Pelacarsen and Lp(a)HORIZON: Interpreting the Disconnect Between Lipoprotein(a) Lowering and Cardiovascular Outcomes.

Lipoprotein(a) [Lp(a)] is a genetically determined causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Pelacarsen, a hepatocyte-directed antisense oligonucleotide targeting apolipoprotein(a), was evaluated in Lp(a)HORIZON, the first large phase 3 cardiovascular outcomes trial specifically designed to test whether pharmacological Lp(a) lowering reduces cardiovascular events. Topline results announced in September 2026 indicated that pelacarsen lowered Lp(a) but did not reduce the primary composite cardiovascular endpoint in patients with established cardiovascular disease. Full trial data are awaited, and the mechanisms underlying this neutral result remain uncertain. We discuss potential explanations, including treatment after prolonged cumulative Lp(a) exposure, advanced vascular disease, intensive background prevention, the magnitude and duration of Lp(a) suppression, patient selection, baseline cardiovascular risk, and biological heterogeneity. We also examine implications for emerging therapies, including olpasiran, zerlasiran, lepodisiran, and muvalaplin, and for the design of ongoing cardiovascular outcome trials.