New trial readouts at the American Heart Association Scientific Sessions add to a run of cardiovascular setbacks for risk-reduction approaches built on biomarker lowering. In the HORIZON Phase 3 program, pelacarsen (pelacarsen) sharply lowered lipoprotein(a) but did not reduce major heart outcomes over nearly five years. A second AHA-reported effort, the ZEUS study of ziltivekimab targeting IL-6, similarly reduced IL-6 levels without lowering heart attacks, strokes, or deaths compared with placebo. Novo Nordisk halted additional ziltivekimab trials HERMES and ATHENA after data monitoring committees signaled futility. Together, the results tighten the link between biomarker modulation and clinical benefit—showing that lowering Lp(a) or IL-6 alone was not sufficient to change event rates.