Indications
Bempedoic acid is prescribed to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to tolerate statin therapy and have established cardiovascular disease, or are considered at high risk for cardiovascular events. It is also used as an adjunct to diet, with or without additional LDL-C lowering treatments, for reducing LDL-C levels in adults with primary hyperlipidemia, including those diagnosed with heterozygous familial hypercholesterolemia (HeFH). Additionally, bempedoic acid, in combination with ezetimibe, is indicated for similar purposes.
Pharmacodynamics
Bempedoic acid functions by inhibiting cholesterol synthesis in the liver, thereby lowering LDL-C levels. This action reduces the formation of atherosclerotic plaques, which are associated with an increased risk of cardiovascular events. Clinical trials have demonstrated that bempedoic acid results in a dose-dependent decrease in LDL-C levels, accompanied by a reduction in LDL particle number, apolipoprotein B, non-HDL cholesterol, and high-sensitivity C-reactive protein levels. Unlike statins, bempedoic acid does not cause myositis, a common adverse effect. Recent studies confirm the drug's effectiveness in significantly lowering LDL-C levels after 12 weeks of usage and achieving further reductions when combined with ezetimibe and statin therapy. However, the effects of bempedoic acid on overall mortality remain undetermined.
Absorption
Bempedoic acid is absorbed rapidly in the small intestine, with the peak plasma concentration (Tmax) of a 180 mg tablet occurring approximately 3.5 hours after ingestion.
Metabolism
Bempedoic acid is metabolized primarily into two metabolites: ETC-1002-CoA and ESP15228. The drug undergoes elimination through the metabolism of its acyl glucuronide. It is reversibly converted into the active metabolite ESP15228, as observed in in vitro studies. Both metabolites are further processed into inactive glucuronide conjugates by the enzyme UGT2B7.
Mechanism of Action
Bempedoic acid is a prodrug that requires metabolic activation in the liver, where it is converted to its active form, ETC-1002-CoA, by the enzyme very-long-chain acyl-CoA synthetase-1 (ACSVL1). The active metabolite ETC-1002-CoA exerts its effects by directly inhibiting ATP lyase, an essential component in the cholesterol biosynthesis pathway. This inhibition results in upregulation of the low-density lipoprotein (LDL) cholesterol receptors, enhancing the hepatic uptake and clearance of LDL cholesterol from the bloodstream. Consequently, bempedoic acid contributes to a reduction in circulating LDL cholesterol levels, thereby mitigating the risk of atherosclerosis and associated cardiovascular events. Additionally, in rodent studies, ETC-1002 has been observed to activate AMP-activated protein kinase (AMPK), which subsequently inhibits cholesterol synthesis through the suppression of HMG-CoA reductase activity. However, the significance of this effect in humans has yet to be determined.
