What is the indication and usage of bempedoic acid in patients with high low-density lipoprotein cholesterol (LDL-C)?

Bempedoic Acid: Indication and Usage

Bempedoic acid is FDA-approved as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL-C lowering. 1

FDA-Approved Indications

Bempedoic acid received FDA approval in 2020 for two specific patient populations requiring additional LDL-C reduction beyond maximally tolerated statin therapy 1:

• Adults with heterozygous familial hypercholesterolemia (HeFH) who need further LDL-C lowering despite maximally tolerated statins 1
• Adults with established ASCVD who require additional LDL-C reduction beyond what statins alone can achieve 1

Mechanism and Efficacy

Bempedoic acid inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway, resulting in upregulation of LDL receptors and improved LDL clearance 1. The drug is administered as a prodrug and activated by very-long-chain acyl-CoA synthetase-1, an enzyme present in liver cells but not muscle cells, which theoretically reduces muscle-related adverse effects 1.

LDL-C Reduction Efficacy:

• Monotherapy in statin-intolerant patients: Reduces LDL-C by approximately 24.5% compared to placebo 1, 2
• Added to statin therapy: Provides an additional 15-17.8% LDL-C reduction 1, 2
• In HeFH patients specifically: Achieves approximately 21.2% LDL-C reduction at week 12 3
• Fixed-dose combination with ezetimibe: Provides 38% additional LDL-C reduction when added to statin therapy 1

Treatment Hierarchy and Positioning

The American College of Cardiology recommends bempedoic acid as third-line therapy after ezetimibe and PCSK9 inhibitors in statin-tolerant patients, but it moves to first-line in truly statin-intolerant patients. 4

For Statin-Tolerant Patients:

1. First: Add ezetimibe 10 mg daily (provides ~18% additional LDL-C reduction) 4
2. Second: Add PCSK9 inhibitor like evolocumab if LDL-C remains ≥70 mg/dL (provides 40-65% reduction) 4
3. Third: Consider bempedoic acid 180 mg daily if LDL-C remains elevated despite above therapies 4

For Statin-Intolerant Patients:

1. First: Bempedoic acid 180 mg daily 4
2. Second: Ezetimibe 4
3. Third: PCSK9 inhibitor 4

Dosing and Administration

The standard dose is 180 mg taken orally once daily, with or without food, swallowed whole. 5, 6

Critical Dosing Considerations:

• No dose adjustment needed for mild-to-moderate renal impairment (eGFR ≥30 mL/min/1.73 m²) 6
• No dose adjustment needed for mild-to-moderate hepatic impairment (Child-Pugh A or B) 6
• Limited experience in severe renal impairment (eGFR <30 mL/min/1.73 m²); not studied in dialysis patients 6
• Not studied in severe hepatic impairment (Child-Pugh C) 6

Drug Interactions Requiring Dose Limitations:

• Avoid simvastatin >20 mg daily when combined with bempedoic acid due to increased statin exposure 5
• Avoid pravastatin >40 mg daily when combined with bempedoic acid due to increased statin exposure 5
• Separate from bile acid sequestrants by 2 hours before or 4 hours after 5

Safety Profile and Monitoring

Bempedoic acid demonstrates an acceptable safety profile, though specific adverse events occur more frequently than placebo 1:

Adverse Events to Monitor:

• Gout: 1.5% vs 0.4% with placebo; mean uric acid increase of 0.8 mg/dL 1, 4
• Tendon rupture: 0.5% vs 0% with placebo 1, 4
• Benign prostatic hyperplasia: 1.3% vs 0.1% with placebo 1
• Atrial fibrillation: 1.7% vs 1.1% with placebo 1
• Creatine kinase elevation: 1.0% vs 0.6% with placebo 1
• Elevated liver enzymes: 2.8% vs 1.3% with placebo 2

Monitoring Recommendations:

• Assess serum uric acid before initiation and monitor if hyperuricemia symptoms occur 5
• Monitor for tendinitis or tendon rupture signs; discontinue immediately if rupture occurs 5
• Monitor liver function tests as clinically indicated 5, 7
• No contraindications exist for baseline elevated liver enzymes; can initiate and monitor 7

Clinical Outcomes Data

At the time of the 2022 ACC guidelines, the CLEAR Outcomes trial was ongoing with expected completion in late 2022 1. This trial enrolled 14,014 patients with ASCVD or high ASCVD risk who were statin-intolerant with LDL-C ≥100 mg/dL, evaluating the composite endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization 1.

Important caveat: The 2022 ADA guidelines noted that at that time, there were no completed trials demonstrating cardiovascular outcomes benefit, and bempedoic acid should be considered for patients who cannot use or tolerate other evidence-based LDL-C lowering approaches 1.

Practical Implementation Considerations

Cost and Access:

• Branded product only (no generic available) with prior authorization typically required 1, 4
• Patient assistance programs and discount copay cards available for eligible patients 1, 4
• Fixed-dose combination with ezetimibe may improve adherence in patients requiring multiple agents 1, 4

Clinical Scenarios for Use:

In HeFH patients: 32% achieved LDL-C <100 mg/dL at week 12, and 27% at week 52 with bempedoic acid treatment 3. This makes it a reasonable option for HeFH patients unable to reach goals with statins alone.

In statin-intolerant patients: The muscle-sparing mechanism (hepatic-only activation) makes bempedoic acid particularly valuable, as it reduced LDL-C by 23-24.5% without the muscle symptoms associated with statins 1, 2.

Common Pitfalls to Avoid

• Do not adjust dose based on LDL-C response; the dose remains fixed at 180 mg daily regardless of lipid levels 5
• Do not combine with high-dose simvastatin (>20 mg) or pravastatin (>40 mg) due to increased statin exposure risk 5
• Do not overlook uric acid monitoring in patients with history of gout or hyperuricemia 4, 5
• Do not dismiss tendon symptoms; counsel patients about tendon rupture risk, particularly those with prior tendon disorders 4