What are non-statin cholesterol medications aside from Zetia (ezetimibe) and fenofibrate?

Non-Statin Cholesterol Medications Beyond Ezetimibe and Fenofibrate

For patients requiring cholesterol-lowering therapy who cannot take statins, ezetimibe, or fenofibrate, the most effective alternative options are bile acid sequestrants, PCSK9 inhibitors, and niacin-based preparations. These medications offer different mechanisms of action and varying degrees of LDL-C reduction to address cardiovascular risk.

Bile Acid Sequestrants (BAS)

• BAS work by binding bile acids in the intestinal lumen, diverting them from enterohepatic circulation, which depletes the liver of bile and upregulates LDL receptor activity 1
• Examples include cholestyramine, colestipol, and colesevelam 1
• Typically reduce LDL-C by 18-25% as monotherapy 1
• Good evidence from randomized controlled trials showing approximately 20% reduction in cardiovascular disease events in primary prevention 1
• Colesevelam has the added benefit of modestly improving glycemic control in patients with type 2 diabetes 1
• Common side effects include gastrointestinal complaints (particularly constipation) and potential drug interactions 1
• Contraindicated in patients with triglycerides ≥300 mg/dL due to risk of severe hypertriglyceridemia 1

PCSK9 Inhibitors

• Powerful LDL-lowering drugs that reduce LDL-C by 40-65% 1
• Examples include evolocumab and alirocumab 1
• Strong evidence for cardiovascular risk reduction when added to statin therapy, with approximately 50% reduction in cardiovascular events 1, 2
• Generally well-tolerated but long-term safety data continues to accumulate 1
• Administered as subcutaneous injections rather than oral medications 2
• More expensive than other non-statin therapies, which may limit accessibility 1
• In the FOURIER trial, evolocumab significantly reduced the risk of cardiovascular events including myocardial infarction, stroke, and coronary revascularization 2

Niacin-Based Preparations

• Available as crystalline niacin (short-acting) or extended-release niacin 1
• Reduce LDL-C by 20-25% and also significantly lower triglycerides (up to 50%) while raising HDL-C (up to 30%) 1
• As monotherapy, has shown approximately 20% reduction in cardiovascular disease events with reductions in mortality profile 1
• Also lowers lipoprotein(a) by up to 30%, which may provide additional cardiovascular benefit 1
• Side effects include flushing, pruritus, gastrointestinal disturbances, and potential liver enzyme elevations 1
• More recent trials have shown neutral outcomes when added to statin therapy in patients with well-controlled LDL-C 1

Other Emerging Options

• Bempedoic acid: ATP citrate lyase inhibitor that reduces LDL-C by 20-28% 1
• Lomitapide: Microsomal triglyceride transfer protein (MTP) inhibitor that reduces LDL-C by 35-50%, primarily used in homozygous familial hypercholesterolemia 1
• Mipomersen: Apolipoprotein B antisense oligonucleotide that reduces LDL-C by 30-45%, also primarily for homozygous familial hypercholesterolemia 1

Combination Therapy Considerations

• Combining non-statin therapies may provide additive LDL-C lowering effects 1
• For patients at very high cardiovascular risk, combination therapy may be necessary to achieve target LDL-C levels 1
• When considering combinations, monitor for potential drug interactions and cumulative side effects 1
• The addition of ezetimibe to a bile acid sequestrant can provide complementary LDL-C lowering through different mechanisms 3

Clinical Decision-Making Algorithm

1. First-line non-statin option (if ezetimibe and fenofibrate cannot be used):

   • PCSK9 inhibitors for highest LDL-C reduction (40-65%) and demonstrated cardiovascular benefit 1, 2
   • Consider cost and insurance coverage limitations 1

2. Second-line options:

   • Bile acid sequestrants (particularly colesevelam for better tolerability) 1
   • Consider if moderate LDL-C reduction (18-25%) is sufficient 1
   • Avoid in patients with elevated triglycerides 1

3. Third-line option:

   • Niacin-based preparations 1
   • Consider when additional benefits on triglycerides and HDL-C are desired 1
   • Monitor for flushing and other side effects 1

4. For specialized cases:

   • Newer agents like bempedoic acid, lomitapide, or mipomersen for specific patient populations 1
   • Consider referral to lipid specialist for complex cases 1

Monitoring Recommendations

• Assess lipid levels 4-8 weeks after initiating therapy to evaluate response 4
• Monitor for medication-specific adverse effects 1
• Adjust therapy based on LDL-C response and tolerability 1
• For bile acid sequestrants, monitor for potential drug interactions with other medications 1
• For niacin, monitor liver enzymes periodically 1

Remember that while statins remain the cornerstone of lipid-lowering therapy, these non-statin options provide important alternatives for patients who cannot tolerate statins or require additional LDL-C lowering beyond what statins alone can provide 1.