Pierre Sabouret, Dario Mafrica, Domenico Mario Giamundo, Joanna Popiolek Kalisz, Elad Asher, Dan Atar, Giuseppe Ando
The 2026 ACC/AHA Multisociety Guideline marks a major shift in dyslipidemia management, extending the traditional LDL-C-centered approach to include non-HDL-C, ApoB, lipoprotein(a), triglyceride-rich lipoproteins, inherited lipid disorders, and severe hypertriglyceridemia. The introduction of PREVENT-ASCVD, the renewed use of explicit lipid targets, and the structured integration of risk enhancers and coronary artery calcium support a more individualized approach to cardiovascular prevention. This review critically examines the guideline's main innovations, with particular attention to the distinction between recommendations supported by cardiovascular outcome evidence and those relying mainly on observational data, surrogate endpoints, or extrapolation. It also compares the US framework with the 2025 ESC/EAS Focused Update, highlighting growing agreement on LDL-C goals but persistent differences in risk estimation, imaging, biomarkers, and treatment pathways. Finally, we discuss unresolved issues involving implementation, adherence, access, cost, health equity, inclisiran outcomes, and emerging lipoprotein(a)-lowering therapies. The guideline's impact will depend on translating greater precision into timely, feasible, and equitable care.