Non-Statin LDL-Lowering Strategies

Introduction to Non-Statin Therapies

The American College of Cardiology recommends ezetimibe as 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, 2

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, 2, 3
Ezetimibe reduces LDL-C by approximately 18% as monotherapy and provides an additional 25% reduction when combined with statins 1, 2, 4
The American College of Cardiology states that ezetimibe has proven cardiovascular benefit in the 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, 2, 3
The American College of Cardiology also notes that ezetimibe demonstrated benefit in the SHARP trial for patients with chronic kidney disease 3, 4

The American College of Cardiology recommends PCSK9 monoclonal antibodies (alirocumab, evolocumab) as the preferred second-line agents when additional LDL-lowering is needed beyond ezetimibe 1, 5
PCSK9 inhibitors reduce LDL-C by 40-65% when added to statin therapy 6
The American College of Cardiology states that PCSK9 inhibitors have demonstrated cardiovascular outcomes benefit in the FOURIER and ODYSSEY Outcomes trials 5

Bempedoic acid 180 mg daily reduces LDL-C by approximately 24.5% as monotherapy and 15-17.8% when added to statin therapy 7
The American College of Cardiology notes that bempedoic acid is particularly useful for statin-intolerant patients due to lack of muscle activation 7
Bempedoic acid is available as monotherapy or fixed-dose combination with ezetimibe (provides 38% additional LDL-C reduction when added to statin) 7

For patients with ASCVD at very high risk, the American College of Cardiology recommends starting with maximally tolerated statin therapy, then adding ezetimibe if <50% LDL-C reduction or LDL-C ≥55 mg/dL, and finally adding a PCSK9 inhibitor if still inadequate 5
For patients with ASCVD not at very high risk, the American College of Cardiology recommends optimizing to high-intensity statin if not already taking, then considering ezetimibe if <50% LDL-C reduction or LDL-C ≥70 mg/dL 5

The American College of Cardiology recommends referring patients with ASCVD and baseline LDL-C ≥190 mg/dL not achieving targets on maximally tolerated statin plus nonstatin therapy to a lipid specialist 1, 2, 10
The American College of Cardiology also recommends referring patients with intolerance to ≥2-3 statin therapies to a lipid specialist 1, 2, 10
The American College of Cardiology states that ezetimibe should be avoided during pregnancy and lactation (no safety data in humans) 1, 3