Lipid-lowering therapy: Evidence and future perspective

Abstract

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of atherosclerotic cardiovascular disease (ASCVD) prevention, with robust evidence supporting the principle that “the lower, the better,” particularly in secondary prevention. Contemporary guidelines recommend intensive LDL-C lowering to <70 mg/dL in high-risk patients and <55 mg/dL in very high-risk populations, including those with acute coronary syndrome and familial hypercholesterolemia. In addition to statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, including monoclonal antibodies and small interfering RNA, have emerged as highly effective therapies, demonstrating substantial LDL-C reduction and cardiovascular event risk reduction, as exemplified by the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial. Patients with peripheral arterial disease, including lower extremity arteriosclerosis obliterans, represent a particularly high-risk population in whom PCSK9 inhibition provides marked absolute risk reduction. Despite intensive LDL-C lowering, considerable residual cardiovascular risk persists. Accumulating evidence indicates that elevated triglyceride (TG) levels are independently associated with cardiovascular events. However, clinical trials targeting TG reduction, including fibrate-based therapies such as pemafibrate, have not consistently demonstrated cardiovascular benefit, highlighting the complexity of lipid metabolism and the limitations of TG lowering alone. Lipoprotein(a) [Lp(a)] has recently gained recognition as a genetically determined, independent risk factor for ASCVD. Emerging antisense and RNA-targeted therapies have shown profound Lp(a)-lowering effects and are currently being evaluated in large-scale outcome trials. Future lipid management strategies will require a comprehensive approach that integrates LDL-C lowering, residual risk modification, and novel therapeutic targets such as Lp(a), with personalized risk stratification to optimize clinical benefit and cost-effectiveness.