Usage
Bempedoic acid + Ezetimibe is prescribed as an adjunct to diet and maximally tolerated statin therapy (or alone or in combination with other LDL-C lowering therapies in patients who cannot tolerate statins) to lower low-density lipoprotein cholesterol (LDL-C) in adults with:
- Primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).
- Established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-C.
The bempedoic acid component is also indicated to reduce the risk of myocardial infarction and coronary revascularization in adults unable to take recommended statin therapy (including those not taking a statin) with established CVD or a high risk for a CVD event but without established CVD.
It is classified as a lipid-lowering agent, specifically a combination of an ACL inhibitor and a cholesterol absorption inhibitor.
Bempedoic acid inhibits hepatic ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. This reduces cholesterol synthesis, leading to increased LDL receptor expression and enhanced LDL-C clearance from the blood. Ezetimibe inhibits intestinal cholesterol absorption. The combined effect results in a significant reduction in LDL-C levels.
Alternate Names
The combination of bempedoic acid and ezetimibe is marketed under the brand name Nexlizet. Nustendi is a brand name for the drug in some areas outside the US. There are no widely used alternate names for this specific combination. Bempedoic acid is also available as a single-agent medication.
How It Works
Pharmacodynamics: Bempedoic acid lowers LDL-C by inhibiting ATP-citrate lyase, an enzyme involved in cholesterol synthesis in the liver. This leads to upregulation of LDL receptors, increasing LDL clearance. Ezetimibe acts on the small intestine to reduce cholesterol absorption. The two drugs work synergistically to significantly lower LDL-C.
Pharmacokinetics:
- Absorption: Both drugs are orally administered and absorbed from the gastrointestinal tract. Food does not significantly affect absorption.
- Metabolism: Bempedoic acid is primarily conjugated with glucuronic acid in the liver. Ezetimibe undergoes glucuronidation in the intestine and liver, forming an active metabolite, ezetimibe-glucuronide.
- Elimination: Both drugs and their metabolites are excreted in both urine and feces.
Mode of Action: Bempedoic acid inhibits ATP Citrate Lyase (ACL), an enzyme proximal to HMG-CoA reductase in the cholesterol biosynthesis pathway, thus blocking cholesterol production in the liver. Ezetimibe specifically acts on the brush border of the small intestine to decrease cholesterol absorption. This dual mechanism contributes to the overall LDL-C lowering effect. Bempedoic acid does not get activated in skeletal muscle, thereby reducing the possibility of muscular side effects seen with statins.
Receptor Binding/Enzyme Inhibition: Bempedoic acid inhibits ACL. Ezetimibe targets Niemann-Pick C1-Like 1 (NPC1L1) protein, a sterol transporter, which is responsible for cholesterol absorption.
Dosage
Standard Dosage
Adults:
One tablet (180 mg bempedoic acid/10 mg ezetimibe) orally once daily, with or without food.
Children:
Safety and efficacy have not been established in pediatric patients.
Special Cases:
- Elderly Patients: No dose adjustment is necessary.
- Patients with Renal Impairment: No dose adjustment is necessary for mild to moderate impairment (eGFR ≥ 30 mL/min/1.73 m²). Caution advised in severe renal impairment (eGFR < 30 mL/min/1.73 m²) due to limited experience.
- Patients with Hepatic Dysfunction: No dose adjustment necessary for mild impairment (Child-Pugh A). Not recommended in moderate to severe hepatic impairment due to increased ezetimibe exposure.
Clinical Use Cases
The drug is not typically used in acute clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It’s meant for chronic management of hyperlipidemia.
Dosage Adjustments
Dose adjustments may be needed in patients with severe renal or hepatic impairment.
Side Effects
Common Side Effects:
Upper respiratory tract infection, back pain, bronchitis, muscle spasms, hyperuricemia, abdominal pain, pain in extremities, anemia, elevated liver enzymes, diarrhea, arthralgia, sinusitis, fatigue, and influenza.
Rare but Serious Side Effects:
Tendon rupture, gout, hypersensitivity reactions (including angioedema, rash, urticaria, and anaphylaxis).
Long-Term Effects:
The long-term effects are still under investigation. However, monitoring for hyperuricemia and gout, and tendon issues is important.
Adverse Drug Reactions (ADR):
Tendinopathy and tendon rupture, gout flares, hypersensitivity reactions, and significant elevations in uric acid levels.
Contraindications
Hypersensitivity to ezetimibe or bempedoic acid. Pregnancy.
Drug Interactions
- Simvastatin/Pravastatin: Bempedoic acid increases simvastatin/pravastatin concentrations. Avoid simvastatin doses >20 mg or pravastatin doses >40 mg.
- Cyclosporine: Coadministration increases concentrations of both drugs; monitor cyclosporine levels.
- Bile Acid Sequestrants: Administer Nexlizet at least 2 hours before or 4 hours after bile acid sequestrants.
- Fibrates: Increased risk of cholelithiasis with fenofibrate. Coadministration with other fibrates not recommended.
Pregnancy and Breastfeeding
Pregnancy: Nexlizet is contraindicated during pregnancy due to potential fetal harm. Discontinue the drug upon recognition of pregnancy.
Breastfeeding: Breastfeeding is not recommended due to the potential for serious adverse reactions in the breastfed infant.
Drug Profile Summary
- Mechanism of Action: Bempedoic acid inhibits ACL, reducing cholesterol synthesis; ezetimibe inhibits cholesterol absorption.
- Side Effects: Common: URI, back pain, bronchitis, hyperuricemia, muscle spasms. Serious: Tendon rupture, gout.
- Contraindications: Hypersensitivity to components, pregnancy.
- Drug Interactions: Simvastatin, pravastatin, cyclosporine, bile acid sequestrants.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding not recommended.
- Dosage: One tablet (180 mg/10 mg) orally once daily.
- Monitoring Parameters: LDL-C, uric acid, liver enzymes, creatinine, monitor for signs and symptoms of myopathy and tendinopathy.
Popular Combinations
Often combined with maximally tolerated statin therapy when statins are tolerated.
Precautions
Monitor for hyperuricemia, gout, and tendon rupture. Obtain baseline liver function tests and monitor periodically. Assess cardiovascular risk profile.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Bempedoic acid + Ezetimibe?
A: One tablet (180mg bempedoic acid/10mg ezetimibe) orally once a day.
Q2: How does Bempedoic acid + Ezetimibe compare to statins in lowering LDL-C?
A: It provides additional LDL-C lowering when added to maximally tolerated statin therapy or as an alternative for statin-intolerant patients. Head-to-head comparative efficacy data is limited.
Q3: What are the most common side effects of Bempedoic acid + Ezetimibe?
A: Upper respiratory tract infections, back pain, bronchitis, hyperuricemia, muscle spasms, and abdominal pain.
Q4: Can Bempedoic acid + Ezetimibe be used during pregnancy?
A: No, it is contraindicated during pregnancy due to the potential for fetal harm.
Q5: How should Bempedoic acid + Ezetimibe be administered if a patient is also taking a bile acid sequestrant?
A: Administer Nexlizet at least 2 hours before or 4 hours after the bile acid sequestrant.
Q6: Are there any specific monitoring parameters for patients on Bempedoic acid + Ezetimibe?
A: Monitor LDL-C levels, uric acid levels, liver function tests, and creatinine. Monitor for signs and symptoms of myopathy or tendinopathy.
Q7: What should be done if a patient experiences tendon pain while taking this medicine?
A: Tendon pain should be promptly evaluated. The medication should be discontinued if tendon rupture is suspected.
Q8: Can Bempedoic acid + Ezetimibe be used in patients with liver disease?
A: It can be used in patients with mild hepatic impairment. Use is not recommended in those with moderate to severe hepatic impairment.
Q9: Is there a risk of gout with this combination?
A: Yes, bempedoic acid can elevate uric acid levels which may increase the risk of gout, especially in patients with a history of gout. Monitor uric acid levels and consider prophylactic therapy in high-risk individuals.
