From the Guidelines
Bempedoic acid is not generally considered better than statins for most patients, but it offers a valuable alternative for those who cannot tolerate statins due to muscle pain or require add-on therapy. Bempedoic acid works by inhibiting ATP-citrate lyase, an enzyme in the cholesterol synthesis pathway, which results in the up-regulation of the LDL receptor and improved clearance of LDL, thereby reducing blood LDL-C levels 1. Unlike statins, bempedoic acid is activated by very-long-chain acyl-CoA synthetase-1, an enzyme present in liver cells but not muscle cells, which may explain its lower incidence of muscle-related side effects 1.
Key Points
- Typical dosing of bempedoic acid is 180 mg once daily, with or without food.
- Bempedoic acid typically lowers LDL cholesterol by 15-25%, which is less than high-intensity statins that can reduce LDL by 50% or more.
- The CLEAR Outcomes trial found a reduction in four-point major adverse cardiovascular events by 13% compared with placebo for individuals with established ASCVD or at high risk for ASCVD considered to be intolerant to statin therapy 1.
- Prespecified subanalyses evaluated the impact for individuals with diabetes and showed a 17% reduction in four-point major adverse cardiovascular events when treated with bempedoic acid 1.
Considerations
- Bempedoic acid can cause side effects including elevated uric acid levels, risk of gout, and tendon problems.
- While it offers an important option for statin-intolerant patients, statins remain first-line therapy for most people needing cholesterol-lowering medication because they have more extensive clinical evidence showing reduction in heart attacks and strokes 1.
Clinical Decision
The choice between bempedoic acid and statins should be based on individual patient needs and tolerability, with statins remaining the first-line therapy for most patients and bempedoic acid offering a valuable alternative for those who cannot tolerate statins.
From the FDA Drug Label
Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers LDL-C by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway Bempedoic acid and its active metabolite, ESP15228, require coenzyme A (CoA) activation by very long-chain acyl-CoA synthetase 1 (ACSVL1) to ETC-1002-CoA and ESP15228-CoA, respectively. ACSVL1 is expressed primarily in the liver. Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of low-density lipoprotein receptors.
Bempedoic acid works by inhibiting ACL, which is an enzyme involved in the cholesterol biosynthesis pathway. This inhibition leads to decreased cholesterol synthesis in the liver and lowers LDL-C in the blood. The provided information does not directly compare bempedoic acid to statins, therefore no conclusion can be drawn about whether bempedoic acid is better than statins 2.
From the Research
Mechanism of Action of Bempedoic Acid
- Bempedoic acid reduces hepatic cholesterol synthesis by inhibiting the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway 3.
- It is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle 3.
Comparison with Statins
- Bempedoic acid has a weaker efficacy compared to high-intensity statins, but it may be a useful adjunct in individuals who achieve less than desirable LDL-C reductions with statins or who cannot tolerate statins 4.
- Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins 3.
- The combination of bempedoic acid, ezetimibe, and atorvastatin has been shown to significantly lower LDL-C, allowing more than 90% of patients to reach guideline-recommended LDL-C goals 5.
Potential Benefits and Limitations
- Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins 3.
- A small increase in serum uric acid is the most noteworthy adverse effect of bempedoic acid 3.
- The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial 3.