Bempedoic Acid

Bempedoic acid is a novel, oral small molecule that reduces atherogenic lipids via a dual-hepatic mechanism of action that is distinct from that of statins. Once absorbed, it is converted to bempedoyl-CoA by the liver-specific enzyme ACSVL1, which directly inhibits ATP-citrate lyase (ACLY), the enzyme responsible for providing cytosolic acetyl-CoA for de-novo cholesterol and fatty-acid synthesis. The hepatic conversion step simultaneously releases free Bempedoic acid, which allosterically activates AMP-activated protein kinase (AMPK). ACLY blockade reduces the availability of substrates for HMG-CoA reductase, resulting in robust up-regulation of LDL receptors and an ≈30 % LDL-C reduction, while AMPK activation leads to suppression of gluconeogenic enzymes (PEPCK, G6Pase) and lipogenic enzymes (ACC, HMGR), resulting in improved insulin sensitivity and inhibition of inflammation. Because ACSVL1 is not expressed in skeletal muscle, the drug cannot be activated in that tissue and therefore avoids the myotoxicity that limits the use of statins.
Bempedoic acid has shown additive efficacy in clinical development: 45 % LDL-C lowering when combined with ezetimibe and an extra 15 % on top of maximally tolerated statins; triglycerides are reduced by 15 % and hs-CRP by 20–30 %. The benefits were preserved in people with type 2 diabetes, among whom Bempedoic acid modestly reduced HbA1c and with whom it was associated with 32 % lower odds of new-onset or worsening diabetes versus placebo. In pre-clinical models, there was reduced hepatic steatosis, less aortic cholesterol deposition, and smaller atherosclerotic plaques, suggesting potential utility in NAFLD/NASH and ASCVD prevention.

Fig. 1 Mechanisms of action of Bempedoic Acid. (Biolo G.; et al. 2022)

Liu Y et al. reported a novel local drug delivery system to tackle the low water solubility and bioavailability of bempedoic acid (BPA) in the treatment of periodontitis. BPA was loaded into Tween80-based micelles, and the mechanism of micelle self-assembly was illustrated by molecular dynamics (MD) simulations, which presented a core–shell structure that can dramatically increase the dispersity and stability of BPA. The drug-loaded micelles were further embedded in thermosensitive chitosan/β-glycerophosphate/gelatin hydrogel (BPA@Gel).
Comprehensive characterization has proven that this composite hydrogel is injectable, can undergo fast thermosensitive gelation, is porous in structure, is degradable with controllable degradation, and can provide sustained drug release. Animal experiments have verified that local injection of BPA@Gel can relieve periodontal inflammation and inhibit the destruction of alveolar bone. This micelle–hydrogel composite can achieve the localized and sustained release of hydrophobic BPA and shows great promise for potential clinical applications in periodontitis therapy.

Fig. 2 Micelle–hydrogel composite for controlled Bempedoic Acid delivery. (Liu Y.; et al. 2025)