Lp(a) HORIZON Trial: Lp(a) Fell by 78%, but Cardiovascular Outcomes Unexpectedly Neutral

In an international trial of more than 8,300 adults with established cardiovascular disease and elevated Lp(a), pelacarsen reduced Lp(a) levels by 78% but did not reduce major adverse cardiovascular events after a median follow-up of 4.7 years, according to the trial’s findings. The primary endpoint occurred in 12.3% of the pelacarsen group versus 12.1% of the placebo group, a difference that was not statistically significant (HR=1.02; 95% CI, 0.9-1.15; P=.76).

The trial’s results were presented as a Late-Breaking Science presentation at the American Heart Association’s Scientific Sessions 2026, held Nov. 6-9 in Chicago, and simultaneously published in The New England Journal of Medicine. Extended analyses were published in NEJM Evidence. The study was funded by Novartis.

Among the 8,322 patients included in the efficacy analysis, the primary endpoint of major adverse cardiovascular events occurred in 12.3% of the pelacarsen group and 12.1% of the placebo group, a difference that was not statistically significant (HR=1.02; 95% CI, 0.9-1.15; P=.76).

At 12 months, average Lp(a) levels in the pelacarsen group dropped from 236 nmol/L at baseline to 64.4 nmol/L, a 77.7% reduction, according to data presented by the investigators. In the placebo group, levels remained steady at 233.4 nmol/L.

In a subgroup of patients with baseline Lp(a) of at least 90 mg/dL (192 nmol/L), the primary endpoint occurred in 12.3% of both groups (HR=1; 95% CI, 0.87-1.15; P=.99).

Extended analyses found no differences between the groups in the primary outcome under multiple circumstances, including heart attack, stroke or death from any cardiovascular cause; heart attack, urgent revascularization or death from coronary heart disease; change in Lp(a) from enrollment to one year; and death from any cause. The primary endpoint results did not vary by baseline Lp(a), LDL, high-sensitivity C-reactive protein or time between qualifying cardiovascular disease event and enrollment, according to the researchers.

“This was about as neutral a trial as a trial can get,” 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. “Nothing moved the needle: the main analysis, the subgroup analyses, the on-treatment analyses all showed no difference.”

The rate of serious adverse events was 37.3% in the pelacarsen group and 41.1% in the placebo group. The rate of adverse events leading to drug discontinuation was 20.6% in the pelacarsen group and 7.5% in the placebo group. Overall rates of drug discontinuation were 35.1% in the pelacarsen group and 18.3% in the placebo group.

Lp(a) is a form of cholesterol with characteristics similar to LDL cholesterol, including causing plaque buildup in arteries. Levels are largely genetically determined and remain stable over a lifetime. High Lp(a) (125 nmol/L or greater, or 55 mg/dL or higher) is associated with about a 1.4-fold increased long-term risk of heart attack or stroke, according to the American Heart Association. Lifestyle changes, such as exercise and improved diet, have little impact on Lp(a) levels, and neither do statins. There is currently no FDA-approved medication to lower Lp(a).

Nissen said the neutral finding was “unexpected and surprising to the medical community” but does not mean Lp(a) is irrelevant. He said the results provide scientific insights that will inform future research efforts and that measuring Lp(a) remains worthwhile.

“Right now, nothing changes,” Nissen said. “For all my patients, we’re still checking Lp(a) because we know it is a powerful, genetically predicted risk factor for coronary heart disease.”

Three other cardiovascular outcome trials are underway for other investigational compounds that target high Lp(a) in different ways than pelacarsen, according to Nissen. At least four other novel drugs targeting Lp(a) are expected to report results of cardiovascular outcome trials in the next few years.

“Ongoing trials are studying different populations, such as primary prevention and aortic stenosis, and different therapies, such as small interfering RNA,” Nissen said. “A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a) as a strategy to reduce cardiovascular risk.”

Nissen said he believes the olpasiran trial from Arrowhead and Amgen will be next to report results. “This is a different trial, a different drug with different tolerability and more potent Lp(a) lowering,” he said. “I think if that doesn’t work, then we need more serious conversations about what we’re doing with Lp(a), but I don’t think the story’s over.”

Nissen reports receiving institutional research grants from Arrowhead, AstraZeneca, CRISPR Therapeutics, Eli Lilly, Hygieia, Kalexo Bio, NewAmsterdam Pharmaceuticals, Novartis and Silence Pharmaceuticals, and consulting for Amgen. He does not accept personal compensation from drug and device companies.