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About one in five people worldwide has a lipoprotein(a) level above 50 mg/dl, an estimated 1.4 billion people according to the authors. The level is largely genetically determined, and diet, exercise or statins barely change it. Genetic and epidemiological studies suggest high Lp(a) contributes causally to atherosclerosis and aortic valve stenosis. The obvious question: does targeted lowering prevent heart attacks and strokes?
Lp(a)HORIZON is the first large outcomes trial to test this. The results are now published in the New England Journal of Medicine.
Study design
Pelacarsen is an antisense oligonucleotide inhibiting hepatic production of apolipoprotein(a). The double-blind, placebo-controlled trial ran at 797 sites in 42 countries. Patients aged 18 to 80 qualified with a myocardial infarction, ischaemic stroke or symptomatic peripheral artery disease between 3 months and 10 years earlier and an Lp(a) of at least 70 mg/dl. Before randomisation, secondary prevention was optimised according to guidelines over 30 to 90 days. Patients then received 80 mg pelacarsen subcutaneously or placebo every month.
The primary endpoint was the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or urgent coronary revascularisation. The subgroup with Lp(a) of 90 mg/dl or higher was analysed separately.
8322 patients were analysed. Mean age was 59.7 years, 27.0% were women and 76.6% had a prior myocardial infarction. Median Lp(a) was 236 nmol/l. Risk factors were well controlled: median LDL 64.6 mg/dl, mean systolic blood pressure 125 mmHg, and 77.6% were on high-intensity statin therapy.
Results
Pelacarsen lowered Lp(a) as planned. At 12 months, the median was 64.4 nmol/l versus 233.4 nmol/l on placebo, a reduction of 78.4% versus 3.2%. Averaged over the entire trial, the reduction was 73.9%. LDL fell by an additional 11.3 percentage points compared with placebo.
There was no clinical benefit. After a median of 4.7 years, the primary endpoint occurred in 511 patients (12.3%) on pelacarsen and 503 patients (12.1%) on placebo. The hazard ratio was 1.02 (95% CI 0.90 to 1.15, p = 0.76). In the subgroup at 90 mg/dl or above, the rate was 12.3% in both groups (HR 1.00, 95% CI 0.87 to 1.15). Narrower endpoints, individual components and all-cause death (5.7% vs 5.9%) did not differ either. No prespecified subgroup showed a difference.
Safety
Serious adverse events were less frequent on pelacarsen (37.3% vs 41.1%). Milder side effects were much more common. Influenza-like reactions occurred in 31.9% versus 5.8%, injection-site reactions in 25.6% versus 2.9%. 20.6% versus 7.5% permanently stopped treatment because of adverse events. Anaphylaxis was confirmed in 19 patients on pelacarsen and none on placebo. Eight hypersensitivity reactions led to hospitalisation, none were fatal. After a suspected case in March 2023, injections had to be given under medical supervision for six months.
How the authors interpret the result
The authors offer two explanations. First, genetic studies describe lifelong low Lp(a), whereas the trial lowered it for a few years. The two are not equivalent. Second, LDL and blood pressure were far better controlled than in the genetic cohorts. With such strong background therapy, little room may remain for an additional effect. The authors do not consider the COVID-19 pandemic responsible, since Lp(a) lowering matched expectations from the phase 2 trial.
Limitations
Patients were mostly male and White. With 35.1%, almost twice as many patients stopped pelacarsen early as stopped placebo (18.3%). This shortens actual treatment exposure and may bias the result. Only secondary prevention was studied, not patients without a prior event or immediately after acute coronary syndrome. The manufacturer funded the trial and designed it together with an academic research centre. Five authors are employees of the manufacturer.
What comes next
Further Lp(a)-lowering agents are in phase 3 outcome trials. They lower Lp(a) more, by over 90% or about 85%, enrol patients with higher baseline levels and in part also test primary prevention. Whether they reach a different result is open.
What this means for practice
Lp(a)HORIZON is a clear negative result from a large trial with complete follow-up.
- Elevated Lp(a) remains a risk marker. This trial does not show lowering it prevents events.
- A lower lab value is not a lower risk. A reduction of almost 80% makes this plain.
- In patients with high Lp(a), consistent control of the other risk factors remains what is proven to help.
I am happy to discuss how you handle elevated Lp(a) in your patients on LinkedIn.
Source: Cho L, Nicholls SJ, Frndak S, et al., Nissen SE, for the Lp(a)HORIZON Investigators. Pelacarsen and Cardiovascular Outcomes in Patients with High Lipoprotein(a). N Engl J Med, online 7 Nov 2026. doi:10.1056/NEJMoa2610159. ClinicalTrials.gov NCT04023552.
Source: DOI: 10.1056/NEJMoa2610159 · Original article