The Lp(a) HORIZON trial, a 7-year, phase III, multicenter international study, has found that while the novel medication pelacarsen significantly lowered Lp(a) levels by an average of 78%, it did not reduce the time to major adverse cardiovascular events (MACE) in over 8,300 adults with established cardiovascular disease across 42 countries. The results were presented at the American Heart Association's Scientific Sessions 2026 and simultaneously published in The New England Journal of Medicine and NEJM Evidence.
Participants had Lp(a) levels of 70 mg/dL or higher and were randomized to receive monthly injections of pelacarsen (80 mg) or placebo. The primary outcome was a composite of nonfatal heart attack, stroke, urgent revascularization, or cardiovascular death. Despite the robust reduction in Lp(a), the trial found no difference in MACE between the pelacarsen and placebo groups, even in a subgroup with Lp(a) of 90 mg/dL or higher. Extended analyses of secondary endpoints, including all-cause death and other cardiovascular outcomes, were similarly neutral. "I cannot avoid the disappointing conclusion – it didn't work," said Steven E. Nissen, M.D., FAHA, senior author and chief academic officer of the Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic. "The neutral finding was unexpected and surprising to the medical community."
The trial enrolled 8,323 adults with a mean age of 60 years; 27% were women, and 26% had diabetes. Most participants were already on guideline-directed therapies, including high-intensity statins (77-78%) and antiplatelet medications. Pelacarsen, a small synthetic genetic material that blocks Lp(a) production in the liver, was associated with more adverse reactions than placebo, including flu-like symptoms, injection site reactions, and allergic reactions such as anaphylaxis (19 cases vs. none with placebo). About 21% of patients in the pelacarsen group discontinued treatment due to adverse reactions, compared to more than 7% in the placebo group.
The findings do not negate the importance of Lp(a) as a risk factor. High Lp(a) is a common independent risk factor for cardiovascular disease, as detailed in the 2026 multi-society guideline on the management of dyslipidemia, which recommends measuring Lp(a) at least once in adulthood. "Measuring Lp(a) is still absolutely worthwhile," Nissen said. "Lp(a) is an important risk factor for CVD, and high levels usually do not present with any symptoms." He emphasized that Lp(a) levels, along with blood pressure, cholesterol, and blood sugar, inform prevention and treatment options.
Lp(a) levels are largely genetically determined and remain stable over a lifetime. Lifestyle changes and statins have little impact on Lp(a). Currently, there is no FDA-approved medication to lower Lp(a). The trial had limitations, including that some cardiovascular events occurred during the COVID-19 pandemic and may have been COVID-related, and that 78% of participants self-identified as white, while less than 4% were of African ancestry, a group with average Lp(a) levels twice as high as white people. Future trials will need broader representation.
Three other cardiovascular outcome trials are underway for investigational compounds targeting high Lp(a) in different ways. "I am eager to see the results of those trials in the next few years," Nissen said. For now, the results underscore the need for continued research into Lp(a) mechanisms and its interactions with other risk factors. The trial was funded by Novartis. For more information on Lp(a) and its risks, see the American Heart Association's resources on what lipoprotein (a) is and how it impacts heart health.
