Nexletol (Bempedoic Acid) May be Better than Statins at Lowering Cholesterol

Bempedoic acid is a dicarboxylic acid that was demonstrated to inhibit fatty acid and cholesterol synthesis in experimental animals and these effects were correlated to reductions in plasma triglyceride and lipoprotein levels. Bempedoic acid is a pro-drug that is converted exclusively in the liver to its active CoA-derivative, bempedoyl-CoA. The CoA addition to bempedoic acid is catalyzed by the enzyme called very long-chain acyl-CoA synthetase-1 (ACSVL1) which is encoded by the SLC27A2 gene. The SLC27A2 gene is highly expressed in the liver but is not expressed in adipose tissue, the intestines, nor in skeletal muscle. The conversion of bempedoic acid to its CoA derivative is required for its ability to suppress fatty acid and cholesterol synthesis and to also stimulate mitochondrial fatty acid oxidation.

One of the targets of bempedoyl-CoA is the enzyme, ATP citrate lyase (ACL) that hydrolyzes citrate to acetyl-CoA and oxaloacetic acid. This is a major part of the pathway for the conversion of glucose carbons into those of fatty acids and those of cholesterol.

One advantage of bempedoic acid over statins (e.g. Liptor and Crestor) in the treatment of hypercholesterolemia is that the lack of SLC27A2 expression in skeletal muscle would prevent any adverse side effects in that tissue. The inhibition of muscle cholesterol synthesis by statins is a cause of the associated myotoxicity of that class of drug. Indeed, during clinical trials of bempedoic acid there was an absence of any muscle related symptoms.

Indeed, one of the most common complaints of people taking statins is muscle pain. However, research has shown that in most patients this is an effect called a "nocebo" effect. This is an effect that is related to the fact that people who have negative expectations about a medicine report experiencing the potential side effect at higher rates than the drug should cause. In fact the real risk of developing muscle pain as a result of taking statins is about 5% or less compared with taking a placebo (a pill that doesn't contain medicine). It turns out that a strong predictor or whether or not a patient experiences muscle aches when taking statins is associated with whether or not they read about the potential side effects of the drug.

The US FDA approved the use of orally administered bempedoic acid alone (Nexletol™) or in combination with ezetimibe (Nexlizet™) in February of 2020.

A double-blind, randomized, placebo-controlled trial was carried out involving patients who were classified as statin-intolerant due to unacceptable adverse effects and had, or were at high risk for, cardiovascular disease. The primary end point of this study compared major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

When compared to placebo controls, patients given bempedoic acid saw a decrease in LDL cholesterol (LDL-C) that was nearly 30 mg/dL greater. The patients taking bempedoic acid exhibited no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The only significant negative outcomes were that gout and cholelithiasis (gallstones) were higher with bempedoic acid than with placebo.

TAKE HOME: Patients that experience adverse outcomes with statin class drugs may be the ideal candidates for a switch to bemepedoic acid.