What are the alternative lipid-lowering treatment options for a patient who refuses statin therapy and is already taking 10mg of Zetia (ezetimibe)?

Alternative Lipid-Lowering Options for Statin-Refusing Patients Already on Ezetimibe 10mg

Add bempedoic acid 180 mg daily to the current ezetimibe regimen as the next step, which will provide an additional 15-25% LDL-C reduction and has demonstrated cardiovascular outcomes benefit in statin-intolerant patients. 1

Treatment Algorithm Based on Cardiovascular Risk

For Very High-Risk Patients (Clinical ASCVD with recurrent events, multiple high-risk conditions)

• Add bempedoic acid 180 mg daily to the current ezetimibe 10 mg as the preferred next agent, targeting LDL-C <55 mg/dL and ≥50% reduction from baseline 2, 1
• Bempedoic acid demonstrated a 13% reduction in major adverse cardiovascular events (MACE) in the CLEAR Outcomes trial specifically in statin-intolerant patients 1
• The combination of bempedoic acid plus ezetimibe can lower LDL-C by approximately 35% total 1
• If LDL-C remains ≥55 mg/dL after 4-12 weeks, add a PCSK9 inhibitor (evolocumab or alirocumab preferred over inclisiran due to outcomes data) for an additional ~50% LDL-C reduction 2, 1

For High-Risk Patients (Clinical ASCVD without very high-risk features)

• Add bempedoic acid 180 mg daily to ezetimibe, targeting LDL-C <70 mg/dL and ≥50% reduction from baseline 2, 1
• Monitor liver function tests when initiating bempedoic acid, as it can cause transaminase elevations 1
• Monitor uric acid levels, as bempedoic acid increases gout risk in susceptible patients 3
• Consider adding a PCSK9 inhibitor if LDL-C remains ≥70 mg/dL after bempedoic acid addition and the patient requires >25% additional LDL-C lowering 2, 1

For Moderate-Risk Patients (Primary prevention with diabetes or 10-year ASCVD risk ≥7.5%)

• Add bempedoic acid 180 mg daily to ezetimibe if LDL-C remains ≥100 mg/dL or non-HDL-C ≥130 mg/dL 2, 1
• PCSK9 inhibitors do not have an established role for primary prevention in the absence of clinical ASCVD or baseline LDL-C ≥190 mg/dL 2, 1
• Target LDL-C <100 mg/dL or at least 30-49% reduction from baseline 2

Key Advantages of Bempedoic Acid in This Context

• Bempedoic acid works upstream from statins in the cholesterol synthesis pathway but only activates in the liver, not in skeletal muscle, resulting in very low rates of muscle-related adverse effects 1
• This mechanism makes it particularly valuable for statin-refusing or statin-intolerant patients 1
• It is an oral medication with once-daily dosing, improving adherence compared to injectable PCSK9 inhibitors 1
• The CLEAR Outcomes trial provides cardiovascular outcomes data specifically in statin-intolerant patients, which is the most relevant evidence for this clinical scenario 1

PCSK9 Inhibitor Considerations

• PCSK9 inhibitors (evolocumab, alirocumab) are preferred over inclisiran as the initial PCSK9 inhibitor choice due to demonstrated cardiovascular outcomes benefits in the FOURIER and ODYSSEY Outcomes trials 2
• Inclisiran may be considered for patients with demonstrated poor adherence to PCSK9 monoclonal antibodies, adverse effects from both PCSK9 mAbs, or those unable to self-inject 2
• PCSK9 inhibitors reduce LDL-C by approximately 50% and are well-tolerated in statin-intolerant patients 1, 3
• Assess LDL-C response every 3-6 months when using PCSK9 inhibitors 1

Alternative Options (Less Preferred)

• Bile acid sequestrants (colesevelam, cholestyramine) may be considered if triglycerides are <300 mg/dL and the patient cannot tolerate bempedoic acid, providing 15-30% LDL-C reduction 2, 1
• Bile acid sequestrants have a modest hypoglycemic effect that may benefit diabetic patients 2
• However, they have significant gastrointestinal side effects, drug-drug interactions, and high pill burden, making them less practical 1
• Ezetimibe must be taken ≥2 hours before or ≥4 hours after bile acid sequestrants to avoid reduced efficacy 4

Critical Monitoring and Follow-Up

• Obtain lipid panel 4-8 weeks after adding any new agent to assess response 1
• Monitor liver enzymes (ALT/AST) at baseline and periodically when using bempedoic acid 1
• Monitor uric acid levels and assess for gout symptoms with bempedoic acid 1, 3
• Continue to assess medication adherence and reinforce lifestyle modifications (saturated fat <7% of calories, trans fat <1%, cholesterol <200 mg/day) 1

When to Refer to a Lipid Specialist

• Refer if baseline LDL-C ≥190 mg/dL not due to secondary causes (hypothyroidism, nephrosis, extreme dietary patterns) 2, 1
• Refer for complex mixed dyslipidemia or severe hypertriglyceridemia (>500 mg/dL) 2, 1
• Refer if unable to achieve target LDL-C despite combination therapy with ezetimibe, bempedoic acid, and PCSK9 inhibitor 1

Common Pitfalls to Avoid

• Do not use PCSK9 inhibitors as first-line after ezetimibe in primary prevention without trying bempedoic acid first, as PCSK9 inhibitors lack an established role in this setting and are significantly more expensive 1
• Do not add bempedoic acid if the patient has severe renal impairment (eGFR <30 mL/min/1.73 m²), as it is contraindicated 1
• Do not overlook secondary causes of hyperlipidemia (hypothyroidism, nephrotic syndrome, medications) before escalating therapy 2, 1
• Reassess the statin refusal - 59.3% of patients previously treated with statins reported willingness to try again, and alternative dosing regimens (every other day, twice weekly) may be tolerated 1, 5