Bempedoic Acid for Elevated LDL Cholesterol in Statin-Intolerant Patients
Bempedoic acid is an excellent treatment option for patients with elevated LDL cholesterol who cannot tolerate statins, offering 21-24.5% LDL-C reduction without causing muscle-related side effects and proven cardiovascular benefit with a 13% reduction in major adverse cardiovascular events. 1
Why Bempedoic Acid Works for Statin-Intolerant Patients
The key advantage is its muscle-sparing mechanism. Bempedoic acid is a prodrug activated exclusively by very-long-chain acyl-CoA synthetase-1 (ACSVL1), an enzyme present in liver cells but not in skeletal muscle. 1, 2 This hepatic-specific activation eliminates the statin-associated muscle symptoms that plague many patients, as the drug never becomes active in muscle tissue. 1
The drug 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, 2
Evidence for Cardiovascular Outcomes
The CLEAR Outcomes trial provides definitive evidence that bempedoic acid reduces cardiovascular events, not just cholesterol numbers. In 13,970 statin-intolerant patients with established ASCVD (70%) or high cardiovascular risk (30%), bempedoic acid reduced the composite outcome of four-point major adverse cardiovascular events by 13% compared with placebo. 1
The benefit was particularly striking in primary prevention patients, with a 30% reduction in the primary composite outcome and a hazard ratio of 0.68 (95% CI 0.53-0.87) compared to 0.91 (95% CI 0.81-1.01) in secondary prevention. 1
Mean baseline LDL-C was 139 mg/dL, and bempedoic acid reduced it by 29 mg/dL compared with placebo. 1
Efficacy Data
As monotherapy in statin-intolerant patients: Bempedoic acid 180 mg daily reduces LDL-C by approximately 21-24.5% compared with placebo. 1, 3
When added to existing statin therapy: Provides an additional 15-17.8% LDL-C reduction. 1
In combination with ezetimibe: The fixed-dose combination (180 mg bempedoic acid/10 mg ezetimibe) achieves 38% additional LDL-C reduction when added to statin therapy. 1
Bempedoic acid also reduces non-HDL cholesterol, apolipoprotein B, total cholesterol, and high-sensitivity C-reactive protein. 4, 3
FDA-Approved Indications
Bempedoic acid is FDA-approved as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering. 1, 2
Treatment Algorithm for Statin-Intolerant Patients
First, confirm true statin intolerance: The patient must have documented intolerance to at least 2 different statins, with at least 1 attempted at the lowest approved daily dose. 1, 3
Step 1 - Initiate ezetimibe 10 mg daily first. This provides 15-20% LDL-C reduction with minimal side effects and has proven cardiovascular outcomes benefit. 5, 6
Step 2 - Add bempedoic acid 180 mg daily if LDL-C targets are not met. For very high-risk patients, add bempedoic acid if LDL-C remains ≥55 mg/dL; for high-risk patients, add if LDL-C remains ≥70 mg/dL. 5, 6
Step 3 - Consider PCSK9 inhibitors (evolocumab or alirocumab) if LDL-C remains elevated despite ezetimibe plus bempedoic acid, or if the patient cannot tolerate these therapies. 5, 6
Alternative approach: The fixed-dose combination of bempedoic acid 180 mg plus ezetimibe 10 mg can be used to simplify the regimen and improve adherence. 1, 5
Dosing and Administration
Standard dose: 180 mg orally once daily, with or without food. 7, 2 The tablet should be swallowed whole. 7
No dose adjustment needed for mild or moderate renal impairment (eGFR ≥30 mL/min/1.73 m²) or mild to moderate hepatic impairment (Child-Pugh A or B). 2
Limited experience in severe renal impairment (eGFR <30 mL/min/1.73 m²) and no data in end-stage renal disease on dialysis. 2
Not studied in severe hepatic impairment (Child-Pugh C). 2
Critical Drug Interactions
Avoid concomitant simvastatin >20 mg daily due to 2-fold increase in simvastatin exposure. 7, 2
Avoid concomitant pravastatin >40 mg daily due to 2-fold increase in pravastatin exposure. 7, 2
If combining with bile acid sequestrants: Take bempedoic acid either 2 hours before or 4 hours after the bile acid sequestrant. 7
Atorvastatin and rosuvastatin interactions are minimal (1.7-fold increase) and do not require dose adjustment. 2
Safety Profile and Monitoring
Muscle-related adverse events are NOT increased. In the CLEAR Serenity trial of statin-intolerant patients, myalgia occurred in 4.7% with bempedoic acid versus 7.2% with placebo. 3 This is the critical advantage over statins.
Monitor serum uric acid: Bempedoic acid increases uric acid by a mean of 0.8 mg/dL through weak OAT2 inhibition. 7, 2 Gout occurred in 1.5% versus 0.4% with placebo. 1
Tendon rupture risk: Occurred in 0.5% versus 0% with placebo. 1 Avoid in patients with history of tendon rupture and discontinue immediately if tendon rupture occurs. 7
Other adverse effects to monitor:
- Benign prostatic hyperplasia: 1.3% vs 0.1% 1
- Atrial fibrillation: 1.7% vs 1.1% 1
- Creatine kinase elevation: 1.0% vs 0.6% 1
- Gallstones and abnormal liver function tests 1
Monitor liver function tests at baseline and periodically as clinically indicated. 7
Common Pitfalls to Avoid
Do not adjust the dose based on LDL-C response. The dose is fixed at 180 mg daily regardless of lipid levels. 7
Do not combine with high-dose simvastatin or pravastatin due to significant drug interactions. 7, 2
Do not use in patients with active gout or history of tendon disorders without careful risk-benefit assessment. 5, 7
Do not assume all "statin intolerance" is real. Confirm true intolerance by attempting at least 2 different statins at varying doses before labeling a patient as statin-intolerant. 1
Cost and Access Considerations
Bempedoic acid is commercially available as a branded product (NEXLETOL) and typically requires prior authorization from insurance plans. 1, 5 However, patient assistance programs and discount copay cards are available for eligible patients. 1, 5
The fixed-dose combination with ezetimibe may improve adherence in patients requiring multiple agents and can simplify prior authorization processes. 1, 5