What are the alternatives to statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) for lowering Low-Density Lipoprotein (LDL) cholesterol?

Statin Alternatives for LDL Cholesterol Lowering

For patients who cannot tolerate statins, ezetimibe is the preferred first-line alternative, followed by bempedoic acid or PCSK9 inhibitors depending on the degree of LDL-C lowering required and cardiovascular risk level. 1

Hierarchical Approach to Statin Alternatives

First-Line Alternative: Ezetimibe

• Ezetimibe 10 mg daily is the preferred initial non-statin agent for most patients requiring LDL-C lowering, providing 15-20% reduction in LDL-C levels 2, 3
• Can be used alone when additional statin therapy is not possible, or in combination with maximally tolerated statin doses 3
• Excellent safety profile with no skeletal muscle symptoms or increased risk of new-onset diabetes 4
• FDA-approved for adults with primary hyperlipidemia and heterozygous familial hypercholesterolemia 3
• Should be administered ≥2 hours before or ≥4 hours after bile acid sequestrants 3

Second-Line Alternative: Bempedoic Acid

• Bempedoic acid lowers LDL-C by 24% in patients not taking statins and 15% in those on statins 1
• Acts in the same cholesterol synthesis pathway as statins but lacks activity in skeletal muscle, limiting muscle-related adverse effects 1
• The CLEAR Outcomes trial demonstrated a 13% reduction in major adverse cardiovascular events in statin-intolerant patients with established ASCVD or high ASCVD risk 1
• Small increases in uric acid levels and gout episodes (1.5% vs 0.4%) have been observed 1, 4
• Available as monotherapy or in combination with ezetimibe for enhanced LDL-C lowering (additional 19% reduction) 1

Third-Line Alternative: PCSK9 Inhibitors

Monoclonal Antibodies (Evolocumab and Alirocumab)

• Provide 50-60% reduction in LDL-C when added to maximally tolerated statin therapy 1
• Reduced major adverse cardiovascular events by 15-20% in the FOURIER and ODYSSEY OUTCOMES trials 1
• Excellent safety profile with fewer skeletal muscle-related adverse effects in statin-intolerant populations 1
• Administered by subcutaneous injection every 2-4 weeks 5
• Small increase in injection site reactions (usually mild to moderate intensity) 4

siRNA Therapy (Inclisiran)

• Reduces LDL-C by 49-52% with less frequent dosing (day 1, day 90, then every 6 months) 1
• Exploratory analyses showed reduced cardiovascular events (7.4% vs 10.2% with placebo in one trial) 1
• Maintained 45% LDL-C reduction through 4 years in the ORION-3 extension trial 1
• Cardiovascular outcome trials are ongoing 1

Fourth-Line Alternative: Bile Acid Sequestrants

• Consider when ezetimibe is not tolerated and triglycerides are <300 mg/dL 2
• Cholestyramine starting dose is 4 grams once or twice daily, with maintenance dose of 8-16 grams daily divided into two doses 6
• May have modest hypoglycemic effects beneficial for diabetic patients 2
• Must be taken separately from other medications (other drugs should be given ≥1 hour before or ≥4 hours after) 6
• Should not be taken in dry form; must be mixed with water or other fluids 6

Special Considerations for Statin-Intolerant Patients

Initial Management Steps

• Before abandoning statins entirely, try switching to a different high-intensity statin, lowering the dose, or using nondaily dosing 1
• At least 3 different statins should be tested before declaring complete statin intolerance 7
• Pravastatin or fluvastatin are recommended for rechallenge due to lower muscle toxicity, though less effective for LDL-C lowering 7
• Some patients tolerate atorvastatin or rosuvastatin twice weekly 7

Combination Therapy Approach

• Adding nonstatin therapy to maximum tolerated statin doses (even if very low) is frequently associated with improved medication adherence and achievement of LDL-C goals 1
• For patients achieving <50% LDL-C reduction on maximally tolerated statin, add ezetimibe 2
• If LDL-C remains ≥70 mg/dL in very high-risk ASCVD patients despite statin plus ezetimibe, add a PCSK9 inhibitor 2

Risk-Based Treatment Targets

Secondary Prevention (Established ASCVD)

• Target LDL-C <55 mg/dL (<1.4 mmol/L) with ≥50% reduction from baseline 1
• High-intensity therapy is mandatory regardless of baseline LDL-C levels 1
• Add ezetimibe or PCSK9-directed therapy if goals not met on maximum tolerated statin 1

Primary Prevention (High-Risk Patients)

• Target LDL-C <100 mg/dL, or <70 mg/dL for very high-risk patients 2
• Aim for 30-40% reduction from baseline as minimum therapeutic goal 1, 2

Common Pitfalls and Caveats

• Cost and prior authorization may limit access to PCSK9 inhibitors and bempedoic acid, though patient assistance programs and discount copay cards are available 1
• Combination therapy with statins and fibrates increases risk of myositis and rhabdomyolysis; risk is lower with fenofibrate than gemfibrozil 1
• Ezetimibe may cause liver enzyme elevations; perform liver enzyme testing as clinically indicated and consider withdrawal if ALT or AST ≥3× ULN persist 3
• Bempedoic acid shows slight increases in tendon rupture (0.5%), benign prostatic hyperplasia (1.3%), and atrial fibrillation (1.7%) 1
• Monitor lipid levels 4-6 weeks after initiating or changing therapy, then annually for stable patients 2