Nonstatins for LDL-C lowering: An expansion whose time has come

The 2026 American College of Cardiology/American Heart Association/Multisociety Dyslipidemia Guideline marks a defining moment for lipidology with the reinstatement of low-density lipoprotein cholesterol (LDL‑C) and non-high-density lipoprotein cholesterol treatment goals and a decisive endorsement of combination lipid‑lowering therapy. Although statins remain foundational, statin monotherapy often fails to achieve sufficient LDL‑C lowering, particularly in high-risk patients or patients with statin intolerance or refusal. These realities elevate nonstatin therapies from secondary considerations to core components of evidence‑based care. This commentary reviews the expanded role of currently available nonstatin agents across all guideline‑defined treatment groups. New outcomes data further strengthen the rationale for greater LDL‑C reduction in high‑risk primary prevention populations and reinforce the "lower is better" principle central to lipidology. Finally, we explore the rapidly evolving pipeline of next‑generation LDL‑C-lowering therapies, including long‑acting injectables and oral proprotein convertase subtilisin/kexin type 9 inhibitors, that promise to further individualize care and address longstanding barriers to adherence and goal attainment. These advances underscore a new lipid‑lowering paradigm that includes combination therapy to achieve and sustain optimal LDL‑C levels and meaningfully reduce atherosclerotic cardiovascular disease risk.