Cutting-edge lipid-lowering pharmacological therapies: Improving lipid control beyond statins

Abstract

Statins are crucial for both the prevention and management of atherosclerotic cardiovascular disease (ASCVD). However, even with optimized statin therapy, a significant residual risk of ASCVD remains, highlighting the need for innovative approaches to lipid-lowering therapies (LLT) that more effectively target low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins. Recently, novel pharmacologic agents have been introduced for the management of dyslipidemia. Bempedoic acid, an inhibitor of ATP citrate lyase, has emerged as a promising alternative for patients who exhibit statin intolerance. Moreover, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have transformed the management of hypercholesterolemia by reducing LDL-C levels. PCSK9 is a protein that mediates LDL receptor degradation; its inhibition enhances LDL receptor recycling, facilitating increased LDL-C uptake. New antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have demonstrated significant reductions in these molecules, offering potential therapeutic advantages for certain dyslipidemias. Ongoing research is also evaluating apolipoprotein A1 (apoA1) to leverage the protective effects of high-density lipoprotein cholesterol (HDL-C), though conclusive clinical evidence is still required. This review examines the mechanisms and clinical efficacy of emerging LLT other than statins, focusing on bempedoic acid and PCSK9 inhibitors. Bempedoic acid acts upstream in the cholesterol biosynthesis pathway, offering a potentially safer option for patients intolerant to statins. PCSK9 inhibitors enhance LDL receptor recycling, significantly lowering LDL-C levels and reducing cardiovascular risk. A deeper understanding of these mechanisms is essential for the advancement of therapeutic strategies in dyslipidemia and cardiovascular disease management.