The Lp(a) HORIZON trial, a 7-year, phase III, multicenter, international study, has delivered a sobering result: pelacarsen, a novel medication, lowered Lp(a) levels by an average of 78% in adults with established cardiovascular disease, yet it did not reduce the time to major adverse cardiovascular events (MACE), including nonfatal heart attack, stroke, urgent revascularization, or cardiovascular death. The findings, presented at the American Heart Association’s Scientific Sessions 2026 and simultaneously published in The New England Journal of Medicine and NEJM Evidence, challenge the assumption that lowering Lp(a) alone translates into better cardiovascular outcomes.
More than 8,300 adults with cardiovascular disease and Lp(a) levels ≥70 mg/dL across 42 countries were enrolled. Participants received monthly injections of pelacarsen or placebo. Despite the dramatic reduction in Lp(a), the trial found no difference in MACE across the primary group or subgroups, including those with Lp(a) ≥90 mg/dL. “I cannot avoid the disappointing conclusion – it didn’t work,” said Steven E. Nissen, M.D., senior author and chief academic officer of the Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic. “The neutral finding was unexpected and surprising to the medical community.”
The results carry significant implications for patients and clinicians. Lp(a) is a genetically determined form of cholesterol that affects about 1 in 5 people globally, and high levels are associated with a 1.4-fold increased long-term risk of heart attack or stroke. The 2026 multi-society guideline on the management of dyslipidemia recommends that Lp(a) be measured at least once in adulthood. Nissen emphasized that measuring Lp(a) remains worthwhile: “Lp(a) is an important risk factor for CVD, and high levels usually do not present with any symptoms. Lp(a) levels, along with blood pressure, cholesterol and blood sugar, are important measures that inform prevention and treatment options.”
Despite the neutral outcomes, researchers urge further investigation. “This does not mean Lp(a) is irrelevant. It means we need more in-depth research to understand the underlying mechanisms,” Nissen said. Three other cardiovascular outcome trials targeting Lp(a) with different compounds are underway, and their results, expected in the next few years, may provide a clearer picture. For now, the trial’s safety profile showed more flu-like symptoms, injection site reactions, and allergic reactions, including 19 cases of anaphylaxis in the pelacarsen group versus none with placebo; about 21% of pelacarsen patients stopped treatment due to adverse reactions.
The trial’s limitations include potential COVID-19-related cardiovascular events and a predominantly white participant pool (78%), underrepresenting groups such as people of African ancestry, who have higher average Lp(a) levels. The trial was funded by Novartis. Full details are available in the release link, and the abstract is accessible via the Scientific Sessions 2026 Online Program Planner. For more information on Lp(a) risks, visit What is lipoprotein (a) and how does it impact my heart health?. Additional resources are available at heart.org and stroke.org.
