What are the dosing, administration, monitoring, contraindications, precautions, adverse effects, and alternative therapies for Nexletol (bempedoic acid) in adults with primary hyperlipidemia who need additional LDL‑C reduction beyond a maximally tolerated statin or cannot use statins?

Nexletol (Bempedoic Acid) for Primary Hyperlipidemia

Dosing and Administration

Bempedoic acid is dosed at 180 mg orally once daily, with or without food, and this dose is fixed regardless of LDL-C response. 1

• The tablet must be swallowed whole 1
• When using the fixed-dose combination with ezetimibe, administer one tablet (180 mg bempedoic acid/10 mg ezetimibe) once daily 1
• If combining with bile acid sequestrants, take bempedoic acid either 2 hours before or 4 hours after the bile acid sequestrant to avoid binding interactions 1

Critical Drug Interactions

Avoid concomitant simvastatin >20 mg daily and pravastatin >40 mg daily due to significantly increased statin exposure risk. 1

• These interactions occur because bempedoic acid inhibits OATP1B1/1B3 transporters, increasing statin blood levels 1
• Lower-dose statins can be safely combined with bempedoic acid if tolerated

Indications and Treatment Algorithm

Bempedoic acid is indicated as adjunct therapy for adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering beyond maximally tolerated statin therapy. 2, 3

Stepwise Approach for Statin-Intolerant Patients:

1. First, confirm true statin intolerance by attempting at least 2 different statins at varying doses 4
2. Initiate ezetimibe 10 mg daily as first-line nonstatin therapy 4
3. Add bempedoic acid 180 mg daily if LDL-C targets remain unmet 4
4. Consider the fixed-dose combination (bempedoic acid 180 mg/ezetimibe 10 mg) which achieves 38% additional LDL-C reduction when added to statin therapy 4

For Patients on Maximally Tolerated Statins:

• Add ezetimibe first if LDL-C remains ≥100 mg/dL in severe hypercholesterolemia 2
• Consider bempedoic acid as an alternative or additional agent when ezetimibe alone is insufficient 2

Efficacy Data

Bempedoic acid reduces LDL-C by approximately 21-24.5% as monotherapy and provides an additional 15-17.8% reduction when added to existing statin therapy. 4, 3

• The fixed-dose combination with ezetimibe achieves 38% additional LDL-C reduction on top of statin therapy 4
• In the CLEAR Outcomes trial of 13,970 statin-intolerant patients, bempedoic acid reduced major adverse cardiovascular events by 13% overall (HR 0.87; 95% CI 0.79-0.96) 3
• Primary prevention patients experienced a 32% relative risk reduction (HR 0.68; 95% CI 0.53-0.87; NNT=43) 3
• Secondary prevention patients showed a modest 9% risk reduction (HR 0.91; 95% CI 0.81-1.01), which did not reach statistical significance 3
• Non-fatal myocardial infarction was reduced by 23% (HR 0.77) and coronary revascularization by 19% (HR 0.81) 3

Mechanism of Action

Bempedoic acid is a liver-targeted prodrug that inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway. 4, 3

• It requires activation by very-long-chain acyl-CoA synthetase-1, which is present in the liver but not in skeletal muscle 3
• This explains why bempedoic acid does not cause muscle-related adverse events unlike statins 3
• The mechanism results in upregulation of LDL receptors and improved LDL clearance 4

Monitoring Parameters

Monitor serum uric acid before initiation and assess for symptoms of hyperuricemia during treatment, as bempedoic acid increases uric acid by a mean of 0.8 mg/dL. 1, 3

• Monitor liver function tests at baseline and periodically as clinically indicated 1, 4
• Watch for signs of tendinitis or tendon rupture and discontinue immediately if tendon rupture occurs 1
• Assess for gout symptoms, as gout occurred in 3.1% vs 2.1% with placebo 3
• Monitor for cholelithiasis (2.2% vs 1.2% with placebo) 3

Adverse Effects and Safety Profile

Bempedoic acid has a favorable safety profile with muscle-related adverse events occurring LESS frequently than placebo (myalgia 4.7% vs 7.2%). 4, 3

Common Adverse Events (vs Placebo):

• Gout: 3.1% vs 2.1% 3
• Tendon rupture: 0.5% vs 0% 3
• Cholelithiasis: 2.2% vs 1.2% 3
• Elevated liver enzymes: increased rates compared to placebo 3
• Benign prostatic hyperplasia: 1.3% vs 0.1% 3
• Atrial fibrillation: 1.7% vs 1.1% 3

Key Safety Advantages:

• Does not cause statin-associated muscle symptoms due to lack of activation in skeletal muscle 5, 6
• Does not induce hyperglycemia unlike statins 7
• Overall safety comparable to placebo except for uric acid elevation and rare tendon rupture 5

Contraindications and Precautions

Avoid in patients with active tendon disorders or history of tendon rupture, and use caution in those with hyperuricemia or gout. 3

• Do not exceed simvastatin 20 mg or pravastatin 40 mg when combining with bempedoic acid 1
• Monitor closely for gout flares, especially in patients with baseline elevated uric acid 3
• Use caution in patients with hepatic impairment and monitor liver function tests 1

Alternative Therapies

For patients requiring additional LDL-C lowering beyond maximally tolerated statins and ezetimibe, PCSK9 inhibitors (evolocumab, alirocumab) or inclisiran are alternatives. 2

• PCSK9 inhibitors achieve ≥50% additional LDL-C reduction and are well tolerated 2
• Inclisiran allows less frequent administration (day 1, day 90, then every 6 months) with 50-52% LDL-C reduction 2
• Bile acid sequestrants (e.g., colesevelam 3.75 g daily) provide an additional 18.5% reduction but are limited by gastrointestinal side effects and drug interactions 2
• Bempedoic acid offers advantages over PCSK9 inhibitors in terms of oral administration, lower cost, and proven cardiovascular outcomes in statin-intolerant patients 4, 3

Clinical Pearls

• Do not adjust the 180 mg daily dose based on LDL-C response—the dose is fixed 1
• Bempedoic acid is particularly effective in primary prevention, with a 32% event reduction compared to only 9% in secondary prevention 3
• The combination with ezetimibe achieves LDL-C reductions comparable to moderately intensive statins 7
• In oral triple combination with high-intensity statin and ezetimibe, LDL-C reductions of approximately two-thirds can be achieved 7