extremely disappointing.”

Their surprise and disappointment are understandable.

Virtually every line of evidence seemed to point in the same direction. High Lp(a) is strongly associated with cardiovascular disease. Genetic research has supported a causal role. People born with very high Lp(a) experience more cardiovascular events. And earlier studies demonstrated that pelacarsen could lower the biomarker dramatically.

The next step seemed almost obvious:

Lower Lp(a), and cardiovascular events should decline.

Except they didn’t.

That is why the Pelacarsen Failure is much more interesting than another experimental medicine that simply fizzled. It challenges one of medicine’s most seductive assumptions:

If a risk factor is associated with disease, lowering the risk factor must necessarily prevent the disease.

We have seen that assumption fail before.

Pelacarsen Failure and the Problem With Surrogate Endpoints

Doctors, researchers, regulators and drug companies often rely upon what are called surrogate endpoints. That term sounds technical, but the idea is actually quite simple.

Suppose researchers believe that a laboratory measurement predicts a serious medical problem. Instead of waiting many years to determine whether a medicine prevents heart attacks, strokes, kidney failure, blindness or premature death, they measure the laboratory number.

If the drug improves that number, everyone hopes that patients will ultimately experience better health. LDL cholesterol is one example. Hemoglobin A1c is another. Blood pressure is another.

Sometimes changing a risk factor really does improve important medical outcomes. But not always.

The history of medicine contains sobering examples of drugs that substantially improved a laboratory measurement without improving the health of patients. Some have actually made outcomes worse.

That is what makes the Pelacarsen Failure so provocative. Pelacarsen apparently did what it was designed to do. It lowered Lp(a). What it did not demonstrate was a reduction in the cardiovascular events researchers had expected to prevent. A better lab value does not automatically equal a better outcome.

We Have Seen This Movie Before

Longtime readers of The People’s Pharmacy may recognize the pattern. More than half a century ago, doctors assumed that if a diabetes medicine lowered blood sugar, it should prevent the cardiovascular complications of diabetes.

Then came the University Group Diabetes Program (UGDP). The drug tolbutamide (Orinase) lowered blood sugar. Yet the clinical trial produced an alarming cardiovascular signal. People taking the medicine experienced substantially more cardiovascular deaths than people receiving placebo.

The lesson was disturbing. A drug could improve the laboratory number everyone was watching while failing miserably at the outcome that really mattered. Later, cardiologists became enthusiastic about raising HDL, the so-called “good” cholesterol. High HDL levels were associated with lower cardiovascular risk. It therefore seemed logical that a medicine that raised HDL should protect against heart disease.

Pfizer developed torcetrapib to do exactly that. The laboratory results looked impressive. Torcetrapib raised HDL dramatically and also lowered LDL cholesterol.

Then came the large outcomes trial. The drug did not protect patients. Cardiovascular events and deaths actually increased.

That debacle taught an important lesson:

Changing a biomarker and changing a patient’s fate are not necessarily the same thing.

The Pelacarsen Failure may ultimately become another chapter in that history.

Does the Pelacarsen Failure Kill the Lp(a) Hypothesis?

Not so fast. It would be premature to conclude that lowering Lp(a) cannot prevent cardiovascular disease. For one thing, Novartis has not yet released the complete Lp(a)HORIZON results.

We don’t yet know all the details. How much did Lp(a) decline in this particular Phase III population? Did people starting with extraordinarily high Lp(a) levels fare differently? Did any subgroup appear to benefit? Were there differences based on baseline risk, age, sex or other treatments?

Those questions cannot be answered from the topline announcement.

Another question intrigues us.

The patients in Lp(a)HORIZON were receiving aggressive guideline-directed treatment. As mentioned, that included widespread use of statin-type cholesterol-lowering medications. Years ago, Dr. Tsimikas and his colleagues reported that statins can actually raise Lp(a) in some patients.

We are not suggesting that statins caused the pelacarsen trial to fail. We simply don’t have the data to draw that conclusion. But when the complete trial results become available, we hope investigators will examine background treatment carefully.

There is an even more important reason not to close the book on Lp(a):

Pelacarsen is not the only drug being tested.

Several pharmaceutical companies have developed medicines that lower Lp(a), sometimes by different mechanisms and in some cases by more than 90 percent. Their large cardiovascular outcome trials may tell us whether the Pelacarsen Failure represents a problem with one particular drug or a much deeper problem with the assumption that dramatically lowering Lp(a) will prevent heart attacks and strokes.

After the Pelacarsen Failure, All Eyes Turn to Olpasiran

Olpasiran, from Amgen, works differently from pelacarsen. Pelacarsen is an antisense oligonucleotide. Olpasiran uses small interfering RNA, or siRNA, to shut down the production of apolipoprotein(a) in the liver.

The distinction matters because olpasiran can produce extraordinarily large and sustained reductions in Lp(a). In the Phase II OCEAN(a)-DOSE trial (New England Journal of Medicine, Nov. 17, 2022), some doses reduced Lp(a) by more than 95 percent.

Now comes the really important test.

The Phase III OCEAN(a)-Outcomes study is evaluating whether those dramatic reductions actually translate into fewer heart attacks, coronary deaths and urgent coronary procedures. The study includes more than 7,000 people with cardiovascular disease and elevated Lp(a).

Amgen has also launched OCEAN(a)-PreEvent, designed to investigate whether olpasiran might prevent a first major cardiovascular event in people with elevated Lp(a) who have not already experienced one. The results of these studies have suddenly become far more important.

If olpasiran dramatically lowers Lp(a) and reduces cardiovascular events, researchers will have to determine what makes it different from pelacarsen.

Pelacarsen Failure Puts Lepodisiran in the Spotlight

Eli Lilly is also betting heavily on lowering Lp(a). Its injectable drug lepodisiran is another siRNA medicine designed to suppress production of apo(a). Earlier results were remarkable.

Dr. Steven Nissen and his colleagues reported results from the Phase II ALPACA trial in the New England Journal of Medicine (May 1, 2025). With the highest-dose regimens, average Lp(a) reductions approached or exceeded 90 percent over extended periods.

Now Lilly is conducting the enormous Phase III ACCLAIM-Lp(a) trial. The study is evaluating whether lepodisiran reduces major cardiovascular events in people with elevated Lp(a) who either already have atherosclerotic cardiovascular disease or are considered at risk for a first cardiovascular event.

After the Pelacarsen Failure, the important question is no longer whether lepodisiran can lower Lp(a). We already know that it can. The question is whether patients will actually experience fewer heart attacks, strokes and cardiovascular deaths.

Pelacarsen Failure Also Raises the Stakes for Muvalaplin

Another Lilly drug takes a completely different approach. Muvalaplin is neither an antisense drug like pelacarsen nor an siRNA drug like olpasiran and lepodisiran. And it has another potentially important advantage:

It is a pill.

Muvalaplin is an oral small-molecule drug designed to interfere with the assembly of the Lp(a) particle.

In the Phase II KRAKEN trial, muvalaplin produced substantial reductions in Lp(a), reaching approximately 86 percent with one method of measuring intact Lp(a). That comes from a report in JAMA (Jan. 21, 2025).

Lilly is now studying muvalaplin in the huge Phase III MOVE-Lp(a) cardiovascular outcomes trial. Approximately 10,450 people are expected to participate. The study is designed to find out whether an oral Lp(a)-lowering drug can prevent major cardiovascular events in people with elevated Lp(a).

An effective pill that lowers Lp(a) would obviously have enormous appeal. But the Pelacarsen Failure has changed the standard by which all these drugs should be judged. Lowering the number is no longer enough.

Other Lp(a) Drugs Could Clarify the Pelacarsen Failure

Another experimental siRNA treatment is zerlasiran, previously called SLN360, developed by Silence Therapeutics. Dr. Steven Nissen and his colleagues published results from the Phase II ALPACAR trial in JAMA (Dec. 17, 2024). Zerlasiran produced time-averaged Lp(a) reductions of more than 80 percent, while reductions at some individual time points exceeded 90 percent.

Zerlasiran has not yet provided the kind of giant cardiovascular-outcomes evidence we now desperately need. There are also other Lp(a)-lowering compounds in development. As you can tell, the pharmaceutical industry was all-in on Lp(a)-lowering drugs! There were billions of dollars at stake and lots of companies wanted a piece of the action.

Pelacarsen’s failure does not prove that every way of lowering Lp(a) will fail. But it raises the bar dramatically.

From now on, reductions of 80, 90 or even 95 percent in a laboratory measurement will be interesting — but they will not settle the question. Researchers will need to demonstrate that patients actually have fewer heart attacks, fewer strokes, fewer cardiovascular deaths or fewer disabling cardiovascular complications.

The Pelacarsen Failure Leaves One Giant Question

The Lp(a) story is far from over. In fact, the Pelacarsen Failure may have made the next several clinical trials much more important than anyone expected. If olpasiran, lepodisiran or muvalaplin dramatically lowers Lp(a) and prevents heart attacks and strokes, researchers will have to understand why pelacarsen failed.

• Was the mechanism different?
• Did people with extremely elevated Lp(a) respond differently from those with lower levels?
• Was the degree of Lp(a) reduction insufficient?
• Did patients start the drug too late for it to do any good against established cardiovascular disease?
• Were patients already so intensively treated with statins and other cardiovascular medicines that there was less remaining risk for pelacarsen to reduce?
• Could statins have influenced the effectiveness of pelacarsen?

Could Lp(a) be involved in several different biological pathways, so that merely reducing its blood concentration does not eliminate all of its cardiovascular consequences? Or is something much more fundamental going on? If the other experimental drugs also reduce Lp(a) dramatically but fail to improve cardiovascular outcomes, medicine will face a deeply uncomfortable question:

Have we mistaken an extraordinarily convincing cardiovascular risk marker for a useful therapeutic target?

That is precisely why the Pelacarsen Failure matters far beyond Novartis.

It is a reminder that a drug can score a spectacular victory against a laboratory number and still lose the battle that patients care about most.

Can People with Elevated Lp(a) Numbers Do Anything to Reduce Risk?

By now you must be feeling overwhelmed and perhaps a bit depressed, especially if you have elevated Lp(a) levels. Most cardiologists were eagerly awaiting the results from the pelacarsen clinical trial in the hope that they would have a new and powerful tool against cardiovascular disease. They too are probably feeling disappointment.

But wait, there are some old-fashioned possibilities that might be worth talking about with your physician. Dr. Tsimikas runs a very special clinic for cardiology patients who have been diagnosed with elevated levels of Lp(a). He has also been studying this risk factor for a long time.

In our interview with Dr. Tsimikas, he talks about aspirin as a potentially useful strategy. Here is a link:

Show 1421: Is Lp(a) the Heart Risk No One Talks About? (Archive)

Download the mp3, or listen to the podcast on Apple Podcasts or Spotify.

Dr. Tsimikas also talks about the value of niacin. It used to be prescribed by cardiologists before statins became available. It modestly lowers Lp(a) levels. Dr. Tsimikas also discusses this old-fashioned way of lowering cholesterol on the podcast.

There is also some data to suggest that a low-carb approach might be helpful. You can read more about research at this link.

Which Is Better for Blood Lipids–Low-Carb or Low-Fat?

Final Words:

We have tried to bring you the story behind the Pelacarsen Failure headlines. Did you find this information helpful? Was it too technical? We very much appreciate your feedback in the comment section below.

Have you ever been tested for Lp(a)? What were your numbers? How did your doctor react? We would love to hear your story. If you think this article was helpful, please share it with friends and family. Thank you for supporting our work.

When the other Lp(a) lowering drug studies are completed, would you like to learn about the results?