A drug that reduced levels of lipoprotein(a), a genetically determined cardiovascular risk factor, by about 78 per cent failed to reduce heart attacks, strokes or cardiovascular deaths in a major trial. The result left researchers stunned.

Dr Amanda Doran, an assistant professor of medicine at Vanderbilt University Medical Center, said she 'really thought that this was going to be a slam dunk'. Vanderbilt was one of nearly 800 sites, and she said the result 'obviously hurts'.

The Lp(a)HORIZON trial tested pelacarsen, a monthly injection, in 8,350 adults with high lipoprotein(a), or Lp(a), and established cardiovascular disease. The efficacy analysis included 8,322 participants. Results were presented at the American Heart Association Scientific Sessions 2026.

The findings were published in the New England Journal of Medicine. The primary outcome occurred in 12.3 per cent of patients on pelacarsen and 12.1 per cent on placebo, showing no benefit.

Cholesterol Falls, Risk Does Not

Lp(a) is a largely genetically determined cardiovascular risk factor associated with plaque build-up in arteries and an increased risk of blood clots.Diet and exercise have little effect on it, which is why researchers have long sought a targeted therapy.

Participants received 80mg of pelacarsen monthly or a matching placebo. Median Lp(a) at 12 months was 64.4nmol/L with the drug versus 233.4nmol/L with placebo.

The primary outcome combined cardiovascular death, non-fatal heart attack, non-fatal ischaemic stroke and urgent coronary revascularisation requiring hospitalisation. The hazard ratio was 1.02, showing no difference between the groups.

Rates were identical in patients with Lp(a) of at least 90mg/dL, with both groups at 12.3 per cent. Dr Steven Nissen, the trial chair at Cleveland Clinic, said the result does not represent a near miss.

No individual component of the primary outcome improved, and all-cause mortality was unchanged. Secondary analyses published in NEJM Evidence, including total events and subgroups, were also neutral.

Nissen said there was no evidence that patients with greater Lp(a) reductions fared better. Landmark analyses at three months found no benefit regardless of reduction size.

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Drug-Related Adverse Events More Common With Pelacarsen

Drug-related adverse events were reported in 56.8 per cent of pelacarsen recipients compared with 18.0 per cent of placebo recipients. Adverse events led to discontinuation in 20.6 per cent of the drug group versus 7.5 per cent of the placebo group.

Investigator-reported hypersensitivity reactions affected 17.1 per cent of the pelacarsen group and 5.4 per cent of the placebo group. Premature discontinuation for any reason occurred in 35.1 per cent versus 18.3 per cent.

Possible Reasons Behind the Result

Nissen said Lp(a) was lowered for a median of 4.7 years, while people with genetically low Lp(a) have lower levels from birth. Lifelong reduction may therefore be needed for protection from Lp(a)-related events.

Intensive background care may also have limited any added benefit. Participants had very low LDL cholesterol and controlled blood pressure, and event rates were relatively low, which lengthened the trial, Nissen noted.

Dr Karol Watson, co-director of the UCLA Program in Preventive Cardiology, who was not involved in the research, said she had not seen a more shockingly neutral trial in a while. She suggested the therapy may have come too late in life.

What Comes Next for Lp(a)

Nissen stressed that the results apply only to pelacarsen in patients with existing disease. Primary prevention was not studied, so effects in people without prior events remain unknown.

Ongoing trials of olpasiran, lepodisiran and muvalaplin include primary prevention patients. The first two are siRNA agents that reduce Lp(a) more potently than pelacarsen, according to Nissen.

Dr Leslie Cho, the trial's first author, said Lp(a) remains a causal risk factor and the study shows how crucial lowering LDL cholesterol remains. Nissen said a single negative trial does not define the ultimate clinical value of lowering Lp(a).

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