Nihon Yakurigaku Zasshi. 2026;161(5):395-406. doi: 10.1254/fpj.26059.
ABSTRACT
Bempedoic acid (Nexletol®) is a novel cholesterol-lowering agent that is converted to its active CoA ester by very long-chain acyl-CoA synthetase 1 (ACSVL1), an enzyme selectively expressed in hepatocytes. The active metabolite selectively inhibits ATP citrate lyase (ACL), leading to a reduction in cytosolic acetyl-CoA levels and subsequent activation of SREBP2. This results in increased expression of LDL receptors and enhanced clearance of LDL cholesterol (LDL-C). Because ACSVL1 is not expressed in skeletal muscle, bempedoic acid is not activated in muscle tissue and is therefore less likely to cause muscle-related toxicity. Nonclinical studies have demonstrated direct ACL inhibition, suppression of hepatic lipid synthesis, and LDL-C-lowering effects with attenuation of atherosclerotic lesion progression in multiple animal models. In domestic and international clinical studies, bempedoic acid reduced LDL-C levels in patients with elevated LDL-C, regardless of their response to statin therapy. The LDL-C-lowering effect was observed from the first scheduled assessment after treatment initiation. With respect to safety, no significant safety concerns requiring special consideration were identified, and bempedoic acid was generally well tolerated. In addition, an international Phase III trial in patients with hypercholesterolemia who were statin-intolerant and had established cardiovascular disease or were at high cardiovascular risk demonstrated that bempedoic acid not only reduced and sustained reductions in LDL-C levels but also significantly reduced the risk of cardiovascular events, the primary endpoint of the study.
PMID:42686560 | DOI:10.1254/fpj.26059