Innovative Lipid-Lowering Strategies: RNA-Based, Small Molecule, and Protein-Based Therapies

Dyslipidemia remains a central modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, as well as ezetimibe, fibrates, and omega-3 fatty acids have established roles in lipid lowering, significant residual risk persists in many patients due to insufficient low-density lipoprotein cholesterol (LDL-C) reduction, elevated triglyceride-rich lipoproteins, and genetically determined elevations of lipoprotein(a) (Lp(a)). Recent years have witnessed remarkable advances in therapeutic modalities, including next-generation small molecules, monoclonal antibodies, protein-based infusions, and ribonucleic acid (RNA)-based strategies. These agents target diverse pathways such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C-III, apolipoprotein B, cholesteryl ester transfer protein (CETP), and Lp(a), achieving potent lipid modulation with improved convenience and safety. Clinical outcome trials have validated bempedoic acid, PCSK9 inhibitors, and icosapent ethyl, while large-scale programs are ongoing for obicetrapib, oral PCSK9 inhibitors, Lp(a)-targeted oligonucleotides, and ANGPTL3-directed RNA therapeutics. This review summarizes the mechanisms, pivotal trials, and clinical implications of innovative lipid-lowering therapies, highlighting how they may reshape future treatment algorithms for ASCVD prevention.