Introduction
Nexlizet (bempedoic acid/ezetimibe) is a novel, fixed-dose combination medication approved by the FDA in February 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. This combination therapy offers a unique approach to cholesterol management by targeting two complementary pathways in cholesterol metabolism.
Mechanism of Action
Nexlizet combines two distinct mechanisms of action:
- Bempedoic acid: An adenosine triphosphate-citrate lyase (ACL) inhibitor that reduces cholesterol synthesis in the liver. It is a prodrug that requires activation by very long-chain acyl-CoA synthetase 1 (ACSVL1), an enzyme predominantly expressed in the liver, resulting in targeted hepatic effects with minimal muscle-related effects.
- Ezetimibe: A selective cholesterol absorption inhibitor that localizes at the brush border of the small intestine and inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein, reducing intestinal absorption of dietary and biliary cholesterol.
This dual mechanism provides complementary LDL-C reduction through both decreased cholesterol synthesis and reduced intestinal cholesterol absorption.
Indications
Nexlizet is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of:
- Adults with heterozygous familial hypercholesterolemia
- Adults with established atherosclerotic cardiovascular disease
Who require additional lowering of LDL-C
Dosage and Administration
- Recommended dosage: One tablet (180 mg bempedoic acid/10 mg ezetimibe) orally once daily
- Administration: Can be taken with or without food
- Special populations:
- Renal impairment: No dosage adjustment necessary - Hepatic impairment: Not recommended in patients with moderate or severe hepatic impairment - Geriatric patients: No dosage adjustment necessary - Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
- Absorption: Bempedoic acid Tmax ≈ 3.5 hours; Ezetimibe Tmax ≈ 1-2 hours
- Distribution: Bempedoic acid protein binding ≈ 99%; Ezetimibe protein binding >90%
- Metabolism: Bempedoic acid undergoes glucuronidation; Ezetimibe undergoes glucuronidation in the intestine and liver
- Elimination: Bempedoic acid half-life ≈ 21 hours; Ezetimibe half-life ≈ 22 hours
- Excretion: Primarily hepatic elimination for both components
Contraindications
- Hypersensitivity to any component of Nexlizet
- Concomitant use with simvastatin >20 mg daily
- Pregnancy
- Breastfeeding
- Moderate to severe hepatic impairment
Warnings and Precautions
- Hyperuricemia: May increase blood uric acid levels; monitor and treat appropriately
- Tendon rupture: Reports of tendon rupture, particularly in patients >60 years, those taking corticosteroids, or with renal failure
- Hepatic toxicity: Monitor liver enzymes before initiation and during therapy
- Myopathy: Risk may be increased in elderly patients and those with renal impairment
- Fetal toxicity: Contraindicated in pregnancy due to potential fetal harm
Drug Interactions
- Simvastatin: Concomitant use limited to ≤20 mg daily
- Pravastatin: May increase pravastatin exposure; consider dose reduction
- Cyclosporine: Contraindicated due to increased ezetimibe exposure
- Fibrates: May increase risk of cholelithiasis
- Warfarin: Monitor INR as ezetimibe may potentiate effect
Adverse Effects
Most common adverse reactions (≥2%):- Upper respiratory tract infection
- Muscle spasms
- Hyperuricemia
- Back pain
- Abdominal pain
- Bronchitis
- Pain in extremity
- Anemia
- Elevated liver enzymes
- Tendon rupture
- Hyperuricemia
- Hepatic enzyme elevations
- Myopathy
Monitoring Parameters
- LDL-C levels: At baseline and 8-12 weeks after initiation
- Liver enzymes (ALT, AST): At baseline and as clinically indicated
- Serum uric acid: At baseline and periodically during treatment
- Creatine kinase: In patients with muscle symptoms
- Renal function: At baseline and periodically
- Pregnancy status: In women of childbearing potential
Patient Education
- Take once daily with or without food
- Report any unexplained muscle pain, tenderness, or weakness immediately
- Inform healthcare providers of all medications being taken
- Notify provider if pregnancy is planned or suspected
- Report any tendon pain, swelling, or inflammation
- Maintain appropriate dietary measures
- Understand that this medication is adjunctive to statin therapy
- Regular follow-up appointments are essential for monitoring
References
1. FDA prescribing information: Nexlizet (bempedoic acid and ezetimibe) tablets. February 2020. 2. Goldberg AC, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019;322(18):1780-1788. 3. Ray KK, et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019;380(11):1022-1032. 4. Ballantyne CM, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis. 2018;277:195-203. 5. Laufs U, et al. Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance. J Am Heart Assoc. 2019;8(7):e011662.