In early September, pharmaceutical giant Novartis issued a press release that sent shock waves through the cardiology community. A drug called pelacarsen, once expected to be a potential blockbuster, had failed to reduce the risk of heart problems and stroke in people with underlying cardiovascular disease.

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Michelle O’Donoghue, a cardiologist at Brigham and Women’s Hospital in Boston, Massachusetts, says her initial reaction to the news was “a state of disbelief”.

Pelacarsen lowers the levels of a type of cholesterol-carrying molecule called lipoprotein(a), often referred to as Lp(a) or Lp little a. Similar to low-density lipoprotein, or LDL, high levels of Lp(a) increase the risk of heart attacks and other heart-related problems. But unlike LDL (sometimes called bad cholesterol), Lp(a) levels are determined mostly by genetics, rather than lifestyle. So, the roughly one in five people who have high Lp(a) levels cannot reduce them through changes in diet and exercise. And although people can lower their LDL levels with statins and other medications, there are no approved drugs that substantially lower Lp(a).

That is why cardiologists were so excited about pelacarsen and a handful of other Lp(a)-lowering drugs that are currently in late-stage clinical trials. “Lp(a) has really been the talk of the town over the past several years in the cardiovascular community, in part because of a lot of enthusiasm over these therapies,” says O’Donoghue, who is an investigator on one of the trials. The therapies lower Lp(a) by 80% or more. All researchers had to prove was that this reduction leads to better clinical outcomes — fewer heart-related deaths, heart attacks, strokes and emergency bypass surgeries.

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Why the trial, known as Lp(a)HORIZON, failed isn’t yet clear (see go.nature.com/4sv4ekx). Novartis representatives did not reply to a request for comments. But the high-profile miss has cardiologists questioning what they know about the relationship between Lp(a) and major heart-related problems, and wondering whether other Lp(a)-lowering therapies will meet a similar fate. The US drug firms Amgen and Eli Lilly have large trials under way to test therapies that target Lp(a) using a different approach.

“We had hoped that this would be the first step into a big new area of therapy,” says Harpreet Bhatia, a cardiologist at the University of California, San Diego. Now, he and other researchers are awaiting further details on the Novartis trial and the results from other trials to see whether there is still a future for such approaches to reducing Lp(a).

Cryptic cholesterol

Lp(a) and LDL both carry cholesterol, a fatty substance that is produced mostly in the liver. The body needs cholesterol, but when its levels are high, it can be deposited in artery walls and form hard plaques, a process known as atherosclerosis. These plaques can grow so thick that they choke off blood flow or rupture, causing blood clots that can prompt a heart attack.

Study after study has shown that people with higher Lp(a) levels are at greater risk of coronary events such as heart attacks, heart-valve problems and heart failure than are individuals with lower levels¹. And over the past 30 years, genetic data have bolstered the idea that Lp(a) is not just a marker of risk, but also a causal factor². “Genetically, I don’t think you could ask for better evidence for this as a drug target,” says Børge Nordestgaard, a cardiologist at the University of Copenhagen and president of the European Atherosclerosis Society in Gothenburg, Sweden.

Structurally, Lp(a) isn’t much different from LDL. Both are essentially globs of fat surrounded by a protein called apolipoprotein B (see ‘Stopping lipoprotein(a)’). Both are produced in the liver. There is, however, one major difference. Lp(a) has a tail composed of apolipoprotein(a), which loops in segments called ‘kringles’ — named after the twists of a Scandinavian pastry. Lp(a) levels depend, in part, on the number of copies of a particular type of kringle encoded in the gene for apolipoprotein(a). People carry anywhere from 1 to more than 40 copies; the fewer the copies, the smaller the particle, and the higher the Lp(a) level. That is because liver cells seem to have an easier time producing and secreting the smaller particles.

Researchers are still trying to unpack how that structural difference affects the particle’s function and its role in cardiovascular disease. Particle for particle, Lp(a) carries six times the risk that LDL does. That could be because it’s more effective at depositing cholesterol on artery walls, or because it promotes inflammation, which can contribute to plaque deposition. But Nordestgaard thinks it has more to do with the impact of Lp(a) on blood clotting. The particle’s tail might make it more difficult for the body to break down clots, which could lead to larger blockages.

Many countries recommend that adults get their Lp(a) levels tested at least once. European atherosclerosis and cardiology societies first recommended that physicians test Lp(a) levels in 2019, and earlier this year, those in the United States followed suit. Because there is no approved therapy for lowering Lp(a), the standard of care for people with high levels is to aggressively reduce other risk factors for cardiovascular disease.

But high Lp(a) levels don’t always cause problems. Bhatia says that sometimes older people have high Lp(a) levels but never have a cardiovascular event. “And sometimes we don’t even see plaque when we look with imaging,” he says. “It may just be that it’s the overall picture of risk, and that Lp(a) is just one piece of that bigger puzzle.”

Questions abound