PELACARSEN lowered lipoprotein(a), a cholesterol-carrying particle, but did not reduce major cardiovascular events.
The international, randomized, placebo-controlled Lp(a)HORIZON trial evaluated whether lowering lipoprotein(a) with an antisense oligonucleotide could prevent major adverse cardiovascular events. Despite substantially lower lipoprotein(a) concentrations with pelacarsen, the primary cardiovascular outcome was similar between groups over a median follow-up of 4.7 years.
Investigators randomized 8,350 patients with preexisting cardiovascular disease and lipoprotein(a) levels of at least 70 mg/dL. Participants received monthly subcutaneous pelacarsen, 80 mg, or matching placebo. The efficacy analysis included 8,322 patients: 4,157 assigned to pelacarsen and 4,165 to placebo.
The mean age was 59.7 years, and 27.0% of participants were women. Median baseline lipoprotein(a) was 236 nmol/L.
At 12 months, lipoprotein(a) concentrations were 64.4 nmol/L in the pelacarsen group and 233.4 nmol/L in the placebo group. This biochemical separation did not translate into fewer primary endpoint events.
The primary endpoint combined cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization. Events occurred in 511 patients receiving pelacarsen (12.3%) and 503 receiving placebo (12.1%), yielding a hazard ratio of 1.02 (95% CI: 0.90–1.15; P=0.76).
Results were also neutral among participants with baseline lipoprotein(a) levels of at least 90 mg/dL. In this population, events occurred in 402 of 3,266 patients receiving pelacarsen and 403 of 3,274 receiving placebo, corresponding to 12.3% in both groups (hazard ratio: 1.00; 95% CI: 0.87–1.15; P=0.99).
Serious adverse events occurred in 1,553 of 4,166 patients receiving pelacarsen (37.3%) and 1,709 of 4,154 receiving placebo (41.1%). These overall frequencies do not establish a safety advantage or describe the distribution of individual adverse events.
For clinicians, the central finding is the separation between biomarker lowering and demonstrated cardiovascular benefit. Monthly pelacarsen reduced lipoprotein(a), but the trial did not demonstrate fewer major cardiovascular events in the population studied. The results do not support assuming that a lower lipoprotein(a) concentration achieved with this regimen translates into improved cardiovascular outcomes over the observed follow-up.
Reference
Cho L et al. Pelacarsen and cardiovascular outcomes in patients with high lipoprotein(a). N Engl J Med. 2026;doi:10.1056/NEJMoa2610159.
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