Don't Miss a Beat: What Lp(a)HORIZON and ZEUS Teach About Clinical Trial Science

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Topline announcements had set expectations heading into the American Heart Association (AHA) Scientific Sessions 2026, and the full Lp(a)HORIZON and ZEUS data presented in Chicago filled in the rest of the story. Pelacarsen and ziltivekimab each lowered their targets, lipoprotein(a) [Lp(a)] and interleukin-6 (IL-6), by wide margins, yet neither reduced major adverse cardiovascular events (MACE) in atherosclerotic cardiovascular disease (ASCVD).

On a recent episode of Don't Miss a Beat, hosts Stephen Greene, MD, of Duke University School of Medicine, and Muthiah Vaduganathan, MD, MPH, of Brigham and Women's Hospital, discussed both trials from Chicago. Their conversation centered on why well-designed studies built on decades of genetic and epidemiologic evidence fell short.

Lp(a)HORIZON randomized 8350 patients with established ASCVD and an Lp(a) level of at least 70 mg/dL to monthly pelacarsen 80 mg or placebo.¹ ZEUS randomized 6376 patients with ASCVD, chronic kidney disease (CKD), and a high-sensitivity C-reactive protein (hsCRP) level of at least 2 mg/L to monthly ziltivekimab 15 mg or placebo.²

Each agent lowered its target by roughly 70% to 80%, yet MACE was unchanged with pelacarsen (HR, 1.02; 95% CI, 0.90-1.15; P = .76) and ziltivekimab (HR, 0.99; 95% CI, 0.88-1.11; P = .84).^1,2 On-treatment and achieved-level analyses also showed no benefit, ruling out drug discontinuation as the explanation. Serious infections were modestly more frequent with ziltivekimab (20.4% vs 17.9%), though not enough to offset meaningful benefit.²

Several hypotheses may explain the disconnect. Mendelian randomization data reflect lifelong low exposure from birth, whereas these trials intervened late in life, in patients with established disease already on statins and other standard therapies.

Potent LDL cholesterol lowering may also saturate a final common atherosclerotic pathway, limiting further gains from Lp(a) reduction. In ZEUS, CKD-driven, nonatherosclerotic mechanisms may have dominated residual risk, and the degree of lowering needed for clinical benefit remains unknown.

Ongoing programs should help separate population effects from drug effects. Ziltivekimab trials in heart failure with preserved ejection fraction, HERMES and ATHENA, were stopped early, while ARTEMIS continues to test the agent soon after acute myocardial infarction, when inflammation peaks. Additional Lp(a)-lowering agents are being tested in lower-risk primary prevention populations.

Collectively, the results deliver definitive answers at the tested doses and degrees of target engagement, unlike the borderline or underpowered findings common in cardiovascular research. With positive signals from CANTOS and colchicine trials still standing, success in both pathways will likely hinge on precise selection of patients, timing, and magnitude of lowering.

References

1. Cho L, Nicholls SJ, Frndak S, et al. Pelacarsen and cardiovascular outcomes in patients with high lipoprotein(a). N Engl J Med. Published online November 7, 2026. doi:10.1056/NEJMoa2610159

2. Ridker PM, Lincoff AM, Marx N, et al. Interleukin-6 inhibition with ziltivekimab for atherosclerotic disease. N Engl J Med. Published online November 7, 2026. doi:10.1056/NEJMoa2612126