Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome

Abstract

Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid and glucose metabolism as well as inflammation via downregulation of ATP-citrate lyase and upregulation of AMP-activated protein kinase (AMPK). The primary effect is the reduction of cholesterol synthesis in the liver and its administration is generally not associated to unwanted muscle effects. Suppression of hepatic fatty acid synthesis leads to decreased triglycerides and, possibly, improved non-alcoholic fatty liver disease. Bempedoic acid may decrease gluconeogenesis leading to improved insulin sensitivity, glucose metabolism, and metabolic syndrome. The anti-inflammatory action of bempedoic acid is mainly achieved via activation of AMPK pathway in the immune cells, leading to decreased plasma levels of C-reactive protein. Effects of bempedoic acid on atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been assessed in randomized clinical trials but require further confirmation. Safety clinical trials in phase III indicate that bempedoic acid administration is generally well-tolerated in combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to achieve low-density lipoprotein cholesterol targets. The aim of this narrative review on bempedoic acid is to explore the underlying mechanisms of action and potential clinical targets, present existing evidence from clinical trials, and describe practical management of patients.

Bempedoic acid: new evidence and recommendations on use

“…About 70% of bempedoic acid and its active form bempedoil – CoA is conjugated with glucuronic acid and cleared via renal system. Residual 30% of bempedoic acid and bempedoil – CoA are secreted through liver [26].…”

“…Although there is no need for adjustment of a daily dose of bempedoic acid for those who suffer from mild or moderate impairment of liver function, physicians are advised not to prescribe bempedoic acid to patients with known severe liver impairment. Dose adjustment for patients with chronic kidney disease is not needed and, irrespective of the degree of impairment, bempedoic acid is well tolerated [19,26,52]. In the pooled analysis that included 3619 patients who were divided in three subgroups depending on the level of kidney impairment adverse effects, levels of creatinine and reduction of LDL cholesterol were similar in each group [53].…”

Comparison of colorimetric, fluorometric, and liquid chromatography-mass spectrometry assays for acetyl-coenzyme A

“…Consequently, acetyl-CoA is an important biological molecule to consider when evaluating the metabolic and energetic status of cells. Acetyl-CoA metabolism constitutes a drug target actively under investigation for multiple diseases including one approved drug (bempedoic acid) for cholesterol and lipid reduction with demonstrated benefit [2]. Therefore, sensitive and specific techniques for quantitating acetyl-CoA in various biological samples are of interest to researchers with diverse biological interests.…”

From common to rare: repurposing of bempedoic acid for the treatment of glycogen storage disease type 1

“…Bempedoic acid is a prodrug which has to be activated to bempedoyl-CoA catalysed by very long-chain acyl-CoA synthase 1 (ACSVL1). This enzyme is present in the liver and to a lesser extent in kidney [7,8]. Therefore, substantial concentrations of the active drug can only be found in the liver and kidney.…”

“…In dyslipidaemias, BA is safe, and mild elevations of uric acid were observed in some patients. Uric acid may rise slightly, as BA glucuronide competes with uric acid for the same renal transporter [7,8]. In most patients with dyslipidaemia, elevation of uric acid in blood is not critical.…”