Bempedoic acid

Bempedoic acid is a lipid-lowering agent that can be used to treat primary hypercholesterolemia and mixed dyslipidemia in addition to dietary changes and exercise and in combination with other lipid-lowering agents.

Significance:

Lowering cholesterol levels is of considerable importance in reducing the risk of atherosclerosis and serious cardiovascular events (BorénJ et al 2020, Tokgozoglu L, Libby P 2022). As this is a causal and cumulative lifetime risk, the early and sustained reduction of LDL cholesterol to the lowest possible levels over the entire lifespan is crucial as a therapeutic goal (Ference BA et al 2018). Statins are highly effective and reduce cardiovascular risk and are therefore still the drug of first choice. However, the target values for lowering LDL cholesterol are often not achieved (Ray K et al 2021). Side effects such as muscle pain play a major role here, especially when high doses of statins are necessary. Recently, it has been advocated that early combination therapy is preferable to high-dose monotherapy (ESC/EAS guidelines, Mach F et al 2019). Bempedoic acid, with its new, liver-specific mechanism of action and no side effects on the muscle, offers a new additional treatment option for combination therapy and an alternative in cases of statin intolerance.

Bempedoic acid is a new drug with a novel mechanism of action to lower cholesterol.

Bempedoic acid is a prodrug that is converted to its active form bempedoyl-CoA in the liver by long-chain acyl-CoA synthetase-1 (ACSVL1). Bempedoyl-CoA inhibits the enzyme ATP(adenosine triphosphate) citrate lyase(ACL)(ACL inhibitor). ACL converts citrate into acetyl-CoA, which is required as a starting substance for cholesterol synthesis. This lowers the intracellular cholesterol content, more LDLreceptors are expressed on the cell surface, more LDL cholesterol is taken up from the blood into the cell and this in turn lowers the plasma LDL cholesterol (LDL-C) level. In addition, ACL inhibition leads to a suppression of the biosynthesis of fatty acids in the liver.

Similar to statins, which inhibit the HMG-CoA reductase of cholesterol synthesis, bempedoic acid also acts in cholesterol synthesis but one step before the HMG-CoA reductase. Since bempedoic acid is only converted into its active form in the liver, unlike statins, bempedoic acid acts specifically in the liver and not in the skeletal muscles. This avoids muscle complaints (muscle pain, muscle weakness), which are a major side effect of statins (Ruscica M et al 2022, Pinkovsky SL et al 2016).

Evidence/clinical phase III studies:

CLEAR study program on safety and efficacy, as well as outcome (see also positive cardiovascular risk profile).

Combination therapy statin with bempedoic acid lowers LDL-C significantly more (additional reduction in LDL-C approx. 15%) without more or additional side effects e.g. statin (moderate intensity) with bempedoic acid causes greater reduction in LDL-C than doubling the statin dose but without corresponding side effects (Ray KK et al 2019).

In addition to lowering LDL-C, significant reduction in hsCRP (from approx. 18-32%), i.e. also anti-inflammatory effect (presumably via independent effect on AMPK in immune cells), as well as less recurrence of diabetes and slight reduction in HbA1c in diabetics observed (Ray KK et al 2019). Since high-dose statins in particular often lead to a deterioration in blood glucose levels, bempedoic acid can be used additionally or preferably.

In the case of statin intolerance, an LDL-C reduction of approx. 23-30% can be expected with bempedoic acid monotherapy (Clear Tranquility study, Clear Serenity study)( ).

Combination therapy bempedoic acid plus ezetimibe causes approx. 45% LDL-C reduction

Combination bempedoic acid plus moderate intensity statin plus ezetimibe results in approx. 60% LDL-C reduction

ACL inhibitors are currently also being investigated for efficacy in carcinoma therapy (Hatzivassiliou G et al 2005, Xiang W et al 2023). There may also be therapeutic potential in the treatment of fatty liver disease (Liu JY et al 2025).

The recommended dose is

1x daily 180 mg for the monopreoarate ^Nilemdo® or

1x daily 180mg/10mg for the fixed combination with ezetimibe ^Nustendi®.

In the case of concomitant therapy with ^Nilemdo® or ^Nustendi® and simvastatin, limit the dose of simvastatin to 20 mg (possibly 40 mg in the case of severe hypercholesterolemia or high risk of cardiovascular complications) due to the risk of severe myopathy or myositis with life-threatening complications (see adverse effects).

Bempedoic acid is contraindicated:

during pregnancy and lactation

in children and adolescents under 18 years of age! No data is available on this.

in case of intolerance to the active substance or components of the drug

in the case of persistently elevated unexplained transaminase levels and active liver disease

Do not use at doses of simvastatin ≥ 40 mg daily. Risk of severe myopathy/myositis with rhabdomyolysis, myoglobinuria, renal failure and death possible in rare cases!

If statins are used at the same time, especially in high doses, the information in the specialist information for the respective statin must be consulted and observed!

rare hereditary galactose intolerance

complete lactase deficiency

glucose-galactose malabsorption

There is insufficient or no data available for severe hepatic insufficiency, severe renal insufficiency and renal failure; use is not recommended.

The use of the combination preparation bempedoic acid/ezetimibe is no longer recommended even in cases of moderate hepatic insufficiency (see Nustendi and Ezetimibe contraindications).

^Nilemdo® monopreparation Approval 2020

^Nustendi® combination product with the cholesterol absorption inhibitor ezetimibe Approval 2020