What is the recommended treatment for a 66-year-old female with elevated Low-Density Lipoprotein (LDL) cholesterol and intolerance to statins (HMG-CoA reductase inhibitors)?

Treatment for Statin-Intolerant Patient with Severe Hypercholesterolemia

For a 66-year-old female with LDL 235 mg/dL who is statin intolerant, initiate ezetimibe 10 mg daily as first-line therapy, and if LDL remains ≥100 mg/dL after 4-12 weeks, add bempedoic acid or consider PCSK9 inhibitor therapy. 1, 2

First-Line Therapy: Ezetimibe

• Start ezetimibe 10 mg once daily as the primary lipid-lowering agent in statin-intolerant patients 1, 2
• Ezetimibe is recommended as an alternative therapy when statins cannot be tolerated (Class IIa recommendation) 1
• This agent reduces LDL-C by approximately 15-20% as monotherapy 3, 4
• Assess LDL-C response as early as 4 weeks after initiation 2
• Ezetimibe has an excellent safety profile similar to placebo and minimal drug interactions due to glucuronidation rather than CYP metabolism 3, 4

Determining Need for Additional Therapy

Risk Stratification

Your patient requires aggressive LDL lowering given:

• Age 66 years places her in a category requiring treatment 1
• Baseline LDL 235 mg/dL indicates severe primary hypercholesterolemia 1
• Need to determine if she has clinical ASCVD (secondary prevention) or is primary prevention 1

Target LDL Goals

• If she has established ASCVD (very high risk): Target LDL <55 mg/dL with ≥50% reduction 1
• If primary prevention with baseline LDL ≥190 mg/dL: Target LDL <100 mg/dL 1

Second-Line Add-On Therapy

If LDL Goals Not Met on Ezetimibe Alone:

Option 1: Add Bempedoic Acid

• For statin-intolerant patients not achieving goals on ezetimibe, combination with bempedoic acid is recommended (Class I) 1
• This represents the most recent guideline recommendation specifically for statin intolerance 1

Option 2: Add PCSK9 Inhibitor

• Consider PCSK9 inhibitor (alirocumab or evolocumab) if:
  • Primary prevention with baseline LDL ≥220 mg/dL AND on maximum tolerated therapy (ezetimibe in this case) AND LDL remains ≥130 mg/dL (Class IIb) 1
  • Secondary prevention (ASCVD present) with LDL ≥70 mg/dL on ezetimibe (Class IIa for very high risk) 1
• PCSK9 inhibitors reduce LDL-C by approximately 60% when added to existing therapy 1
• Alirocumab specifically studied in statin-intolerant patients (ODYSSEY ALTERNATIVE trial) showed 54.8% LDL reduction with fewer muscle-related adverse events (32.5%) compared to statin rechallenge (46%) 1

Alternative Approaches for Statin Intolerance

Before abandoning statins entirely, consider:

• Trying a different statin at lower doses or alternate-day dosing 1
• Attempting the lowest tolerated statin dose in combination with ezetimibe 1
• However, if truly intolerant to any statin regimen, proceed directly with non-statin therapy 1

Additional Considerations

Bile Acid Sequestrants

• Can be considered as add-on therapy if triglycerides <300 mg/dL 1
• Less commonly used due to gastrointestinal side effects and drug interactions 1
• Administer ezetimibe at least 2 hours before or 4 hours after bile acid sequestrants if used together 2

Monitoring

• Check liver enzymes as clinically indicated; consider withdrawal if ALT/AST ≥3× ULN persist 2
• Monitor for myopathy symptoms, though risk is lower without statin therapy 2
• Reassess lipid panel 4-12 weeks after initiation or dose changes, then annually 1

Common Pitfalls to Avoid

• Do not assume all statins will be intolerated without trying at least 2-3 different statins at various doses 1
• Do not delay ezetimibe initiation while attempting multiple statin trials in truly intolerant patients 1
• Do not use PCSK9 inhibitors as first-line in statin intolerance; ezetimibe (and now bempedoic acid) should be tried first due to cost-effectiveness 1
• Do not forget lifestyle modifications including diet, exercise, and weight management as foundational therapy 1