The La(a)HORIZON trial, the first to test whether a drug that lowers lipoprotein(a) can reduce cardiovascular risk, has produced a negative result, according to Science Media Centre España. Novartis had signalled the outcome in a press release in September, and the full findings were presented on 7 November at the American Heart Association congress and published in NEJM.
The study enrolled more than 8,000 patients who had already experienced a cardiovascular event. Participants were followed for nearly five years and were randomly assigned to receive either pelacarsen or a placebo. The drug drove Lp(a) levels down by more than 70%, yet the rate of heart attacks, strokes and cardiovascular deaths was essentially identical between the two groups: 12.3% among those on the drug versus 12.1% on placebo. Even patients whose Lp(a) was highest at baseline showed no benefit, Science Media Centre España reports.
Why it matters
Lp(a) has long been treated as a promising target. Genetic studies indicated that people born with elevated levels face a higher risk of heart attack, which fuelled expectations that a drug capable of sharply reducing the molecule would translate into fewer events. The trial's design was sound by conventional standards — a large sample, a placebo comparison and long follow-up — which makes the null result difficult to attribute to weak methodology.
The outcome is a setback for the specific hypothesis that lowering Lp(a) in patients with established cardiovascular disease delivers clinical benefit. According to Science Media Centre España, the findings caught researchers by surprise, though the outlet notes that medicine has seen similar reversals before.
A question of timing and damaged arteries
One explanation offered in the Science Media Centre España analysis is that lifelong exposure and late-life intervention are not equivalent. Being born with high Lp(a) and carrying it for decades is a different proposition from reducing it with a drug at around age 60, when atherosclerotic plaque has already formed and arterial damage is established. In that view, genetics is more useful for identifying who is at risk than for proving that a treatment will work.
The outlet's expert commentary also stressed that the result applies to a specific population: patients who had already suffered a cardiovascular event and who were otherwise well treated. It cannot be extended to younger or healthy people. Five years may also be too short a window for a biological effect that operates across a lifetime.
Several other caveats were raised. The composite endpoint included some less severe events, such as urgent catheterisations. It is not yet known how many participants stopped taking the monthly injection. And the trial does not answer whether the drug might help with aortic stenosis, a separate condition also linked to Lp(a).
What the result does not settle
The safety profile looked favourable. Serious adverse events were, if anything, slightly less frequent with pelacarsen than with placebo, according to Science Media Centre España.
The outlet also noted that only the summary has been available so far, and that the full paper still needs to be read closely. Other Lp(a)-lowering drugs remain in development, including trials in people without prior cardiovascular events who are not taking statins and who have higher cholesterol levels. Results in that group could differ. If a benefit does emerge there, the next step would be direct comparison against statins.
For now, the practical advice offered is unchanged: measuring Lp(a) once in a lifetime remains useful for identifying people at higher risk, and for those individuals the priority is lowering LDL cholesterol further, since that is the approach with established evidence.
The commentary accompanying the results came with a disclosure of consultancy, speaking engagements and research projects involving Novartis, Amgen, Lilly, Novo Nordisk, AstraZeneca, Boehringer-Ingelheim and Bayer.
Watch for the full NEJM paper and for readouts from the ongoing trials in healthier, statin-naive populations, which will determine whether Lp(a) lowering has a future as a prevention strategy rather than a treatment for established disease.
