Pelacarsen slashes Lp(a) by 78% yet fails to cut heart attacks and strokes
The Lp(a) HORIZON trial found pelacarsen dramatically lowered lipoprotein(a) but did not reduce cardiovascular events, leaving hopes on next-gen siRNA drugs.
Summary
Lipoprotein(a), or Lp(a), is an inherited cholesterol-carrying particle that raises the risk of heart disease and aortic stenosis, and diet or exercise barely changes it. The Lp(a) HORIZON trial tested pelacarsen, an antisense drug that cuts Lp(a) production in the liver, in people with high Lp(a) and existing cardiovascular disease. Pelacarsen lowered Lp(a) by about 78% and LDL cholesterol by about 13%, yet over nearly five years it did not reduce the combined risk of cardiovascular death, stroke, heart attack, or urgent revascularization (HR 1.02). Results were also neutral in those with very high Lp(a). Discontinuation due to side effects was far higher on the drug (20.6% vs 7.5%). Researchers say this may end pelacarsen's road, but not the Lp(a) hypothesis. Trials in primary prevention, aortic stenosis, and with siRNA drugs continue.
Detailed Summary
Lipoprotein(a), or Lp(a), is a genetically determined, highly atherogenic particle that raises the risk of atherosclerotic cardiovascular disease and aortic stenosis. About one in five people worldwide has elevated levels. Unlike LDL cholesterol, Lp(a) is considered unmodifiable through diet or physical activity, which is why drugs that target it have drawn intense interest as a way to reduce inherited heart risk.
The Lp(a) HORIZON trial tested pelacarsen, an antisense oligonucleotide that degrades the liver mRNA coding for apolipoprotein(a), a key step in making Lp(a). Participants had elevated Lp(a) and established cardiovascular disease. Pelacarsen lowered Lp(a) by an estimated 77.7% and LDL cholesterol by 13.3% relative to placebo. Even so, over nearly five years it did not reduce the primary endpoint of cardiovascular death, nonfatal stroke, nonfatal heart attack, or urgent coronary revascularization (HR 1.02, 95% CI 0.90-1.15).
The neutral result held across analyses. In people with Lp(a) of 90 mg/dL or higher, the hazard ratio was 1.00. Modified composite endpoints and each individual outcome also showed no benefit. Tolerability was a problem: 20.6% of people on pelacarsen stopped treatment because of adverse events versus 7.5% on placebo.
Steven Nissen said this may be the end for pelacarsen, but not for the Lp(a) hypothesis. Donald Lloyd-Jones noted that participants already had well-optimized LDL (median 64.6 mg/dL) and blood pressure (125 mmHg), so little residual risk may have been left to remove. Ongoing trials are testing primary prevention, aortic stenosis, and several siRNA therapies, possibly in younger people and over longer periods.
Practically, the trial does not change the importance of controlling LDL cholesterol and blood pressure, and it does not justify dismissing Lp(a) as a risk marker. Caveats: this is one drug, one population, and a conference report; full peer-reviewed data are needed, and different drugs or earlier intervention might still show benefit.
Key Findings
- Pelacarsen cut Lp(a) by 77.7% and LDL cholesterol by 13.3% versus placebo in people with existing cardiovascular disease.
- The primary endpoint showed no benefit over nearly 5 years (HR 1.02, 95% CI 0.90-1.15).
- Patients with Lp(a) of 90 mg/dL or higher also saw no benefit (HR 1.00).
- Side effects led to discontinuation in 20.6% on pelacarsen versus 7.5% on placebo.
- siRNA drugs and primary prevention trials continue to test whether lowering Lp(a) can reduce cardiovascular risk.
Methodology
This is a news report on a late-breaking randomized, placebo-controlled trial presented at the AHA annual meeting, with commentary from the lead investigator and a panelist. MedPage Today is a reputable medical news outlet, but the evidence is from conference presentation, not a full peer-reviewed paper.
Study Limitations
The article is truncated and based on a conference presentation; full data on safety, subgroups, and statistical details need verification in the published paper. Results apply to pelacarsen in secondary prevention and may not extend to siRNA drugs, primary prevention, younger people, or longer follow-up.
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