Novel therapies for lowering low-density lipoprotein levels for atherosclerotic cardiovascular disease prevention: reaching the target where others have failed.

Introduction: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of global morbidity and mortality, with elevated low-density lipoprotein cholesterol (LDL-C) established as a primary causal factor. Despite foundational therapies, many high-risk patients fail to achieve optimal LDL-C targets.

Areas covered: This review examines established LDL-C lowering agents (statins and ezetimibe), detailing their mechanisms and limitations, including statin intolerance and residual cardiovascular risk. We provide a comprehensive analysis of novel therapeutic options, including proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators (monoclonal antibodies, small interfering RNA, and emerging oral agents), ATP-citrate lyase inhibitors (bempedoic acid), angiopoietin-like protein 3 (ANGPTL3) inhibitors, and pioneering gene-editing technologies. We discuss mechanisms of action, pivotal efficacy data (LDL-C reduction and plaque modification), safety profiles, and key findings from major cardiovascular outcome trials.

Expert opinion: Novel LDL-C lowering therapies represent a paradigm shift, offering unprecedented efficacy in reducing LDL-C and mitigating ASCVD risk. However, significant challenges remain, including cost-effectiveness concerns, the need for long-term safety data, profound global disparities in access, and persistent clinical inertia that impedes real-world implementation even in well-resourced healthcare systems. Future research should prioritize personalized lipid management, combination strategies, and development of durable, cost-effective solutions to reduce the residual ASCVD burden.