What is the mechanism of Bempedoic acid?

Bempedoic acid is an emerging therapeutic agent that has garnered notable attention for its role in managing hypercholesterolemia. Understanding its mechanism of action is crucial for appreciating how it helps in lowering cholesterol levels and reducing cardiovascular risk. This blog delves into the biochemical and physiological pathways through which bempedoic acid exerts its effects.

Bempedoic acid is a prodrug, meaning it requires metabolic activation to become pharmacologically active. The journey of bempedoic acid begins in the liver, where it is converted to its active form, bempedoic acid-CoA, by the enzyme very-long-chain acyl-CoA synthetase 1 (ACSVL1). This conversion is a pivotal step, as it enables the drug to interact with its primary target.

Once activated, bempedoic acid-CoA inhibits the enzyme adenosine triphosphate-citrate lyase (ACL). ACL is a critical enzyme in the cholesterol biosynthesis pathway, situated upstream of the well-known HMG-CoA reductase, which is the target of statins. By inhibiting ACL, bempedoic acid reduces the production of acetyl-CoA, a substrate required for the synthesis of cholesterol. This inhibition leads to a reduced intracellular cholesterol pool in hepatocytes, prompting these cells to upregulate low-density lipoprotein (LDL) receptors on their surface.

The increased expression of LDL receptors enhances the clearance of LDL cholesterol from the bloodstream, mirroring the mechanism of action of statins but with a distinct point of intervention. This dual mechanism—decreasing cholesterol synthesis and increasing LDL clearance—results in significant reductions in blood cholesterol levels.

Moreover, bempedoic acid offers an advantage for patients who are statin-intolerant due to its liver-specific activation. Unlike statins, which can be activated in both liver and muscle tissues and thus may cause muscle-related side effects, bempedoic acid is selectively activated in the liver. This selective activation reduces the risk of muscle-related adverse effects, making it a suitable alternative for those who cannot tolerate statins.

Clinical trials have demonstrated the efficacy of bempedoic acid in lowering LDL cholesterol levels. When used alone or in combination with other lipid-lowering therapies, such as ezetimibe or statins, bempedoic acid has been shown to provide additional cholesterol-lowering benefits. This makes it a versatile option in the lipid management arsenal, especially for patients with high cardiovascular risk who require aggressive lipid lowering.

In conclusion, the mechanism of bempedoic acid involves its conversion to an active form in the liver, inhibition of ACL, reduction in cholesterol synthesis, and upregulation of LDL receptors, leading to enhanced clearance of LDL cholesterol from the bloodstream. Its liver-specific activation profile distinguishes it from statins, offering a promising alternative for patients with hypercholesterolemia, particularly those who are statin-intolerant. As research continues to evolve, bempedoic acid stands out as a noteworthy addition to the strategies aimed at reducing cardiovascular risk through effective cholesterol management.