Two late-breaking cardiovascular trial disclosures at the American Heart Association meeting underscored that biomarker movement is not translating into clinical event reduction. Novartis’ pelacarsen cut lipoprotein(a) levels substantially in the HORIZON phase 3 program, but failed to reduce heart attacks, strokes, urgent coronary revascularization, or deaths over nearly five years. Separately, Novo Nordisk’s ZEUS trial of the IL-6 pathway antibody ziltivekimab lowered IL-6, but did not improve rates of heart attacks, strokes, or deaths versus placebo. Both results compound recent setbacks in the field where genetically or inflammatoryly guided hypotheses have not delivered the hoped-for outcomes.