Introduction
Nexletol (bempedoic acid) is an oral, once-daily, non-statin cholesterol-lowering medication approved by the FDA in February 2020. It represents a novel therapeutic class of adenosine triphosphate-citrate lyase (ACL) inhibitors that work upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.
Mechanism of Action
Bempedoic acid is a prodrug that requires activation by very long-chain acyl-CoA synthetase 1 (ACSVL1), an enzyme predominantly expressed in the liver. Once activated, bempedoic acid inhibits adenosine triphosphate-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. By inhibiting ACL, bempedoic acid reduces hepatic cholesterol synthesis and upregulates LDL receptor expression, resulting in increased clearance of LDL-C from the bloodstream. Unlike statins, bempedoic acid is not activated in skeletal muscle, which may contribute to its favorable muscle-related side effect profile.
Indications
Nexletol is indicated:
- As an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia
- As an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with established atherosclerotic cardiovascular disease who require additional lowering of LDL-C
Dosage and Administration
Recommended dosage: 180 mg 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: Median Tmax approximately 3.5 hours; bioavailability approximately 67% Distribution: Protein binding >99%; volume of distribution approximately 18L Metabolism: Primarily via uridine diphosphate-glucuronosyltransferase (UGT) 2B7 with minor contributions from UGT1A1, UGT1A3, and UGT1A9; forms bempedoic acid glucuronide (inactive) Elimination: Half-life approximately 21 hours; primarily excreted in urine (70%) and feces (30%)Contraindications
- Hypersensitivity to bempedoic acid or any component of the formulation
Warnings and Precautions
Tendon rupture: Reports of tendon rupture, particularly of the Achilles tendon, have occurred. Discontinue immediately if tendon rupture is suspected. Hyperuricemia: May increase blood uric acid levels. Monitor uric acid levels as appropriate. Renal function: May worsen renal function. Assess renal function during therapy. Fetal toxicity: May cause fetal harm based on animal data. Advise females of reproductive potential of potential risk.Drug Interactions
Simvastatin: May increase simvastatin exposure; limit simvastatin dosage to 20 mg daily Pravastatin: May increase pravastatin exposure; limit pravastatin dosage to 40 mg daily Other OATP1B1 substrates: May increase exposure of drugs that are OATP1B1 substratesAdverse Effects
Most common adverse reactions (≥2%):- Upper respiratory tract infection
- Muscle spasms
- Hyperuricemia
- Back pain
- Abdominal pain or discomfort
- Bronchitis
- Pain in extremity
- Anemia
- Elevated liver enzymes
- Tendon rupture
- Hyperuricemia
- Renal impairment
Monitoring Parameters
- LDL-C levels (baseline and 8-12 weeks after initiation/titration)
- Hepatic enzymes (baseline and as clinically indicated)
- Serum uric acid levels (baseline and periodically during treatment)
- Renal function (baseline and periodically during treatment)
- Signs and symptoms of tendon rupture
Patient Education
- Take Nexletol exactly as prescribed, once daily with or without food
- Report any tendon pain, tenderness, or weakness immediately
- Inform healthcare providers of all medications being taken
- Notify your physician if you experience muscle pain, tenderness, or weakness
- Regular blood tests will be needed to monitor therapy effectiveness and safety
- Inform your physician if you are pregnant, planning pregnancy, or breastfeeding
- Continue adherence to dietary and lifestyle modifications
References
1. FDA Prescribing Information: Nexletol (bempedoic acid) tablets 2. Goldberg AC, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on LDL 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. 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. 5. 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.