What is the role of NEXLETOL (bempedoic acid) in lowering Low-Density Lipoprotein Cholesterol (LDL-C)?

NEXLETOL (Bempedoic Acid) for LDL-C Lowering

NEXLETOL (bempedoic acid) is an effective oral LDL-cholesterol lowering agent that reduces cardiovascular events in statin-intolerant patients and provides additional LDL-C reduction when added to maximally tolerated statin therapy in high-risk patients with ASCVD or heterozygous familial hypercholesterolemia. 1

FDA-Approved Indications

Bempedoic acid has two distinct FDA-approved indications:

• Cardiovascular risk reduction: To reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommended statin therapy (including those not taking a statin) with established CVD or high CVD risk 1

• LDL-C lowering: As adjunct to diet, in combination with other LDL-C lowering therapies, or alone when concomitant therapy is not possible, to reduce LDL-C in adults with primary hyperlipidemia including heterozygous familial hypercholesterolemia 1

Mechanism of Action

Bempedoic acid inhibits ATP-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway 2. This mechanism results in:

• Liver-specific activation: Administered as a prodrug activated by very-long-chain acyl-CoA synthetase-1, an enzyme present in liver cells but not muscle cells 2
• Upregulation of LDL receptors: Decreased hepatic cholesterol synthesis leads to increased LDL receptor density and improved LDL clearance 2, 1
• Reduced muscle symptoms: Unlike statins, the lack of muscle cell activation theoretically reduces statin-associated muscle symptoms 2

LDL-C Lowering Efficacy

The magnitude of LDL-C reduction depends on background therapy:

• Monotherapy (statin-intolerant patients): Approximately 24.5% reduction in LDL-C compared to placebo 2
• Added to statin therapy: Additional 15-18% placebo-corrected incremental reduction 2
• Combination with ezetimibe (fixed-dose): Additional 38% placebo-corrected incremental reduction when added to statin therapy 2

Dosing and Administration

• Standard dose: 180 mg orally once daily, with or without food 2
• Fixed-dose combination: One tablet (180 mg bempedoic acid/10 mg ezetimibe) orally once daily 2
• Timing with bile acid sequestrants: Take either 2 hours before or 4 hours after bile acid sequestrants if used in combination 2

Cardiovascular Outcomes Evidence

The CLEAR Outcomes trial demonstrated cardiovascular benefit in statin-intolerant patients: 3

• Study population: 14,014 individuals aged 18-85 years with ASCVD or high ASCVD risk, statin intolerance, and LDL-C ≥100 mg/dL 2
• Primary endpoint: Composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization 2
• Results: Significant reduction in the primary endpoint compared to placebo 3

Critical Safety Considerations

Monitor for these specific adverse effects:

Hyperuricemia and Gout

• Assess serum uric acid before initiation and when clinically indicated 2
• Monitor for symptoms of hyperuricemia 2
• Initiate urate-lowering drugs as appropriate 2
• Increased gout incidence: 1.5% vs. 0.4% in trials 2

Tendon Rupture

• Discontinue immediately if tendon rupture occurs 2
• Consider discontinuing if joint pain, swelling, or inflammation develops 2
• Advise patients to rest at first sign of tendinitis 2
• Consider alternative therapy in patients with history of tendon disorders 2
• Increased tendon rupture: 0.5% vs. 0% in trials 2

Other Notable Adverse Effects

• Upper respiratory tract infection, muscle spasms, back pain, abdominal pain, bronchitis, anemia, elevated liver enzymes 2
• Atrial fibrillation: 1.7% vs. 1.1% 2
• Benign prostatic hyperplasia: 1.3% vs. 0.1% 2
• Elevated creatine kinase: 1.0% vs. 0.6% 2

Drug-Drug Interactions

Avoid specific statin dose combinations: 2

• Simvastatin >20 mg daily
• Pravastatin >40 mg daily

Special Populations

Pregnancy and Lactation

• Discontinue when pregnancy is recognized unless benefits outweigh risks 2
• Breastfeeding not recommended during treatment 1

Renal Impairment

• No dose adjustment needed for mild or moderate impairment 1
• Limited experience with severe renal impairment (eGFR <30 mL/min/1.73 m²) 1
• Not studied in end-stage renal disease on dialysis 1

Hepatic Impairment

• No dose adjustment for mild or moderate impairment (Child-Pugh A or B) 1
• Not studied in severe hepatic impairment (Child-Pugh C) 1

Geriatric Patients

• No overall differences in safety or effectiveness observed in patients ≥65 years 1

Clinical Positioning

Use bempedoic acid in these specific scenarios according to ACC guidelines: 2

1. Statin-intolerant patients with ASCVD or high CVD risk requiring LDL-C lowering
2. Patients on maximally tolerated statin therapy with ASCVD or HeFH who require additional LDL-C reduction
3. Patients with adherence issues to multidrug regimens (consider fixed-dose combination with ezetimibe)

Practical Implementation Considerations

• Cost and prior authorization: Commercially available as branded product; requires prior authorization in most cases 2
• Patient assistance: Discount copay cards and patient assistance programs available for eligible patients 2
• Pill burden: Once-daily dosing; fixed-dose combination with ezetimibe reduces pill burden 2
• Adherence and persistence: Real-world data shows 99% adherence and 90% persistence 4

Real-World Performance

Recent real-world evidence demonstrates: 4

• 46-54% of patients achieved therapeutic LDL-C targets
• 28% LDL-C reduction in patients on intensive statins/ezetimibe
• 45% LDL-C reduction in statin-intolerant patients
• Well tolerated with only 10% experiencing reversible side effects
• Contributed to healthcare cost savings