ADD-ONS / MEDICATION
Bempedoic acid
David Goldemund M.D.
Updated on 21/03/2024, published on 18/03/2024
- in recent years, there has been a significant decrease in the prevalence of cardiovascular diseases (CVD) due to the effective management of vascular risk factors in primary and secondary prevention (mainly arterial hypertension and dyslipidemia)
- the target serum lipid levels are often not achieved on statin therapy (⇒ proceed with combination therapy), or statins are not well-tolerated (~ 7-9% of cases; alternative therapy should be chosen) (Bytes, 2022)
- bempedoic acid, which inhibits ATP-citrate lyase, is one of the newer hypolipidemics that can be used in statin-intolerant patients or as part of combination hypolipidemic therapy
Mechanism of action
Mechanism of action- inhibition of the enzyme ATP citrate lyase (ACLY) reduces endogenous cholesterol synthesis, similar to statin therapy (bempedoic acid acts in an identical cascade, just two steps further down the line)
- bempedoic acid is administered as a prodrug that is activated upon binding to coenzyme A catalyzed by hepatic acyl-CoA synthetase 1 (ASCV1L); this produces the active form of bempedoyl-CoA
- the activation of the drug in the liver and its extensive first-pass metabolism result in limited systemic exposure to the active ingredient, which explains the excellent tolerability and minimal adverse effects
Pharmacokinetics
- bempedoic acid is absorbed in the gastrointestinal tract, with peak plasma concentrations (Cmax) reached approximately 3.5 hours after oral administration
- it is a prodrug that is activated in the liver by very-long-chain acyl-CoA synthetase-1 (ACSVL1) to its corresponding active coenzyme A (CoA) derivative
- the active metabolite is approximately 99% bound to plasma proteins, primarily albumin, which may affect its distribution dynamics
- the elimination half-life of bempedoic acid is approximately 20 to 30 hours, allowing for once-daily dosing
- bempedoic acid and its metabolites are primarily excreted in the urine; a small fraction may also be excreted in feces
Adverse events
Therapy is safe and well-tolerated; any side effects observed mild generally mild and reversible
- moderate decrease in hemoglobin
- moderate elevation in urea, creatinine, and uric acid levels
- higher incidence of gout
- elevated uric acid concentrations are reversible after treatment
- caused by inhibition of the OATC2 transporter in the kidney and is a fully reversible effect thus it is not a toxic effect of treatment
- moderate elevation of aminotransferases (usually maximum up to 3 times the upper limit of normal)
Indication
- bempedoic acid can be used in adults with familial hypercholesterolemia or mixed dyslipidemia
- in combination with a statin or other hypolipidemic drugs for people who do not achieve target LDL-C concentrations despite taking the maximum tolerated dose of a statin (e.g., with ezetimibe)
- as monotherapy (e.g., with ezetimibe) in individuals with complete statin intolerance or in whom a statin is contraindicated
- bempedoic acid therapy may be considered in patients at high and very high CV risk who have higher CRP levels
- bempedoic acid has significant potential to achieve target serum lipid levels, especially in combination therapy (see table)
- if the patient cannot tolerate even a minimal dose of a statin, it is recommended to use monotherapy with bempedoic acid or its fixed combination with ezetimibe (or combination with another hypolipidemic drug)
- if target LDL-C levels are not achieved in this way, consider adding a PCSK9 inhibitor or inclisiran
- the initial treatment strategy should be designed with baseline and target LDL-C levels in mind (refer to the table below)
| Medication | predicted decrease in LDL-C levels (%) |
| bempedoic acid | 17-27 |
| low-dose statin+ bempedoic acid | 40-45 |
| low-dose statin + EZE + bempedoic acid | 55-60 |
| high-dose statin +bempedoic acid | 65 |
| high-dose statin + EZE + bempedoic acid | 70-75 |
| high-dose statin + EZE +bempedoic acid + PCSK9i/inklisiran | > 85 |
Dosing
(bempedoic acid 180 mg)
(bempedoic acid 180 mg + ezetimibe 100 mg)
- one 180 mg tablet daily
- fixed combination with ezetimibe can be used (bempedoic acid 180 mg + ezetimibe 10 mg)
- the occurrence of myopathy should be monitored when used in combination with a statin (bempedoic acid increases plasmatic levels of statins)
- reduce the dose of simvastatin to 20mg and pravastatin to 40mg; no dose adjustment is required for other statins
- the administration of bempedoic acid in combination with 80 mg simvastatin is contraindicated
- reduce statin dose if myopathy occurs, discontinue both drugs if CK is > 10x ULN
- women of childbearing age must use contraception (same as for statins)
- dose reduction is unnecessary for mild nephropathies and hepatopathies; insufficient data exist for more severe disorders
Hypolipidemic treatment strategies
- the effects of particular hypolipidemic drugs, as well as their combinations, can be predicted with a high degree of accuracy
- it is generally recommended to start treatment with one drug and add more if the therapeutic goal is not achieved; the risk is that the recommended levels are not reached or are reached later
- an alternative treatment strategy is to determine the desired percentage reduction in LDL and, if necessary, opt for combination therapy as the primary treatment
| baseline LDL-C level (mmol/l) | % LDL reduction required | treatment |
| 2.8 | 50% | high-dose statin |
| 2.8-4.1 | 65% | high-dose statin + EZE |
| 4.1-5.7 | 75% | high-dose statin + EZE + bempedoic acid |
| 5.7-9.6 | 85% | high-dose statin + EZE + PCSK9i/inclisiran |
| >9.6 | 85% | high-dose statin + bempedoic acid + EZE + PCSK9i/inclisiran |
FAQs
- bempedoic acid is a prodrug that inhibits ATP citrate lyase, an enzyme involved in cholesterol biosynthesis
- this inhibition leads to decreased hepatic cholesterol synthesis and upregulation of the LDL receptor, resulting in reduced levels of plasma low-density lipoprotein cholesterol (LDL-C)
- bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C
- bempedoic acid is administered orally, typically 180 mg once daily (with or without food)
- the primary contraindications include a history of hypersensitivity to bempedoic acid or any of its components
- caution is advised in patients with a history of tendon disorders related to statin use
- common side effects include hyperuricemia, which may lead to gout, and increased hepatic enzymes
- tendon rupture has also been reported but is less common
- bempedoic acid can increase the concentration of statins and their active metabolites, potentially increasing the risk of statin-related side effects
- concomitant use with simvastatin or pravastatin should be approached with caution, and dose adjustments may be necessary
- bempedoic acid requires no dose adjustment in mild to moderate renal impairment but is not recommended in severe renal impairment (eGFR <30 mL/min/1.73 m^2) due to lack of data
- for patients with hepatic impairment, caution is advised due to potential increases in exposure and the risk of hepatotoxicity
- yes, bempedoic acid offers an alternative lipid-lowering therapy for patients who are statin-intolerant due to its different mechanism of action and site of metabolism, potentially avoiding the muscle-related side effects associated with statins
- patients should be monitored for serum uric acid levels, liver enzyme levels, and signs of tendon rupture or injury
- lipid levels should also be regularly assessed to evaluate the efficacy of the treatment regimen.
- trials suggest that bempedoic acid can reduce the risk of cardiovascular events in patients with established cardiovascular disease, particularly when added to statin therapy. However, ongoing studies are further evaluating its impact on major adverse cardiovascular events (MACE).
