Lp(a) After Lp(a)HORIZON: From Causal Biomarker to Unproven Therapeutic Target

The first major Lp(a)-lowering outcomes trial fails its primary endpoint, and the entire class — olpasiran, lepodisiran, zerlasiran, muvalaplin — must now answer a harder question than it expected.

By Peter A. McCullough, MD, MPH

Measurement of lipoprotein (a) is standard of care in clinical lipidology. For decades we have been waiting for drugs that can effectively lower rates of this independent risk factor for atherosclerotic cardiovascular disease.

🧬 The Pelacarsen Paradox: When Lowering a Risk Factor Fails to Lower Risk

September 13, 2026. In a result that will reshape clinical lipidology for a decade, Novartis announced on September 4 that its flagship antisense oligonucleotide (ASO), pelacarsen, failed to meet its primary endpoint in the pivotal Lp(a)HORIZON trial. Across more than 8,300 patients with elevated Lp(a) and established cardiovascular disease, pelacarsen did lower lipoprotein(a) — potently, and as designed — but that reduction did not translate into fewer heart attacks, strokes, cardiovascular deaths, or urgent revascularizations.