Perspectives on Bempedoic Acid, ATP-citrate lyase inhibitor: Targeting Lipid Metabolism and Inflammation.

Abstract

Bempedoic acid is a novel oral low-density lipoprotein cholesterol (LDL-C)-lowering agent that selectively inhibits ATP-citrate lyase (ACL), an enzyme located upstream of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Inhibition of ACL suppresses acetyl-CoA production, leading to reduced cholesterol synthesis and increased hepatic expression of LDL receptors, which lowers circulating LDL-C. Clinical trials have demonstrated an approximately 20% reduction in LDL-C when bempedoic acid is used in combination with statins. To offer a new perspective on the underlying mechanism, we reviewed the literature examining the LDL-C-lowering effects of bempedoic acid based on Michaelis-Menten kinetics. This framework helps explain why adding bempedoic acid to statin therapy may result in a synergistic increase in LDL-C reduction, greater than from increasing the statin dose alone. In animal studies, reductions observed in both hepatic and plasma triglyceride (TG) levels have been attributed to suppressed fatty acid synthesis due to decreased acetyl-CoA availability following ACL inhibition. Additionally, bempedoic acid has been shown to lower high-sensitivity C-reactive protein (hs-CRP) and inflammatory cytokines, suggesting potential anti-inflammatory and anti-lipotoxic effects. These findings support broader metabolic benefits of bempedoic acid, particularly in conditions such as obesity and fatty liver with hypercholesterolemia. In this review article, we outline the synergistic effects of bempedoic acid with statins, and its potential metabolic benefits based on the mechanism of action of bempedoic acid, and discuss its prospective role in future lipid management strategies.