Phase 3 Lp(a)HORIZON cardiovascular outcome trial examined the safety and efficacy of pelacarsen in patients with elevated lipoprotein(a) and pre-existing cardiovascular disease
November 7, 2026 – Results from a landmark clinical trial led by Cleveland Clinic showed that the drug pelacarsen lowered lipoprotein(a), an important risk factor for heart disease, but did not reduce major adverse cardiovascular events after 4.7 years of follow up. The drug also caused mild side effects and rare allergic reactions.
Phase 3 of the Lp(a)HORIZON trial examined patients with existing heart disease who were already taking standard treatments.
The primary endpoint was the time until a patient’s first major cardiovascular event – defined as heart-related death, heart attack, stroke or urgent heart procedure needing hospitalization. The primary endpoint occurred in 12.3% of patients in the pelacarsen treatment group and 12.1% in the placebo group.
The results were presented today during a late-breaking science presentation at the American Heart Association’s Scientific Sessions 2026 in Chicago and were simultaneously published in the New England Journal of Medicine.
“Although the results are disappointing, neutral trials also provide scientific insights that help inform future research efforts,” said senior author Steven Nissen, M.D., Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic. “A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a) as a strategy to reduce cardiovascular risk.”
Lipoprotein(a), often shortened to Lp(a), has similarities to low-density lipoprotein (LDL) or “bad cholesterol.” Unlike other types of cholesterol particles, Lp(a) levels are 80-90% genetically determined.
The structure of the Lp(a) particle causes the accumulation of plaque in arteries and promotes clotting, which greatly increases the risk of heart attack and stroke.
Elevated Lp(a) is estimated to affect 64 million people in the United States and 1.4 billion people worldwide.
The double-blind, randomized, placebo-controlled trial involved patients from 797 sites in 42 countries and included patients 18 to 80 years old who had prior cardiovascular disease and a Lp(a) level of greater than or equal to 70 mg per deciliter. From December 2019 through July 2022, 8,322 patients were randomly assigned to receive pelacarsen 80 mg or matching placebo via a self-administered injection every month.
Patients were followed for a median of 57 months (4.7 years) for both treatment groups.
Established cardiovascular disease was defined as a prior heart attack or a stroke occurring between 3 months and 10 years prior to enrollment, or symptomatic peripheral arterial disease. Patients received secondary prevention therapies before enrollment, including maximally tolerated lipid-lowering treatment according to local guidelines.
Key secondary endpoints included time to death from any cause and the change in Lp(a) levels after one year. The study also looked at two narrower combinations of heart events: one excluding urgent procedures and another focusing specifically on coronary-related heart events instead of stroke.
The reduction from baseline in Lp(a) after one year was 3.2% in the placebo group and 78.4% in the pelacarsen group with an estimated treatment difference of 77.7% percentage points.
After one year, LDL (“bad”) cholesterol fell to 62.3 mg/dL with pelacarsen, but rose to 71.2 mg/dL with the placebo. Overall, pelacarsen lowered LDL by 13.3 percentage points compared to placebo.
Serious adverse events occurred in 37.3% of patients in the pelacarsen group and in 41.1% of the placebo group. Adverse events were more common in the pelacarsen group, including flu-like symptoms, injection site reactions and other events that led to permanent study drug discontinuation.
“The HORIZON trial is not the end of the story,” added Dr. Nissen. “Ongoing trials are studying different populations, such as primary prevention or aortic stenosis, and different therapies such as small interfering RNA (siRNA) that silences specific genes by breaking down complementary messenger RNA. We look forward to their results.”
The study was funded by Novartis Pharmaceuticals Corporation.
Dr. Nissen has served as a consultant for many pharmaceutical companies and has overseen recent clinical trials for Novartis Pharmaceuticals Corporation. However, he does not accept honoraria, consulting fees or other compensation from commercial entities.
About Cleveland Clinic
Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation, Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. Cleveland Clinic is consistently recognized in the U.S. and throughout the world for its expertise and care. Among Cleveland Clinic’s 83,000 employees worldwide are more than 6,600 salaried physicians and researchers, and 21,900 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,725-bed health system that includes a 173-acre main campus near downtown Cleveland, 23 hospitals, 300 outpatient facilities, including locations in northeast Ohio; Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2025, there were 15.9 million outpatient encounters, 343,000 hospital admissions and observations, and 336,000 surgeries and procedures throughout Cleveland Clinic’s health system. Visit us at clevelandclinic.org. Follow us at x.com/CleClinicNews. News and resources are available at newsroom.clevelandclinic.org.
