Nexletol (Bempedoic Acid) Efficacy for LDL-C Lowering
Nexletol (bempedoic acid) reduces LDL-C by approximately 15-25% when used alone, and by 28-45% depending on background therapy, with the highest reductions seen in statin-intolerant patients not on background statins. 1
LDL-C Reduction: Magnitude and Context
Monotherapy Efficacy
- Bempedoic acid 180 mg daily lowers LDL-C by approximately 15-24% as monotherapy, which is substantially less potent than high-intensity statins (which achieve ~50% reduction) 2, 3
- The FDA label reports a 20% mean reduction in LDL-C at 6 months in the CLEAR Outcomes trial population 1
- In patients not taking statins, bempedoic acid achieves 24% LDL-C reduction, compared to 15% in those on background statin therapy 2
Combination Therapy Performance
- When added to maximally tolerated statin therapy, bempedoic acid provides an additional 18% reduction in LDL-C at 12 weeks 1
- Bempedoic acid combined with ezetimibe produces approximately 35% LDL-C reduction, offering a more robust lipid-lowering effect 2
- In real-world Italian clinical practice, patients on intensive statins/ezetimibe who added bempedoic acid achieved 28% LDL-C reduction, while statin-intolerant patients achieved 45% reduction 4
Cardiovascular Outcomes: The Critical Context
Bempedoic acid reduces major adverse cardiovascular events (MACE) by 13% compared to placebo in statin-intolerant patients, which is clinically meaningful but more modest than the 24-37% risk reduction seen with statins. 2, 3
CLEAR Outcomes Trial Results
- The primary composite endpoint (MACE-4: CV death, nonfatal MI, nonfatal stroke, or coronary revascularization) was reduced with hazard ratio 0.87 (95% CI: 0.79-0.96; p=0.0037) 1
- The key secondary endpoint (MACE-3: CV death, nonfatal MI, or nonfatal stroke) showed hazard ratio 0.85 (95% CI: 0.76-0.96; p=0.0058) 1
- Non-fatal myocardial infarction was reduced by 27% (HR 0.73,95% CI: 0.62-0.87), representing the most robust individual component benefit 1
- Coronary revascularization was reduced by 19% (HR 0.81,95% CI: 0.72-0.92) 1
Special Population: Diabetes
- In patients with diabetes, bempedoic acid demonstrated a 17% reduction in MACE-4 events, slightly better than the overall population 2, 3
- For primary prevention in high-risk diabetic patients, bempedoic acid showed a 30% reduction in primary composite outcomes compared to placebo 2
Additional Lipid Effects
- Non-HDL-C, apolipoprotein B, and total cholesterol are all significantly reduced with bempedoic acid therapy 1, 5
- High-sensitivity C-reactive protein (hs-CRP) is significantly reduced, suggesting anti-inflammatory effects beyond lipid lowering 5, 6
- Minimal effect on lipoprotein(a) levels, so this drug should not be chosen if Lp(a) reduction is a therapeutic goal 5
- HDL-C decreases by approximately 6%, and triglycerides increase modestly by 3% 1
Clinical Positioning and Treatment Algorithm
When to Use Bempedoic Acid
Bempedoic acid is FDA-approved for two distinct indications: 1
- Cardiovascular risk reduction in statin-intolerant patients with established CVD or high CVD risk (including those not taking any statin)
- LDL-C lowering as adjunct therapy in primary hyperlipidemia including heterozygous familial hypercholesterolemia
Recommended Treatment Sequence
For statin-intolerant patients, the American College of Cardiology recommends the following hierarchy: 2, 7
- First-line alternative: Ezetimibe (15-25% LDL-C reduction)
- Second-line addition: Bempedoic acid (adds 15-25% further reduction)
- Third-line consideration: PCSK9 inhibitors for very high-risk patients if LDL-C remains ≥70 mg/dL despite ezetimibe and bempedoic acid 7
For patients on maximally tolerated statins not reaching LDL-C goals: 2, 3
- Add ezetimibe first (provides 15-25% additional reduction)
- If still not at goal, add bempedoic acid (provides additional 15-18% reduction)
- Reserve PCSK9 inhibitors for highest-risk patients or those with baseline LDL-C ≥190 mg/dL
Safety Profile and Tolerability
Bempedoic acid is activated only in the liver and not in skeletal muscle, which explains its low incidence of muscle-related adverse effects compared to statins. 2, 3
Key Safety Considerations
- Muscle-related adverse events are rare (10% in real-world practice, mostly reversible), making this an excellent option for statin-intolerant patients 4, 8
- Hyperuricemia and gout risk is increased; monitor uric acid levels before initiation and when clinically indicated 2, 1
- Tendon rupture risk exists; discontinue immediately if tendon rupture occurs, and consider discontinuation with tendinitis symptoms 2
- Elevated liver enzymes, gallstones, and abnormal liver function tests occurred more frequently in the CLEAR Outcomes trial 2
- Adherence is excellent (99% in real-world studies) with 90% persistence, likely due to favorable tolerability 4
Contraindications and Monitoring
- Avoid in pregnancy; discontinue when pregnancy is recognized unless benefits outweigh risks 2
- Avoid concomitant simvastatin >20 mg daily or pravastatin >40 mg daily 2
- Monitor liver function tests and assess uric acid levels as clinically indicated 2, 7
Real-World Performance and Target Achievement
In real-world Italian clinical practice, 46% of patients achieved therapeutic LDL-C targets with bempedoic acid, with the drug primarily used in high-risk patients who failed to reach goals with statins/ezetimibe. 4
- Maximum LDL-C lowering effects occur at Week 4 of therapy 1
- The drug demonstrates consistent efficacy across subgroups including age, sex, race, diabetes status, baseline LDL-C, and background therapies 1
- Cost savings were achieved in statin-intolerant patients by avoiding more expensive PCSK9 inhibitors 4
Critical Pitfalls to Avoid
Do not use bempedoic acid as first-line therapy over statins in statin-tolerant patients—statins remain superior for cardiovascular risk reduction with 24-37% relative risk reduction versus 13% with bempedoic acid 3
Do not skip ezetimibe in the treatment sequence for statin-intolerant patients—ezetimibe should be tried first before bempedoic acid per ACC guidelines 7
Do not assume statin intolerance without proper evaluation—patients must have attempted at least 2 different statins (including one at the lowest approved dose) before being classified as statin-intolerant 2, 7
Do not overlook hyperuricemia monitoring—assess uric acid before initiation and monitor for signs/symptoms of gout, initiating urate-lowering therapy as needed 2
Do not use for Lp(a) reduction—bempedoic acid has minimal effect on lipoprotein(a) levels 5