Bempedoic Acid in Hypercholesterolemia Management
Bempedoic acid is an effective adjunct therapy for patients with hypercholesterolemia who require additional LDL-C lowering beyond maximally tolerated statin therapy, particularly valuable for statin-intolerant patients due to its liver-selective activation that avoids muscle-related side effects. 1, 2
Mechanism of Action
Bempedoic acid works through a novel mechanism:
- Inhibits ATP-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway 3
- Functions as a prodrug that requires activation by very long-chain acyl-CoA synthetase 1 (ACSVL1), which is primarily expressed in the liver but not in muscle tissue 2, 3
- This liver-selective activation provides a key advantage for patients with statin-associated muscle symptoms 1, 2
- Reduces acetyl-CoA availability for cholesterol synthesis 2
- Upregulates LDL receptors, improving LDL clearance from the bloodstream 3
Efficacy
Bempedoic acid demonstrates significant lipid-lowering effects:
- Reduces LDL-C by approximately 15-25% when added to maximally tolerated statin therapy 2
- Monotherapy reduces LDL-C by approximately 24.5% in statin-intolerant patients 1
- When combined with ezetimibe, provides up to 38% additional LDL-C reduction 1, 2
- Also significantly lowers:
Cardiovascular Outcomes
The CLEAR Outcomes trial demonstrated significant cardiovascular benefits:
- 13% reduction in composite major adverse cardiovascular events (MACE) compared to placebo 2, 4
- 24% reduction in myocardial infarction risk 4
- 31% reduction in unstable angina 4
- Greater benefit in primary prevention (30% reduction) compared to secondary prevention 2
- 17% reduction in MACE in patients with diabetes 2
Clinical Applications
Bempedoic acid is FDA-approved for:
- Adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL-C lowering 1, 2
- Use as an adjunct to diet and maximally tolerated statin therapy 1
- Available as monotherapy (180 mg daily) or in fixed-dose combination with ezetimibe 10 mg 1, 2
Patient Selection
Bempedoic acid is particularly valuable for:
- Patients with statin intolerance due to muscle-related side effects 1, 2
- Patients who have not achieved ≥50% LDL-C reduction and LDL-C <70 mg/dL on maximally tolerated statin therapy 2
- Patients with established ASCVD or HeFH requiring additional LDL-C lowering 1, 2
- Patients with adherence issues who may benefit from the combination preparation with ezetimibe 1
Safety Profile
Bempedoic acid has a generally favorable safety profile with some notable considerations:
- Overall safety comparable to placebo in most aspects 4
- Increased risk of gout (1.2-1.5% vs. 0.3-0.4% with placebo) due to elevated uric acid levels 1, 4
- Slight increases in:
- Higher incidence of adverse events leading to discontinuation (10.9% vs. 7.1% with placebo) 5
Pharmacokinetics
Key pharmacokinetic properties include:
- Oral administration with median time to maximum concentration of 3.5 hours 3
- Food does not affect bioavailability 3
- Mean half-life of 21 ± 11 hours at steady-state 3
- Steady-state achieved after 7 days 3
- Primary elimination through glucuronide metabolism 3
- No dose adjustment needed with food 3
Clinical Considerations
Important considerations when prescribing bempedoic acid:
- Monitor for elevated uric acid levels and symptoms of gout 1, 2
- Watch for potential tendon disorders 2
- Consider cost implications as it is available as a branded product 1
- Patient assistance programs and discount copay cards are available for eligible patients 1
- May be considered after ezetimibe or PCSK9 inhibitors in the treatment algorithm 2
Bempedoic acid represents an important addition to the lipid-lowering armamentarium, particularly for patients who cannot tolerate statins or require additional LDL-C reduction despite maximally tolerated statin therapy.