What are the alternatives to statins for lowering Low-Density Lipoprotein (LDL) cholesterol?

Non-Statin Options for Lowering LDL Cholesterol

For patients who cannot achieve adequate LDL-C reduction with statins or who are statin-intolerant, ezetimibe should be considered as the first-line non-statin therapy due to its demonstrated safety, tolerability, and convenience as a single daily dose. 1

First-Line Non-Statin Options

• Ezetimibe (10 mg daily) is the preferred initial non-statin agent for most patients requiring additional LDL-C lowering, providing an additional 15-20% reduction in LDL-C levels 1, 2
• Ezetimibe can be used as monotherapy in statin-intolerant patients or as add-on therapy to maximally tolerated statin doses 3
• Bile acid sequestrants (BAS) may be considered as an alternative if patients are ezetimibe-intolerant, particularly when triglycerides are <300 mg/dL 1
• BAS may have modest hypoglycemic effects that can benefit some diabetic patients 1

Advanced Non-Statin Options

• PCSK9 inhibitors (evolocumab, alirocumab) can provide substantial additional LDL-C lowering (50-60%) and are appropriate for:

  • Patients with familial hypercholesterolemia 1
  • Very high-risk patients with atherosclerotic cardiovascular disease (ASCVD) who have not achieved LDL-C goals on maximally tolerated statin plus ezetimibe 1
  • Patients with statin intolerance who require significant LDL-C reduction 1

• Bempedoic acid (ATP citrate lyase inhibitor) is a valuable option for statin-intolerant patients 4

Combination Approaches

• For patients with <50% reduction in LDL-C on maximally tolerated statin therapy, adding ezetimibe should be considered 1
• In very high-risk ASCVD patients with LDL-C ≥70 mg/dL despite maximally tolerated statin therapy, consider adding ezetimibe or a PCSK9 inhibitor 1
• Combination therapy with statin plus ezetimibe can provide additional 15-20% LDL-C reduction beyond statin monotherapy 5, 2

Lifestyle Modifications

• Therapeutic lifestyle changes should be implemented alongside medication therapy, including:
  • Reducing saturated fat intake to <7% of total calories 2
  • Reducing dietary cholesterol to <200 mg/day 2
  • Increasing physical activity and weight management if needed 2
  • Consider adding plant stanols/sterols to diet for additional LDL-C lowering 1

Special Considerations

• For patients with familial hypercholesterolemia and extremely high LDL-C levels, more aggressive combination therapy may be required 5, 6
• In statin-intolerant patients, consider sequential trials of different statins, including low or intermittent dosing, before moving to non-statin therapies 1, 6
• For patients with mixed dyslipidemia (elevated LDL-C and triglycerides), fibrates may be considered, but use caution with statin-fibrate combinations due to increased myopathy risk 2, 7

Emerging Therapies

• Inclisiran (small interfering RNA targeting PCSK9) shows effects comparable to PCSK9 monoclonal antibodies 4
• Antisense oligonucleotides targeting apolipoprotein B can reduce LDL-C in homozygous familial hypercholesterolemia 7, 4
• Evinacumab (angiopoietin-like 3 monoclonal antibody) reduces LDL-C in patients with refractory hypercholesterolemia 4

Monitoring Recommendations

• Check lipid panel and liver function tests 4-6 weeks after initiating therapy to assess response and tolerability 5, 2
• For patients on combination therapy, monitor for potential drug interactions and adverse effects 3
• The goal should be to achieve at least a 30-50% reduction in LDL-C from baseline 5, 2, 8

Remember that the degree of LDL-C reduction is more important than the specific means used to achieve it, with each 1% reduction in LDL-C corresponding to approximately 1% reduction in coronary heart disease risk 8.