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In the phase III Lp(a) HORIZON trial, monthly pelacarsen substantially lowered lipoprotein(a) but did not reduce the main cardiovascular event outcome compared with placebo. The finding challenges the case for pelacarsen in this secondary-prevention population, while leaving open whether other drugs or patient groups may benefit.
The phase III Lp(a) HORIZON trial found that pelacarsen did not reduce major cardiovascular events among people with high lipoprotein(a) and existing cardiovascular disease, despite sharply lowering the particle. Steven Nissen of Cleveland Clinic presented the results at the American Heart Association’s annual meeting in Chicago, raising questions about pelacarsen as a secondary-prevention treatment while leaving the broader Lp(a)-lowering approach unresolved.
Among 8,350 participants, the primary outcome—cardiovascular death, nonfatal stroke, nonfatal heart attack or urgent coronary revascularization—occurred at a rate that showed no meaningful difference between pelacarsen and placebo over a median 57 months. The hazard ratio was 1.02 (95% confidence interval 0.90 to 1.15). The estimate is consistent with no treatment effect; the confidence interval also means the trial result does not establish that the treatments are exactly equivalent.
Pelacarsen reduced Lp(a) by an estimated 77.7% relative to placebo and also lowered LDL cholesterol by 13.3%. Yet analyses of participants with Lp(a) of at least 90 mg/dL, as well as several alternative composite outcomes and individual events, also showed no efficacy, according to the report. Exploratory analyses accounting for adherence, adverse events and the size of early Lp(a) reductions did not change the overall finding.
Tolerability was another concern: adverse events leading to treatment discontinuation occurred in 20.6% of the pelacarsen group, compared with 7.5% of those given placebo, Nissen said. The study enrolled people whose prior cardiovascular event had occurred three months to 10 years before enrollment; all had Lp(a) levels of at least 70 mg/dL. Participants received monthly injections alongside optimized prevention care.
A Large Lp(a) Drop, No Event Benefit
The result highlights a distinction between changing a biological marker and preventing illness. Pelacarsen produced a large reduction in Lp(a), but the trial did not show fewer cardiovascular events in this population over the follow-up period. That makes the clinical benefit of this particular drug and regimen uncertain, despite the clear effect on the measured particle.
The findings matter to patients and clinicians because elevated Lp(a) is inherited and is not generally lowered through diet or exercise, unlike some other cardiovascular risk factors. But the study does not establish that lowering Lp(a) can never reduce risk. It tests one therapy in people with established disease, already receiving substantial preventive treatment; other drugs, populations and durations may yield different results.
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What HORIZON Tested
Lipoprotein(a) is a genetically influenced blood particle associated with atherosclerotic cardiovascular disease and aortic stenosis. The source report estimates that about one in five people worldwide has elevated Lp(a). Association with disease risk, however, does not by itself prove that lowering the particle with a specific drug will prevent events.
Pelacarsen is an antisense oligonucleotide designed to reduce production of apolipoprotein(a) in the liver. In HORIZON, 8,350 people were assigned in equal proportions to monthly 80-mg pelacarsen or placebo. The trial ran across nearly 800 sites in 42 countries. Participants entered after a cardiovascular event and first went through a period intended to optimize standard risk-factor treatment; median baseline LDL cholesterol was 64.6 mg/dL, and average systolic blood pressure was 125 mmHg.
Most participants were taking high-intensity statins. The cohort’s mean age was just under 60, 27% were women, and 78% were White. These details frame how broadly the findings can be applied: they describe a selected secondary-prevention group rather than all people with elevated Lp(a).
“A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a) as a strategy to reduce cardiovascular risk.”
— Steven Nissen, Cleveland Clinic
What the Trial Cannot Settle
The findings do not establish why the substantial Lp(a) reduction failed to translate into a detectable outcome benefit. The report raises the possibility that well-controlled LDL cholesterol and blood pressure, the study population, treatment duration or the drug’s properties could matter, but none is established as the explanation. The trial’s confidence interval also leaves room for a modest benefit or harm that the study did not clearly distinguish.
It remains unknown whether younger people, patients without prior cardiovascular events, people with aortic stenosis, or recipients of different Lp(a)-lowering drugs would have different outcomes. The reported discontinuation rate also does not, by itself, identify which adverse effects drove participants to stop treatment. The supplied report says the trial was published simultaneously, but provides no journal citation or additional publication details.
Other Lp(a) Drugs Under Study
Attention is shifting to other therapies, including the small-interfering RNA drugs lepodisiran and olpasiran, which the report says are advancing to large cardiovascular-outcome trials. Nissen said siRNA treatments may be more tolerable, more effective and require less frequent administration, but those are expectations rather than proven clinical advantages; outcomes data are needed.
Further results from trials involving different patient groups and treatment strategies will help determine whether the HORIZON outcome applies beyond pelacarsen in secondary prevention. Lloyd-Jones also pointed to research on the biology of Lp(a) and the possibility that reductions from PCSK9 monoclonal antibodies may contribute to their cardiovascular effects. For now, the HORIZON result is a negative outcome finding for pelacarsen in the population studied—not a final answer on the entire Lp(a) hypothesis.
Key Questions
Did pelacarsen lower Lp(a) in the trial?
Yes. Pelacarsen reduced Lp(a) by an estimated 77.7% relative to placebo, but the trial did not find a reduction in its primary cardiovascular outcome.
What was the primary outcome?
It combined cardiovascular death, nonfatal stroke, nonfatal heart attack and urgent coronary revascularization. The comparison between pelacarsen and placebo produced a hazard ratio of 1.02 (95% CI 0.90 to 1.15).
Does this prove that lowering Lp(a) cannot prevent heart disease?
No. The result applies to pelacarsen in the trial’s secondary-prevention population. Researchers say studies of other drugs and populations are needed before drawing conclusions about Lp(a)-lowering as a broader strategy.
What other treatments are being tested?
The report identifies the siRNA therapies lepodisiran and olpasiran as advancing to large cardiovascular-outcome trials. Whether they improve clinical outcomes remains to be shown.
Source: medpagetoday.com
