What are the non-statin strategies for lowering Low-Density Lipoprotein (LDL) cholesterol?

Non-Statin LDL-Lowering Strategies

Ezetimibe should be the first-line non-statin agent for LDL-lowering, followed by PCSK9 inhibitors for patients requiring additional reduction, with bempedoic acid reserved for those intolerant to or inadequately controlled on these therapies. 1

Hierarchical Approach to Non-Statin Therapy

First-Line: Ezetimibe

• Ezetimibe 10 mg daily is the preferred initial non-statin agent due to demonstrated cardiovascular outcomes benefit, safety profile, tolerability, convenience, and availability as a generic medication 1
• Reduces LDL-C by approximately 18% as monotherapy and provides an additional 25% reduction when combined with statins 1
• Proven cardiovascular benefit in IMPROVE-IT trial: reduced composite endpoint of CV death, nonfatal MI, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke when added to moderate-intensity statin in acute coronary syndrome patients 1
• Also demonstrated benefit in SHARP trial for patients with chronic kidney disease 1
• Well-tolerated with common adverse effects including upper respiratory tract infection, diarrhea, and arthralgia 1, 2
• Administer either ≥2 hours before or ≥4 hours after bile acid sequestrants if used in combination 1, 2

Second-Line: PCSK9 Inhibitors

PCSK9 monoclonal antibodies (alirocumab, evolocumab) are the preferred second-line agents when additional LDL-lowering is needed beyond ezetimibe 1

Alirocumab and Evolocumab

• Reduce LDL-C by 40-65% when added to statin therapy 1
• Demonstrated cardiovascular outcomes benefit in FOURIER and ODYSSEY Outcomes trials 1
• Alirocumab dosing: 75 mg every 2 weeks or 300 mg every 4 weeks subcutaneously; may increase to 150 mg every 2 weeks if inadequate response 3
• For patients on 300 mg every 4 weeks, measure LDL-C just prior to next dose as levels can vary between doses 3
• Indicated for cardiovascular risk reduction in established ASCVD and as adjunct therapy for primary hyperlipidemia including heterozygous familial hypercholesterolemia 3

Inclisiran

• RNA interference therapy targeting PCSK9 with twice-yearly dosing after initial loading 1
• May be considered in place of PCSK9 mAbs for patients with poor adherence to injectable medications or those unable to self-inject 1
• Cardiovascular outcomes trials (ORION-4, VICTORION-2P) anticipated completion in 2026-2027 1
• Should not be combined with PCSK9 mAbs as there is no evidence for additional benefit 1

Third-Line: Bempedoic Acid

• Bempedoic acid 180 mg daily reduces LDL-C by approximately 24.5% as monotherapy and 15-17.8% when added to statin therapy 1
• Inhibits ATP-citrate lyase upstream of HMG-CoA reductase; activated only in liver cells, not muscle cells 1
• Particularly useful for statin-intolerant patients due to lack of muscle activation 1, 4, 5
• Available as monotherapy or fixed-dose combination with ezetimibe (provides 38% additional LDL-C reduction when added to statin) 1
• CLEAR Outcomes cardiovascular trial completed in 2022 with results now available 1
• Cautions: slight increases in tendon rupture (0.5%), gout (1.5%), benign prostatic hyperplasia (1.3%), atrial fibrillation (1.7%), and creatine kinase elevation (1.0%) 1
• Use with caution in patients with history of gout or tendon rupture 1

Alternative Options: Bile Acid Sequestrants

• Reduce LDL-C by 18-25% 1
• May be considered as optional alternative if ezetimibe intolerant and triglycerides <300 mg/dL 1
• Good evidence for ~20% CVD risk reduction in primary prevention with cholestyramine monotherapy 1
• No evidence for net cardiovascular benefit when added to statin therapy 1
• May have modest hypoglycemic effect beneficial in diabetic patients 1

Clinical Decision-Making Algorithm

For Patients with ASCVD at Very High Risk

1. Start with maximally tolerated statin therapy 1
2. If <50% LDL-C reduction or LDL-C ≥55 mg/dL: Add ezetimibe 1
3. If still inadequate: Add PCSK9 inhibitor (mAb preferred) 1
4. If further reduction needed: Consider adding bempedoic acid 1
5. For rapid risk reduction in very high-risk patients: May consider simultaneous addition of two agents (e.g., ezetimibe + PCSK9 inhibitor) 1

For Patients with ASCVD Not at Very High Risk

1. Optimize to high-intensity statin if not already taking 1
2. If <50% LDL-C reduction or LDL-C ≥70 mg/dL: Consider ezetimibe 1
3. If inadequate response: May consider bempedoic acid or PCSK9 inhibitors 1

For Statin-Intolerant Patients

1. First attempt: Try different statin, lower dose, or alternate-day dosing 1, 4, 5
2. If complete intolerance: Start ezetimibe monotherapy 4, 5
3. If additional lowering needed: Add bempedoic acid (preferred due to lack of muscle effects) 1, 4, 5
4. For severe cases: PCSK9 inhibitors as monotherapy or combination 4, 5

Important Caveats

Referral Considerations

• Refer to lipid specialist for patients with ASCVD and baseline LDL-C ≥190 mg/dL not achieving targets on maximally tolerated statin plus nonstatin therapy 1
• Consider referral for intolerance to ≥2-3 statin therapies 1
• Refer to registered dietitian/nutritionist for all patients with ASCVD or baseline LDL-C ≥190 mg/dL 1

Monitoring

• Assess LDL-C as early as 4 weeks after initiating therapy 2
• For alirocumab 300 mg every 4 weeks, measure LDL-C just before next scheduled dose 3
• Monitor liver transaminases when ezetimibe combined with statins 1, 2

Pregnancy and Lactation

• Avoid ezetimibe during pregnancy and lactation (no safety data in humans) 1
• Refer to individual product labeling for PCSK9 inhibitors and bempedoic acid 3

1, 3, 2, 4, 5